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5,175,488,425,883,827,000 | . Scientific Frontline: Virology
Showing posts with label Virology. Show all posts
Showing posts with label Virology. Show all posts
Wednesday, November 8, 2023
Temperature increase triggers viral infection
Illustration of phage virus injecting its DNA into a cell
Illustration Credit: Alex Evilevitch and Ting Liu
Researchers at Lund University, together with colleagues at the NIST Synchrotron Facility in the USA, have mapped on an atomic level what happens in a virus particle when the temperature is raised.
"When the temperature rises, the virus's genetic material changes its form and density, becoming more fluid-like, which leads to its rapid injection into the cell," says Alex Evilevitch who led the study.
Viruses lack their own metabolism and the ability to replicate independently; they are entirely dependent on a host cell to multiply. Instead, the virus hijacks the internal machinery of the infected cell to produce new virus particles, which are then released and spread to infect other cells.
In most cases, the virus's genetic material, DNA, is enclosed within a protective protein shell called a capsid. A research group at Lund University is working to understand the process by which the virus ejects its genetic material from the capsid and into cells and what causes the virus's DNA to be released.
It all began with a study published in 2014, where the Lund University researchers observed that there seems to be a sudden change in the virus's genetic material when exposed to the infection temperature, around 37 degrees.
Monday, November 6, 2023
Success of Wolbachia-infected mosquitoes in fighting dengue may be underestimated
Alex Perkins, associate professor of biological science
Photo Credit: Courtesy of University of Notre Dame
The fight against dengue fever has a new weapon: a mosquito infected with the bacteria Wolbachia, which prevents the spread of the virus. These mosquitoes have now been deployed in several trials demonstrating their potential in preventing disease transmission.
Now, researchers at the University of Notre Dame have conducted an analysis of the World Mosquito Program’s randomized control trial of Wolbachia-infected mosquitoes in Indonesia, looking at how excluding transmission dynamics impacted the original interpretation of the trial’s results.
“Randomized controlled trials are the gold standard for evaluating the efficacy of any medical or public health intervention. That is very difficult for vector interventions against dengue because incidence of the disease can be somewhat unpredictable and sporadic, requiring very large-scale trials,” said Alex Perkins, associate professor of biological sciences at Notre Dame and senior author on the study.
Wednesday, November 1, 2023
The Unraveling of a Protist Genome Could Unlock the Mystery of Marine Viruses
Light-microscopy image of clusters of Aurantiochytrium limacinum cells. The marine protist is prevalent in the world’s oceans.
Image Credits: Laura Halligan, Joshua Rest and Jackie Collier
Viruses are the most prevalent biological entities in the world’s oceans and play essential roles in its ecological and biogeochemical balance. Yet, they are the least understood elements of marine life. By unraveling the entire genome of a certain marine protist that may act as a host for many viruses, an international research team led by scientists from Stony Brook University sets the stage for future investigations of marine protist genomes, marine microbial dynamics and the evolutionary interplay between host organisms and their viruses — work that may open doors to a better understanding of the “invisible” world of marine viruses and offers a key to the ecology and health of oceans worldwide. The research is published early online in Current Biology.
Food webs of the oceans provide humanity with essential food sources as well as the wonderment of sea creatures from polar bears to penguins. This wellspring of life is supported mainly by microscopic organisms, including the wide presence of viruses. Learning more about the viruses through DNA research and other forms of investigation is essential to scientists’ understanding of the sea. Novel groups of viruses are still being discovered, such as the recently discovered “mirusvirues” featured in a Nature paper earlier this year.
Tuesday, October 31, 2023
Pinpointing HIV immune response
HIV, the AIDS virus (yellow), infecting a human cell
Image Credit: National Cancer Institute
New research combining computer modeling and experiments with macaques shows the body’s immune system helps control human immunodeficiency virus (HIV) infections largely by suppressing viral production in already infected cells while also killing viral infected cells, but only within a narrow time window at the start of a cell’s infection.
“To eliminate HIV, we have to understand how the immune system attempts to control the infection,” said Ruy M. Ribeiro, a theoretical biologist at Los Alamos National Laboratory who led the development of the model underpinning the research. Ribeiro is the corresponding author of the paper about the findings, published in Nature Communications.
The research team included Los Alamos Senior Fellow Alan S. Perelson and a former Los Alamos postdoctoral researcher now at the Fred Hutchinson Cancer Research Center. Their collaborators at the University of Pittsburg managed the experiments with macaques infected with simian immunodeficiency virus (SIV) to validate the model. SIV infections in monkeys behave the same way as HIV in humans.
Friday, October 27, 2023
Long COVID most prevalent in the most seriously ill
Image Credit: Scientific Frontline
A collaborative study involving researchers from Karolinska Institutet has charted the prevalence of severe physical symptom burden amongst Scandinavians for up to two years after a SARS-CoV-2 infection. Most affected were people who had a severe COVID-19 infection, while the researchers found no elevated prevalence of long COVID in those who had never been bedridden. The study is published in The Lancet Regional Health – Europe.
By mid-October 2023, over 771 million cases of COVID-19 had been reported to the World Health Organization (WHO). An estimated 10 to 20 per cent of the affected have persistent symptoms.
Close to 65,000 participants
In the present study, researchers examined the prevalence of persistent physical symptoms in people with different degrees of COVID-19 severity and compared them with people who had not had a confirmed COVID-19 diagnosis. The study comprised 64,880 adults from Sweden, Denmark, Norway and Iceland with self-reported physical symptoms between April 2020 and August 2022.
Over 22,000 of the participants were diagnosed with COVID-19 during the period, almost 10 per cent of whom were bedridden for at least seven days. The prevalence of chronic symptoms such as shortness of breath, chest pain, dizziness, headaches, and low energy/ fatigue, was 37 per cent higher in those who had had a COVID-19 diagnosis than in those who had not.
Wednesday, October 25, 2023
Zika Infection in Pregnant Macaques Slows Fetal Growth
Female rhesus macaque monkeys and infants at the California National Primate Research Center at UC Davis.
Photo Credit: Courtesy of University of California, Davis
Zika virus infection in pregnant rhesus macaques slows fetal growth and affects how infants and mothers interact in the first month of life, according to a new study from researchers at the California National Primate Research Center at the University of California, Davis. The work, published Oct. 25 in Science Translational Medicine, has implications for both humans exposed to Zika virus and for other viruses that can cross the placenta, including SARS-CoV2, responsible for the COVID-19 pandemic.
“Initially I thought this was a story about Zika, but as I looked at the results, I think this is also a story about how fetal infections in general affect developmental trajectories,” said Eliza Bliss-Moreau, professor of psychology at UC Davis and senior author on the paper.
In most people, Zika virus infection causes mild or no symptoms and leaves long-lasting immunity. But during pregnancy, the virus can cross the placenta and cause damage to the nervous system of the fetus. In extreme cases, it can cause microcephaly in humans.
Scientists uncover cause of mysterious deaths of elephants in Zimbabwe
Photo Credit: Charl Durand
During this unique study, scientists from the Victoria Falls Wildlife Trust, the Animal and Plant Health Agency UK, the University of Surrey and laboratories in South Africa investigated the mysterious deaths of 35 elephants mostly between August and September 2020, in a 40 x 25 km radius of North-Western Zimbabwe. This incident followed the death of approximately 350 elephants in neighboring northern Botswana from May to June 2020, which triggered much international concern.
African savanna elephants are an endangered species with only 350,000 remaining in the wild and ongoing losses estimated at eight percent annually. This finding is very worrying since elephants are on the International Union for Conservation of Nature red list already. Investigating the deaths of these elephants is crucial to sustaining the future of this majestic species.
Post-COVID condition is not linked to ongoing infection or active brain damage
Post COVID-19 condition does not appear to be linked to direct viral invasion of the brain or active brain damage. This has been shown by a study at the University of Gothenburg. Searching for abnormal biomarkers among the participants yielded no hits in either blood or cerebrospinal fluid samples.
The condition that can follow the acute phase of COVID-19 infection, termed “Post-COVID condition,” or “long-covid” can persist for several months subsequent to the initial infection. The condition includes various combinations of fatigue, apathy, and difficulties with memory and concentration.
The current study, published in The Journal of Infectious Diseases, included 25 people with confirmed post-COVID condition, six people without residual symptoms after COVID-19, and 17 control subjects who were completely free of COVID-19.
The strength of the study lies not in the number of participants, which is fairly limited, but in the fact that they all – including the control subjects – underwent not only blood tests but also the considerably more invasive procedure of lumbar punctures to collect cerebrospinal fluid.
At the time when the samples were taken, at least three months had passed since the first symptoms of COVID-19 in those who had had the disease. The samples were taken between February and November 2021, and were analyzed for a total of 37 different biomarkers.
Tuesday, October 24, 2023
Preventing Airborne Infection without Impeding Communication with Ions and Electric Field
Figure 1.
Novel device for preventing airborne infection The design (a) and schematic (b) of the mechanism of the device for capturing infectious droplets and aerosols without hindering communication. The negatively charged ions attach to the droplets and the electric field guides them to the collecting electrode.
Illustration Credit: Courtesy of Tokyo Institute of Technology
A novel device developed by Tokyo Tech researchers in a new study utilizes ions and an electric field to effectively capture infectious droplets and aerosols, while letting light and sound pass through to allow communication. The innovation is significant in the wake of the COVID-19 pandemic, since it shows promise in preventing airborne infection while facilitating communication.
Airborne infections, such as H1N1 influenza, SARS, and COVID-19, are spread by aerosols and airborne droplets. While droplet/aerosol transmission can be prevented using acrylic partitions or, as with the COVID-19 pandemic, by imposing lockdowns in severe cases, these countermeasures can significantly impede communication. This, in turn, can lead to unintended consequences.
For instance, lockdown measures during the COVID-19 pandemic led to severe economic losses as well as a rise in cases of mental illness like depression and suicide around the world. Therefore, as we prepare for a potential future pandemic, it is necessary to develop more sustainable countermeasures that do not disrupt economic activities and daily face-to-face interactions.
To this end, a research team including Kaito Kanda, a graduate student at Tokyo Institute of Technology (Tokyo Tech) at the time of research, Assistant Professor Tetsuya Yamada, from the Institute of Innovative Research at Tokyo Tech, and Professor Takeo Fujiwara from Tokyo Medical and Dental University (TMDU) and Chiba University researchers, has now developed a device that successfully captures droplets and aerosols while allowing the transmission of light and sound for effective communication.
Tuesday, October 17, 2023
Boosting weak immune system: scientists find an unusual weapon against virus
An overview of how the method proposed by the Sieweke group boosts weak immune system. (A) M-CSF cytokine works in the bone marrow to promote generation of monocytes and macrophages, without disturbing the formation of other immune cells; (B) Monocytes and macrophages activate natural killer cells to enable them to target virus-infected cells and kill them through cell–cell contact and the release of toxic agents.
Illustration Credit: © EMBO
(CC BY 4.0 DEED)
Infections with cytomegalovirus (CMV) are extremely common and often pose no major threat to the vast majority of people. They can, however, be deadly for people whose immune system is weakened, e.g., after bone marrow transplantation. Current treatments against CMV infections are very limited and can have severe side effects. Researchers led by Prof. Michael Sieweke at the Center for Regenerative Therapies Dresden (CRTD) at TUD Dresden University of Technology and the Center of Immunology of Marseille Luminy (CIML) propose a new way to protect against CMV. Instead of targeting the virus, their approach boosts the weak immune system and lets it fight the virus on its own. The results were published in the journal EMBO Molecular Medicine.
Some viruses can be dormant throughout a person’s life and cause no harm but become dangerous when the immune system is weakened. One such virus is human cytomegalovirus (CMV). Harmless to the general public but life-threatening to patients with a suppressed immune system.
Friday, October 13, 2023
Targeting a coronavirus ion channel could yield new Covid-19 drugs
MIT chemists found that the SARS-CoV-2 E protein, which acts as an ion channel, has a broad opening at the bottom when in the closed state and a narrower opening in the open state.
Image Credits: Courtesy of the researchers, MIT News, and iStock
(CC BY-NC-ND 3.0 DEED)
The genome of the SARS-CoV-2 virus encodes 29 proteins, one of which is an ion channel called E. This channel, which transports protons and calcium ions, induces infected cells to launch an inflammatory response that damages tissues and contributes to the symptoms of Covid-19.
MIT chemists have now discovered the structure of the “open” state of this channel, which allows ions to flow through. This structure, combined with the “closed” state structure that was reported by the same lab in 2020, could help scientists figure out what triggers the channel to open and close. These structures could also guide researchers in developing antiviral drugs that block the channel and help prevent inflammation.
“The E channel is an antiviral drug target. If you can stop the channel from sending calcium into the cytoplasm, then you have a way to reduce the cytotoxic effects of the virus,” says Mei Hong, an MIT professor of chemistry and the senior author of the study.
MIT postdoc Joao Medeiros-Silva is the lead author of the study, which appears today in Science Advances. MIT postdocs Aurelio Dregni and Pu Duan and graduate student Noah Somberg are also authors of the paper.
Wednesday, October 11, 2023
Antigen testing can reduce, but not eliminate, the risk of COVID-19 clusters according to mathematical model
Illustration Credit: Kojima Kyoko
A research group has created a new model to calculate the probability of the occurrence of localized clusters caused by novel coronavirus infections. Led by Shingo Iwami at Nagoya University with collaborators in the United Kingdom and South Korea model, they revealed that screening of infected persons by antigen testing is effective in significantly reducing the probability of cluster occurrence. However, their findings also suggest that it is not sufficient to prevent clusters caused by highly infectious mutant strains, such as Omicron.
With the availability of COVID-19 vaccines and population immunity, countries around the world are seeking to resume social activities while also trying to prevent the spread of infection. However, outbreaks of new strains of the coronavirus, associated with increased infectiousness and evasion of existing immunity, continue to be a threat. In several countries, new infections are increasing as the northern hemisphere enters the autumn and winter months.
Tuesday, October 10, 2023
Red Algae Could Be Used to Create a Drug for Coronavirus
Chemical research on Laurencia red algae began in 1965.
Photo Credit: 🇸🇮 Janko Ferlič
Laurencia red algae can be used as a basis for new drugs against the SARS-CoV-2 virus, biochemists have found. A team of scientists from the Ural Federal University, the Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences, together with colleagues from Australia and Germany, carried out molecular docking of 300 bioactive components (ligands) of red algae and found seven compounds with the required activity. The scientists published a description of the experiments and results in the journal Microbiology Research
"Laurencia belongs to the family Rhodomelaceae, which is considered one of the largest families of marine red algae, with an estimated 125 genera and 700 species worldwide. Laurencia has recently been the subject of active research. Since 2015, a total of 1,047 secondary metabolites with various useful properties have been isolated from Laurencia species alone," explains Grigory Zyryanov, Chief Researcher of the UrFU Laboratory of Advanced Materials, Green Methods and Biotechnology.
Saturday, October 7, 2023
SARS-CoV-2 Caused More, Deadlier Cases of Sepsis Than Thought
Life-threatening systemic inflammation known as sepsis can follow infection with SARS-CoV-2 (shown in green in this colorized electron micrograph), the virus that causes COVID-19.
Image Credit: National Institute of Allergy and Infectious Diseases
New research suggests that the virus responsible for COVID-19 was a more common and deadly cause of sepsis early in the pandemic than previously assumed — accounting for about one in six cases of sepsis from March 2020 to November 2022.
The results, published online in JAMA Network Open, suggest that clinicians should rethink how they treat sepsis while also providing a framework for future surveillance of viral sepsis.
Sepsis is a serious, sometimes fatal overreaction of the immune system to an infection. Doctors and researchers don’t know as much about sepsis that occurs in response to viral infection as they do about sepsis that arises from bacterial infection.
“Most people, including medical professionals, equate sepsis with bacterial infections,” said first author Claire Shappell, HMS instructor in medicine at Brigham and Women’s Hospital. “This is reflected in treatment guidelines and quality measures that require immediate antibiotics for patients with suspected sepsis.”
Friday, October 6, 2023
Vulnerability to different COVID-19 mutations depends on previous infections and vaccination, study suggests
Image Credit: Alexandra Koch
A new study has found that people differ in how vulnerable they are to different mutations in emerging variants of SARS-CoV-2.
This is because the variant of SARS-CoV-2 a person was first exposed to determines how well their immune system responds to different parts of the virus, and how protected they are against other variants.
It also means that the same COVID-19 vaccine might work differently for different people, depending on which variants of SARS-CoV-2 they have previously been exposed to and where their immune response has focused.
The discovery underlies the importance of continuing surveillance programs to detect the emergence of new variants, and to understand differences in immunity to SARS-CoV-2 across the population.
It will also be important for future vaccination strategies, which must consider both the virus variant a vaccine contains and how immune responses of the population may differ in their response to it.
Monday, October 2, 2023
Heavily mutated SARS-CoV-2 variant BA.2.86 not as resistant to antibodies as first feared
Image Credit: Fusion Medical Animation
Researchers at Karolinska Institutet who studied SARS-CoV-2 variant BA.2.86, found that the new variant was not significantly more resistant to antibodies than several other variants that are circulating. The study also showed that antibody levels to BA.2.86 were significantly higher after a wave of XBB infections compared to before, suggesting that the vaccines based on XBB should provide some cross-protection to BA.2.86.
"We engineered a spike gene that matches that of the BA.2.86 variant and tested the blood of Stockholm blood donors (specifically those donations made very recently) to see how effective their antibodies are against this new variant. We found that although BA.2.86 was quite resistant to neutralizing antibodies, it wasn't significantly more resistant than a number of other variants that are also circulating", says Daniel Sheward, lead author of the study and Postdoctoral researcher in Benjamin Murrell's team at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.
Wednesday, September 27, 2023
Tiny CRISPR tool could help shred viruses
Model of a minimal CRISPR-Cas13bt3 molecule generated with a cryo-electron microscope. The RNA to be recognized and cleaved is colored in light blue, while the scissor is formed by the magenta and cyan colored domains. The two loops for controlling the CRISPR-Cas13bt3 are shown in green and red.
Illustration Credit: Courtesy of the Yang Gao lab/Rice University
Small and precise: These are the ideal characteristics for CRISPR systems, the Nobel-prize winning technology used to edit nucleic acids like RNA and DNA.
Rice University scientists have described in detail the three-dimensional structure of one of the smallest known CRISPR-Cas13 systems used to shred or modify RNA and employed their findings to further engineer the tool to improve its precision. According to a study published in Nature Communications, the molecule works differently than other proteins in the same family.
“There are different types of CRISPR systems, and the one our research was focused on for this study is called CRISPR-Cas13bt3,” said Yang Gao, an assistant professor of biosciences and Cancer Prevention and Research Institute of Texas Scholar who helped lead the study. “The unique thing about it is that it is very small. Usually, these types of molecules contain roughly 1200 amino acids, while this one only has about 700, so that’s already an advantage.”
Monday, June 12, 2023
Gentle cleansers kill viruses as effectively as harsh soaps
Photo Credit: Maria Lin Kim
Gentle cleansers are just as effective in killing viruses – including coronavirus – as harsh soaps, according to a new study from scientists at the University of Sheffield
Healthcare professionals often substitute alcohol-based hand sanitizers and harsh soaps for skin-friendly cleansers in order to treat or prevent irritant contact dermatitis, which develops when chemical or physical agents damage the skin surface faster than the skin can repair
Incidence and severity of irritant contact dermatitis increased from 20 per cent to 80 per cent amongst healthcare professionals during the Covid-19 pandemic
Researchers also found non-enveloped viruses such as norovirus were resistant to all hand wash products tested, and were only killed with bleach disinfectants, which aren’t a feasible option for washing hands
Gentle cleansers are just as effective in killing viruses – including coronavirus – as harsh soaps, a new study by University of Sheffield experts has found.
Friday, June 9, 2023
Bat-Borne Sarbecoviruses Spilled Over in Southeast Asia Pre-Pandemic
Elephant loggers bring in a timber harvest in Myanmar.
Photo Credit: Tierra Smiley Evans/UC Davis
A virus previously found only in bats was detected in the antibodies of people screened for exposure to sarbecoviruses between 2017 and 2020 in rural Myanmar in Southeast Asia, according to a study from the University of California, Davis and collaborators in Myanmar and Singapore. The work is published in the International Journal of Infectious Diseases.
Sarbecoviruses are a group of coronaviruses. This study found exposure to diverse sarbecoviruses, including some known to be closely related to SARS-CoV-2, such as RaTG13.
The study found that people were significantly more likely to have been exposed to sarbecoviruses if their livelihood involved working directly with or close to bats, such as logging, hunting or harvesting bat guano.
“This study provides new evidence that bat-borne coronaviruses can and do spill over to people, underscoring the importance of surveillance in high-risk rural areas, where humans and wildlife closely interact,” said lead author Tierra Smiley Evans, an epidemiologist and research faculty with the One Health Institute in the UC Davis School of Veterinary Medicine.
Thursday, June 8, 2023
Long Covid can impact fatigue and quality of life worse than some cancers
Photo Credit: engin akyurt
Fatigue is the symptom that most significantly impacts the daily lives of long Covid patients, and can affect quality of life more than some cancers, finds a new study led by researchers at UCL and the University of Exeter.
The research, published in BMJ Open and funded by the National Institute for Health and Care Research (NIHR), examines the impact of long Covid on the lives of over 3,750 patients who were referred to a long Covid clinic and used a digital app as part of their NHS treatment for the condition.
Patients were asked to complete questionnaires on the app about how long Covid was affecting them – considering the impact of long Covid on their day-to-day activities, levels of fatigue, depression, anxiety, breathlessness, brain fog, and their quality of life.
The researchers found that many long Covid patients were seriously ill and on average had fatigue scores worse or similar to people with cancer-related anemia or severe kidney disease. Their health-related quality of life scores were also lower than those of people with advanced metastatic cancers, like stage IV lung cancer.
Overall, the team found that the impact of long Covid on the daily activities of patients was worse than that of stroke patients and was comparable to that of patients with Parkinson’s Disease.
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-6,037,648,960,480,978,000 | This site uses cookies. By continuing to browse the site you are agreeing to our use of cookies.
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Maastricht to host 10th International Conference on Carbonic Anhydrase
From April 20 to April 22 2015, researchers of Maastro Clinic and the University of Maastricht (GROW-School for Oncology & Developmental Biology), in collaboration with Prof. dr. Claudiu T. Supuran of the University of Florence, will organize the International Conference on Carbonic Anhydrase (CA) at Grand Hotel de L'Empereur in Maastricht.
The main objective of the triennial conference is to inspire researchers, biologists and pharmacists through interdisciplinary exchange of scientific knowledge, ground-breaking research, ideas and opinions. The program includes lectures, poster- and discussion sessions. During the conference, there will also be the opportunity to meet and speak with colleagues informally. 
International conferences, such as the International Conference on Carbonic Anhydrase, are a major economic driver for the city of Maastricht. Regardless of income, this kind of events are of great importance for the reputation of the city and the employment in the region. The organization expects 150 participants.
When asked why the organization has chosen for Maastricht Professor Lambin of MAASTRO Clinic commented: "Maastricht was chosen because of its location, historic centre, and hospitable character. The atmosphere and size makes it the ideal city to let the event, where international scientists meet, take place. Grand Hotel de L'Empereur is thereby a charming, inspiring hotel with a high level of service, which also has a perfect location; opposite the Central Station, right in Wyck district which is also called 'the door of Maastricht".
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-7,189,169,071,116,841,000 | Structural and functional insights into the lipopolysaccharide ABC transporter LptB2FG
Dong, Haohao, Zhang, Zhengyu, Tang, Xiaodi, Paterson, Neil G and Dong, Changjiang (2017) Structural and functional insights into the lipopolysaccharide ABC transporter LptB2FG. Nature Communications, 8. ISSN 2041-1723
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Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 21 Oct 2017 05:06
Last Modified: 19 Aug 2020 23:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/65202
DOI: 10.1038/s41467-017-00273-5
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-7,006,622,255,424,466,000 | To install this package, start R and enter:
source("http://bioconductor.org/biocLite.R")
biocLite("Vega")
In most cases, you don't need to download the package archive at all.
Vega
An R package for copy number data segmentation
Bioconductor version: 2.14
Vega (Variational Estimator for Genomic Aberrations) is an algorithm that adapts a very popular variational model (Mumford and Shah) used in image segmentation so that chromosomal aberrant regions can be efficiently detected.
Author: Sandro Morganella
Maintainer: Sandro Morganella <sandro at ebi.ac.uk>
Citation (from within R, enter citation("Vega")):
Installation
To install this package, start R and enter:
source("http://bioconductor.org/biocLite.R")
biocLite("Vega")
Documentation
To view documentation for the version of this package installed in your system, start R and enter:
browseVignettes("Vega")
PDF R Script Vega
PDF Reference Manual
Details
biocViews CopyNumberVariation, Software, aCGH
Version 1.12.0
In Bioconductor since BioC 2.8 (R-2.13)
License GPL-2
Depends R (>= 2.10)
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Follow Installation instructions to use this package in your R session.
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-5,274,975,704,406,186,000 | Developmental Transcriptional Diversity In Inhibitory Neurons
News Jan 31, 2017 | Original Story From Université de Genève
Developmental Transcriptional Diversity In Inhibitory Neurons
Dayer Lab, UNIGE.
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6,080,392,691,806,795,000 | radio-biology
radiobiology
[rey-dee-oh-bahy-ol-uh-jee]
noun
the branch of biology dealing with the effects of radiation on living matter.
Origin:
1915–20; radio- + biology
radiobiological [rey-dee-oh-bahy-uh-loj-i-kuhl] , radiobiologic, adjective
radiobiologist, noun
Dictionary.com Unabridged
Based on the Random House Dictionary, © Random House, Inc. 2014.
Cite This Source Link To radio-biology
Collins
World English Dictionary
radiobiology (ˌreɪdɪəʊbaɪˈɒlədʒɪ)
n
the branch of biology concerned with the effects of radiation on living organisms and the study of biological processes using radioactive substances as tracers
radiobiological
adj
radiobio'logically
adv
radiobi'ologist
n
Collins English Dictionary - Complete & Unabridged 10th Edition
2009 © William Collins Sons & Co. Ltd. 1979, 1986 © HarperCollins
Publishers 1998, 2000, 2003, 2005, 2006, 2007, 2009
Cite This Source
American Heritage
Medical Dictionary
radiobiology ra·di·o·bi·ol·o·gy (rā'dē-ō-bī-ŏl'ə-jē)
n.
The study of the effects of radiation on living organisms.
The American Heritage® Stedman's Medical Dictionary
Copyright © 2002, 2001, 1995 by Houghton Mifflin Company. Published by Houghton Mifflin Company.
Cite This Source
Copyright © 2014 Dictionary.com, LLC. All rights reserved.
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8,402,006,342,440,163,000 | Cell Organelles: Mitochondria, Plastids and Endoplasmic Reticulum - Biology Grade XI
Science Notes
Cell Organelles: Mitochondria, Plastids and Endoplasmic Reticulum
Cell Organelles:
They are living sub cellular structures which are embedded within cytoplasm.
a) Mitochondria (Mitochondrion):
Its shape is variable and the size range from 2-6 micrometer. It is double membrane structure. Its outer membrane is smooth and regular. Its inner membrane gives finger like projections towards inner side called cristae. The surface of the cristae contains number of stalked and globular proteins called oxysomes. The cavity bounded by membrane is filled with a liquid mass called matrix. The matrix contains DNA RNA, inorganic and organic molecules. The mitochondria have its own DNA so it expresses its nature and characters own self. It is distributed in the cytoplasm.
Function of mitochondria:
It stores various types of enzymes used in aerobic respiration. It releases energy during oxidation of food material in aerobic respiration and stores energy in the form of ATPs so it is considered as the powerhouse of the cell. It can synthesize some proteins and it is carrier of genetic material.
b) Plastids
Plastids are photosynthetic pigments containing bodies found in the cytoplasm of plant cell. There are three types of plastids
• Chloroplasts: Plastids, which contain green colored photosynthetic pigments, are called chloroplast. It is double membraned. A kind of fluid is enclosed by membrane is called stroma. In the stroma number of sac like membranes found called thyllakoid or lamellae. The group of thyllakoid is called granum. The thyllakoid that connects one granum to another granum is called fret. The stroma also caontains DNA RNA and other organic and inorganic substances.
• Function of chloroplast: The main function of chloroplast is photosynthesis. The green colored pigments, the chlorophylls traps solar energy and the energy is then converted into chemical energy C6H12O6 with the combination of CO2 and H2O. It is also carrier of genetic materials, as it possesses its own DNA.
• Chromoplast: The plastid, which contains colored photosynthetic pigment other than green, is called chromoplast. Yellow coloured pigments are called Xanthophylls. Orange colored pigments is called Carotenes Red colored pigments are called Erythrocyanine and blue colored pigments are called Phycocyanine. The chromoplasts are also doubling membrane. In the stroma grana are absent and the thyllakoids are found degenerating. They are present in colored parts of the plant body. Their main function is to make colorful the body parts like colorful parts of the flower attracts insects.
• Leucoplast: The plastids which contain colorless pigments are called leucoplast. It is doubling membrane. The grana are absent. Developing thyllakoids are present in the stroma. In presence of light the leucoplast changes into chloroplast. The main function of the leucoplast is to store food materials. It is present in the stem and root. The leucoplast which store starch is called amyloplast, which stores oil, is called elaioplast and which stores protein called aleuroplast.
c) Endoplasmic Reticulum:
It is the network of tube-like structures and sac like structures. It arises from nuclear membrane and extends up to cell membrane. The endoplasmic reticulum is formed by three structures.
• Cisternae: They are long elongated flattened unbranched sac like structures lie parallel to each other.
• Vesicles: They are minute spherical or oval sac like structures
• Tubules: They are branched tube like structures they form net work with cisternae and vesicles.
Function of Endoplasmic Reticulum:
It provides mechanical support to the cell. Therefore, it is also known as cytoskeleton. It synthesizes proteins and hormones. It helps to transport ions, molecules and impulse or metabolites. It forms nuclear membrane. It also forms new cell membrane and components.
There are two types of Endoplasmic Reticulum:
Rough ER Smooth ER
It bears ribosomes on its surface
It is found near nuclear membrane It is formed by nuclear membrane In it mainly cisternae are found
It bears no ribosomes
It is found near cell membrane It is formed by rough ER
In it mainly tubules are found
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4,334,634,322,744,594,000 | Actions
Karen Simpson
From Santa Fe Institute Events Wiki
Revision as of 23:41, 1 July 2009 by Kesimpson (talk | contribs)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
I am a graduate student in the Environmental Sciences PhD Program at Wright State University. I am originally from Rochester, NY and have a BS in Biology and Environmental Studies from Niagara University (in Niagara Falls, NY). My prior research has involved aquatic ecology of invasive zooplankton, molecular ecology of invasive and hybrid plants and fish, and the effects of environmental stressors to biological organisms in rivers and streams. I now work in the Nonlinear Dynamics and Complex Systems Laboratory at WSU. My current research looks at and compares underlying dynamics within aquatic ecosystems by analyzing dissolved oxygen (an important water quality parameter) fluctuations over time in lakes, rivers, streams and estuaries. The programming environment I use most is MATLAB for analyzing and displaying environmental data.
Vacation to Cayman Islands in December 2008
I am very interested in improving water quality since clean water is such a valuable resource, and the amount of drinkable freshwater in the world is slowly diminishing.
My hope in attending the CSSS at SFI is to meet other individuals who are interested in similar research, but also to learn about how complex systems (of all kinds) are studied.
When I'm not working on solving the world's drinking water crisis, you can find me playing in the water, walking my 2 beautiful hound-dogs (Jack and Otis), training for triathlons, or playing tennis or volleyball.
Please feel free to e-mail me (or facebook me) at [email protected]. I very much look forward to meeting all of you at CSSS 2009!!
One of my dogs, Jack (an Austrailian Shepherd-Beagle Mix) and I
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
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Taq FS DNA聚合酶
产品编号 产品名称 规格 价格(元) 说明书
A1901A Taq FS DNA Polymerase 250U 200
A1901B 2,500U 1,500
Taq FS DNA 聚合酶是Taq DNA聚合酶中的一种，其经过基因工程改造的Taq (R660D/F667Y) DNA聚合酶基因。该DNA聚合酶具有较强的ddNTP的渗入能力，因此其适用于终止法DNA测序或SNP分析。
组分
组分名称 数量
Taq FS DNA Polymerase (5 U/μl) 50 μl/200 μl
10×HG PCR Buffer 1 1 mlx2/20 ml
单位定义
一个活力单位即在在74°C条件下，30分钟内催化10 nmol dNTP的掺入反应成为酸不溶性物质所需的酶量。
储存
-20℃可保存3年。
使用方法
按下表配制反应液:
Taq FS DNA Polymerase (5 U/μl) 0.25 μl
10×HG PCR Buffer 1 10 μl
dNTP Mixture (2.5 mM each) 2 μl
*1模板DNA *X μl
引物F（10 μM） 2 μl
引物R（10 μM） 2 μl
ddH2O Up to 50 μl
*1模板DNA用量参数(50 μl反应体系):Genomic DNA 100-1000 ng ; Plasmid DNA 5-30 ng ; cDNA from RT reaction 1-5 μl
PCR扩增循环参数
循环数 温度 时间
1st Cycle 95°C 2min
25-35 Cycles 95°C 20s
Tm 20s
72°C 1kb/1min
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-2,194,581,931,806,476,000 | VIDEO | by GREEN.tv
The Extinction Crisis - The Kind of World We Want
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Up to 70percent of the world's known species risk extinction if the global temperatures rise by more than 3.5degC. One third ...
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5,535,223,373,837,687,000 | Bronze-level articleTexans for Better Science Education
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Texans for Better Science Education is a misleadingly-named creationist organization that wants students in Texas to learn "both sides" of the debate between creationism and the theory of evolution[1] Their website[2] lists apparent "weaknesses" of the theory of evolution (many of which sound suspiciously like creationist arguments), but does not list any of evolutionary theory's strengths (or creationism's multiple weaknesses).
Their work is challenged by Texan Citizens for Science[3].
Contents
[edit] Obligatory debunk
Given weakness of evolutionRationalWiki's responses
[edit] Origin of Life Weaknesses
(To quote Wikipedia, "The origin of life is a necessary precursor for biological evolution, but understanding that evolution occurred once organisms appeared and investigating how this happens, does not depend on understanding exactly how life began."[4]But, since you bring it up...)
• The extreme improbability of obtaining any specific amino acid sequence needed for the proteins of life systems.
• The extreme improbability of a designer/creator putting together specific atoms and molecule with no apparent chemical or physical means to do so.
• The high probability of breakdown by hydrolysis of amino acid chains if they were to form in the first place.
• Amides are actually quite difficult to hydrolyze; otherwise, the proteins of a body would "fall apart." The body requires specific enzymes to do so. Probability and facility are confused here. Also, is this not a problem for the designer as well?
• No known way to achieve 100% left-handed amino acids in proteins or the 100% right-handed sugars in RNA and DNA - all of which are universal to life systems.
• All natural processes are known to produce a 50-50% mixture of left-handed and right-handed molecules.
• There is no way to account for left-handed amino acids in an "origin of life" theory, but once life evolved, there is no problem with maintaining chirality, especially if amino acids of one organism, do not interact with amino acids of another, discrete organism. Again, there is still no mechanism for a designer-creator to design chiral amino acids and no explanation as to why such a designer-creator would want one chirality favored over another.
• Photodissociation of water vapor has been a source of oxygen since the Earth formed, and there is substantial geologic evidence that a significant amount of oxygen existed in the atmosphere prior to the advent of photosynthesis. Oxygen breaks down amino acids and sugars that are postulated to have formed!
• There's a difference between oxide minerals (the geologic evidence) and free, molecular O2 in the atmosphere, and mineral evidence shows that metals that normally form insoluble precipitates in the presence of oxygen were mobile and able to accumulate in large bodies of water (Banded Iron Formations). Furthermore, this is a problem for the designer-creator that is not a problem for evolution, as organisms naturally selected mechanisms to deal with oxidative processes. While the details are not known as to how these processes developed, neither is it for the creator-designer.
• There is no known natural source of the information that is present in all life systems. Random processes are never known to produce information.
• That's because nature doesn't deal with information. Random, natural processes cannot create it because it only exists in the perception of the human mind. What nature does produce are random genetic shifts, and those that create useful amino acid sequences get to be preserved and passed on to future generations.
• Also, like most cdesign proponentsists making arguments from information theory, the author doesn't specify whether the mystical "information" that's so problematic is Shannon information or Kolmogorov information, which are not interchangeable. It actually doesn't matter which, though, as an information source in information theory is simply a random process that outputs symbols from a fixed alphabet at a given rate with all symbols being equally probable as output.[5] So yes, random processes are known to produce information.
[edit] Fossil Record Weaknesses
• The Cambrian explosion quickly produced all of the basically different body structures, and some of these have since become extinct. This is very different from the evolutionary tree of life, which suggests a slow and gradual increase in body structures.
• As pointed out on this blog, this is a patently false statement. Evolutionary theory has no problem with rapid, episodic change.
• Even if it did, the Cambrian explosion appears to have lasted between 70 and 80 million years. This is fast in geologic time but it's still a mind-bogglingly long time by the standards of any life form.
• Many life forms persist through large expanses of geologic time with essentially no change. Evolution theory suggests that mutations occur randomly over time and are selected to produce continuing change as the environment continually changes.
• Another false statement. If there is no environmental pressures for evolution, a species can remain constant.[1]
• Most major proposed transitional forms are problematic and controversial. Rarely does the whole organism fit into the proposed developmental path. For example, birds are often said to have transitioned from reptile- hipped dinosaurs like Velociraptor. But these have a different kind of hip structure than birds. Birds have the same kind of hip structure as the dinosaurs like stegosaurus and the horned dinosaurs.
• Transitional fossils are only controversial if you are a creationist, and many are known. Furthermore DNA/genomic evidence for evolution is quite strong.
[edit] Presently Observed Nature Weaknesses
Why creationists and conservatives can't figure out adjectives (nature vs. natural, Democrat vs. Democratic, etc.) is beyond me...
• Selective breeding has produced only very limited change with no new structures occurring over thousands of years and multitudes of generations of selection. This clearly demonstrates that there are natural limits to biological change. Examples: dogs, cattle, pigeons ...
• As pointed out by this blog, the teosintes are an example of new structures occurring over a relatively short time span.
• Induced mutations followed by selection in laboratory experiments have not produced any beneficial structural changes.
• Talk to Richard Lenski. Before then, please define the word "beneficial".
• Most all mutations are detrimental, a few are neutral, and extremely few if any are clearly beneficial.
• There are clearly beneficial mutations. Also, the effect of a mutation is not necessary an "on-off switch."
• Small changes resulting from natural selection are observed, but are not observed to accumulate to produce structural changes.
• This is likely an ID argument--an irreducible complexity argument--that has been debunked before.
• It is extremely difficult for scientists to propose in detail how the structural or biochemical systems of life could change from a more simple form that was functional.
• It is impossible for creationists to propose a mechanism for their creator. Also, just because a part of science is in its infancy does not mean it is incorrect--the argument from ignorance is poor here given the tremendous amount of evidence for evolution.
[edit] General practice to avoid misunderstanding
• When fossils are illustrated, the illustration should indicate which parts of the skeleton are actually present in the fossil material and which parts are inferred. This may be done for example by color, shading, or outline weight.
• There is no weakness with evolution here. Many texts already do this. Maybe they should included a dotted-line creator-designer as well.
• Fossil abundance versus geologic period diagrams should be shown for all life forms discussed in the text or presented in tree of life or cladogram interpretations. One large diagram might be presented at an early point in the discussion of fossils. Where little intact fossil material is known, fine lines or dotted lines should be used to indicate inferred or hypothesized connections or relationships.
• Again, many texts deal quite well with this. If many examples are given, one uber-diagram will be hard to digest. This is a stylistic difference that does not deal with a weakness to evolution.
• If evolution is compared to the change over time of the product of any human endeavor, then the role of intelligence and purpose in that human endeavor must also be clearly recognized and discussed.
• Few books use this sort of comparison as real examples of evolution are much more concrete. In fact, we'd advocate that books rid of this sort of analogy because it is incorrect and misinterpreted by IDers and creationists.
[edit] See also
[edit] Footnotes
1. http://www.nytimes.com/2008/06/04/us/04evolution.html
2. http://www.strengthsandweaknesses.org/
3. http://www.texscience.org/
4. WP cites talk origins http://www.talkorigins.org/indexcc/CB/CB090.html
5. http://www.talkorigins.org/faqs/information/shannon.html#Sources
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-8,981,785,218,200,618,000 | Inactivation of the GacA response regulator in Pseudomonas fluorescens Pf-5 has far-reaching transcriptomic consequences
Karl A. Hassan, Aaron Johnson, Brenda T. Shaffer, Qinghu Ren, Teresa A. Kidarsa, Liam D.H. Elbourne, Sierra Hartney, Robert Duboy, Neal C. Goebel, T. Mark Zabriskie, Ian T. Paulsen, Joyce E. Loper
Research output: Contribution to journalArticlepeer-review
114 Scopus citations
Abstract
The GacS/GacA signal transduction system is a central regulator in Pseudomonas spp., including the biological control strain P. fluorescens Pf-5, in which GacS/GacA controls the production of secondary metabolites and exoenzymes that suppress plant pathogens. A whole genome oligonucleotide microarray was developed for Pf-5 and used to assess the global transcriptomic consequences of a gacA mutation in P. fluorescens Pf-5. In cultures at the transition from exponential to stationary growth phase, GacA significantly influenced transcript levels of 635 genes, representing more than 10% of the 6147 annotated genes in the Pf-5 genome. Transcripts of genes involved in the production of hydrogen cyanide, the antibiotic pyoluteorin and the extracellular protease AprA were at a low level in the gacA mutant, whereas those functioning in siderophore production and other aspects of iron homeostasis were significantly higher in the gacA mutant than in wild-type Pf-5. Notable effects of gacA inactivation were also observed in the transcription of genes encoding components of a type VI secretion system and cytochrome c oxidase subunits. Two novel gene clusters expressed under the control of gacA were identified from transcriptome analysis, and we propose global-regulator-based genome mining as an approach to decipher the secondary metabolome of Pseudomonas spp.
Original languageEnglish (US)
Pages (from-to)899-915
Number of pages17
JournalEnvironmental Microbiology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2010
ASJC Scopus subject areas
• Microbiology
• Ecology, Evolution, Behavior and Systematics
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-1,941,706,882,567,891,500 | Feb 28 2011
A Creationist Challenge
One of my earlier posts on NeuroLogica was Ten Major Flaws in Evolution: A Refutation, published four years ago. This continues to be a popular post, including an updated version I published on Skepticblog, and still attracts the occasional creationist who shows up to snipe at the post, like this one:
i read this and found it funny. It supposedly gives a scientific refutation, but it is full of more bias than fox news, and a lot of emotion as well.
here’s a scientific case by an actual scientists, you know, one with a ph. D, and he uses statements by some of your favorite evolutionary scientists to insist evolution doesn’t exist.
i challenge you to write a refutation on this one.
http://www.icr.org/home/resources/resources_tracts_scientificcaseagainstevolution/
Challenge accepted.
The comment itself is fairly typical – it is nothing more than a few logical fallacies. The commenter starts with some ad hominems, asserting that my post is biased and emotional. They provide no evidence or argument to support this assertion. And of course they don’t even attempt to counter any of the arguments I laid out. They then follow up with an argument from authority – he can link to a PhD creationist – so there.
The article that the commenter links to is by Henry M. Morris, founder for the Institute for Creation Research (ICR) – a young-earth creationist organization. Morris was (he died in 2006 following a stroke) a PhD – in civil engineering. This point is irrelevant to his actual arguments. I bring it up only to put the commenter’s argument from authority into perspective. No disrespect to engineers – but they are not biologists. They have no expertise relevant to the question of evolution – no more than my MD. So let’s stick to the arguments themselves.
The article by Morris is an overview of so-called Creation Science, of which Morris was a major architect. The arguments he presents are all old creationist canards, long deconstructed by scientists. In fact I address many of them in my original refutation. Creationists generally are not very original – they recycle old arguments endlessly, regardless of how many times they have been destroyed.
Morris also makes heavy use of the “taking a quote out of context” strategy favored by creationists. His quotes are often from secondary sources and are incomplete. A more scholarly (i.e. intellectually honest) approach would be to cite actual evidence to support a point. If you are going to cite an authority, then make sure the quote is relevant, in context, and complete. And even better, cite a number of sources to show that the opinion is representative. Rather we get single, partial, and often outdated quotes without context.
Evolution is happening now
Morris separates his article into sections, the first entitled: Evolution is not happening now. Here he repeats the “kinds” argument I already dealt with (nature is not, it turns out, cleanly divided into “kinds”, which have no operational definition). He also repeats this canard:
Such variation is often called microevolution, and these minor horizontal (or downward) changes occur fairly often, but such changes are not true “vertical” evolution.
This is the microevolution/macroevolution false dichotomy. It is only “often called” this by creationists – not by actual evolutionary scientists. There is no theoretical or empirical division between macro and micro evolution. There is just evolution, which can result in the full spectrum of change from minor tweaks to major changes.
But Morris does commit another error here – again demonstrating that creationist arguments against evolution are almost entirely premised on their factual misinformation or their own conceptual misunderstanding of the science. Morris wonders why there are no “dats” – dog-cat transitional species. He misses the hierarchical nature of evolution. As evolution proceeds, and creatures develop a greater and greater evolutionary history behind them, they increasingly are committed to their body plan. This results in a nestled hierarchy of groups – which is reflected in taxonomy (the naming scheme of living things).
So once our distant ancestors developed the basic body plan of chordates, they were committed to that body plan. Subsequent evolution resulted in variations on that plan, each of which then developed further variations, etc. But evolution cannot go backward, undo evolutionary changes and then proceed down a different path. Once an evolutionary line has developed into a dog, evolution can produce variations on the dog, but it cannot go backwards and produce a cat.
Stephen J. Gould described this distinction as the difference between disparity and diversity. Disparity (the degree of morphological difference) actually decreases over evolutionary time, as lineages go extinct and the surviving lineages are committed to fewer and fewer basic body plans. Meanwhile, diversity (the number of variations on a body plan) within groups tends to increase over time.
In other words – the kind of evolutionary changes that were happening in the past, when species were relatively undifferentiated (compared to contemporary species) is indeed not happening today. Modern multi-cellular life has 600 million years of evolutionary history constraining their future evolution – which was not true of species at the base of the evolutionary tree. But modern species are indeed still evolving.
Here is a list of research documenting observed instances of speciation. The list is from 1995, and there are more recent examples to add to the list. Here are some more. And here is a good list with references of more recent cases.
Evolution happened in the past
Next Morris tries to convince the reader that there is no evidence for evolution in the past, focusing on the fossil record. He repeats the false claim (again, which I already dealt with) that there are no transitional fossils:
Even those who believe in rapid evolution recognize that a considerable number of generations would be required for one distinct “kind” to evolve into another more complex kind. There ought, therefore, to be a considerable number of true transitional structures preserved in the fossils — after all, there are billions of non-transitional structures there! But (with the exception of a few very doubtful creatures such as the controversial feathered dinosaurs and the alleged walking whales), they are not there.
This is so factually incorrect, and so often thoroughly refuted, that it is difficult to characterize it as anything other than a lie. I deal with this question at length here, pointing out that there are numerous transitional fossils for the evolution of terrestrial vertebrates, mammals, whales, birds, turtles, and yes – humans from ape ancestors. There are many more examples, these are just some of my favorites.
Much of what follows (as you can see it takes far more space to correct the lies and distortions of Morris than it did to create them) is classic denialism – misinterpreting the state of the science, and confusing lack of information about the details of evolution with lack of confidence in the fact of evolution. Here are some examples – he quotes Niles Eldridge:
“It is a simple ineluctable truth that virtually all members of a biota remain basically stable, with minor fluctuations, throughout their durations. . . .
So how do evolutionists arrive at their evolutionary trees from fossils of organisms which didn’t change during their durations?
Beware the “….” – that means that meaningful parts of the quote are being omitted. I happen to have the book (The Pattern of Evolution) from which Morris mined that particular quote. Here’s the rest of it:
(Remember, by “biota” we mean the commonly preserved plants and animals of a particular geological interval, which occupy regions often as large as Roger Tory Peterson’s “eastern” region of North American birds.) And when these systems change – when the older species disappear, and new ones take their place – the change happens relatively abruptly and in lockstep fashion.”
Eldridge was one of the authors (with Gould) of punctuated equilibrium theory. This states that, if you look at the fossil record, what we see are species emerging, persisting with little change for a while, and then disappearing from the fossil record. They theorize that most species most of the time are at equilibrium with their environment, and so do not change much. But these periods of equilibrium are punctuated by disequilibrium – periods of change when species will have to migrate, evolve, or go extinct.
This does not mean that speciation does not take place. And if you look at the fossil record we see a pattern of descendant species emerging from ancestor species over time – in a nice evolutionary pattern. Morris gives a complete misrepresentation of Eldridge’s point – once again we see intellectual dishonesty in his methods of an astounding degree. His other points are all similar.
The Genetic Evidence
Morris next tackles the genetic evidence, writing:
More often is the argument used that similar DNA structures in two different organisms proves common evolutionary ancestry.
Neither argument is valid. There is no reason whatever why the Creator could not or would not use the same type of genetic code based on DNA for all His created life forms. This is evidence for intelligent design and creation, not evolution.
The genetic evidence is an overwhelming home-run for evolution. As good as the fossil evidence is, the genetic evidence is much better. Here is an excellent summary of the multiple lines of molecular evidence for evolution. Basically, if we look at the sequence of DNA, the variations in trinucleotide codes for amino acids, and amino acids for proteins, and transposons within DNA we see a pattern that can only be explained by evolution (or a mischievous god who chose, for some reason, to make life look exactly as if it had evolved – a non-falsifiable notion).
Here is one example. The genetic code is essentially comprised of four letters (ACGT for DNA), and every triplet of three letters equates to a specific amino acid. There are 64 (4^3) possible three letter combinations, and 20 amino acids. A few combinations are used for housekeeping, like a code to indicate where a gene stops, but the rest code for amino acids. There are more combinations than amino acids, so most amino acids are coded for by multiple combinations. This means that a mutation that results in a one-letter change might alter from one code for a particular amino acid to another code for the same amino acid. This is called a silent mutation because it does not result in any change in the resulting protein.
It also means that there are very many possible codes for any individual protein. The question is – which codes out of the gazillions of possible codes do we find for each type of protein in different species. If each “kind” were created separately there would not need to be any relationship. Each kind could have it’s own variation, or they could all be identical if they were essentially copied (plus any mutations accruing since creation, which would be minimal). But if life evolved then we would expect that the exact sequence of DNA code would be similar in related species, but progressively different (through silent mutations) over evolutionary time.
This is precisely what we find – in every protein we have examined. This pattern is necessary if evolution were true. It cannot be explained by random chance (the probability is absurdly tiny – essentially zero). And it makes no sense from a creationist perspective. This same pattern (a branching hierarchy) emerges when we look at amino acid substitutions in proteins and other aspects of the genetic code.
Further, the picture of the relationship among species that emerges from genetic analysis matches nicely with the morphological and fossil evidence.
Because these lines of reconstructing the evolutionary past are imperfect and incomplete, they do not match precisely in every instance. They match well-enough that they are consistent with evolution, but get progressively fuzzy at finer and finer levels of detail. This is pretty much what we would expect. But Morris uses the denialist tactic of using fuzziness at the fine levels of detail to call into question the big picture (again by taking quotes out of context).
Morris does not seem to grasp the actual science. Instead he just quote mines for snippets that seem to support the conclusion he has already formed.
The Second Law of Thermodynamics? Really?
Yes, Morris goes for the second law of thermodynamics again – in the exact way that I already addressed. He responds to scientists correctly pointing out that the Earth is an open system, by writing:
This naive response to the entropy law is typical of evolutionary dissimulation. While it is true that local order can increase in an open system if certain conditions are met, the fact is that evolution does not meet those conditions. Simply saying that the earth is open to the energy from the sun says nothing about how that raw solar heat is converted into increased complexity in any system, open or closed.
The fact is that the best known and most fundamental equation of thermodynamics says that the influx of heat into an open system will increase the entropy of that system, not decrease it. All known cases of decreased entropy (or increased organization) in open systems involve a guiding program of some sort and one or more energy conversion mechanisms.
Energy has to be transformed into a usable form in order to do the work necessary to decrease entropy. That’s right. That work is done by life. Plants take solar energy (again – I’m not sure what “raw solar heat” means) and convert it into food. That food fuels the processes of life, which include development and reproduction. Evolution emerges from those processes- therefore the conditions that Morris speaks of are met.
But Morris next makes a very confused argument:
Evolution has neither of these. Mutations are not “organizing” mechanisms, but disorganizing (in accord with the second law). They are commonly harmful, sometimes neutral, but never beneficial (at least as far as observed mutations are concerned). Natural selection cannot generate order, but can only “sieve out” the disorganizing mutations presented to it, thereby conserving the existing order, but never generating new order.
The notion that evolution (as if it’s a thing) needs to use energy is hopelessly confused. Evolution is a process that emerges from the system of life – and life certainly can use solar energy to decrease its entropy, and by extension the entropy of the biosphere.
Morris slips into what is often presented as an information argument. (Yet again – already dealt with. The pattern here is that we are seeing a shuffling around of the same tired creationists arguments.) It is first not true that most mutations are harmful. Many are silent, and many of those that are not silent are not harmful. They may be neutral, they may be a mixed blessing, and their relative benefit vs harm is likely to be situational. They may be fatal. And they also may be simply beneficial.
But mutations are not “disorganizing” – that does not even make sense. It seems to be based on a purely creationist notion that species are in some privileged perfect state, and any mutation can only take them farther from that perfection. For those who actually understand biology, life is a kluge of compromises and variation. Mutations are mostly lateral moves from one chaotic state to another. They are not directional.
But they do provide raw material, variation, for natural selection. Natural selection cannot generate variation, but it can select among that variation to provide differential survival. This is an old game played by creationists – mutations are not selective, and natural selection is not creative (does not increase variation). These are true but irrelevant, because mutations increase variation and information, and selection is a creative force that results in the differential survival of better adapted variation.
And all of this has absolutely nothing to do with the thermodynamic argument – it’s a giant misdirection.
Evolution is Science
Morris finishes with a long rambling argument that evolution is religion.
Evolution is promoted by its practitioners as more than mere science. Evolution is promulgated as an ideology, a secular religion — a full-fledged alternative to Christianity, with meaning and morality . . . . Evolution is a religion. This was true of evolution in the beginning, and it is true of evolution still today.
Morris ties evolution to atheism, which, he argues, makes it a religion. This assumes, of course, that atheism is a religion. That depends on how you define atheism and how you define religion – but it is mostly wrong. Atheism is a lack of belief in one particular supernatural claim – that does not qualify it as a religion.
Nor is acceptance of evolution equal to lack of belief in god or the supernatural. There are many scientists who accept evolution who also have faith (like Kenneth Miller).
Morris is confusing (he did that a lot) philosophical naturalism with methodological naturalism. Science requires methodological naturalism. The methods of science can only work within a framework of testable cause and effect. The supernatural cannot be falsified (because it functions like magic) and so is incompatible with science. This is not a choice, it’s not a belief, it’s not religion – it is a logical imperative of the methods of science. Practitioners of science are free to believe whatever they want, but the methods of science must follow methodological naturalism.
Morris also fails to recognize that his argument would apply to all of science, not just evolution. But it doesn’t matter because his entire argument fails from faulty premises and logic.
Conclusion
The point of Morris’s diatribe is to convince his readers that evolution is an atheist conspiracy, not a legitimate science. Unfortunately, for his target audience – his form of misdirection, misinformation, and slippery logic is effective.
I found nothing new in his article, which was comprised entirely of recycled creationist arguments that have long been demolished by careful examination.
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-4,951,209,146,005,395,000 | 论文
论文题目：
第一作者：
联系作者：
刊物名称：
发表年度：
论文题目 发表年度
N(6)-methyladenosine regulates RNA abundance of SARS-CoV-2. 2021
The loss of RNA N(6)-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8(+) T cell dysfunction and tumor growth. 2021
Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance 2021
N(6)-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA. 2021
METTL3-dependent m(6)A modification programs T follicular helper cell differentiation. 2021
MYC promotes cancer progression by modulating m(6) A modifications to suppress target gene translation. 2021
Germline variants of DNA repair genes in early onset mantle cell lymphoma. 2021
Compositional Variability and Mutation Spectra of Monophyletic SARS-CoV-2 Clades. 2021
RNF8 ubiquitinates RecQL4 and promotes its dissociation from DNA double strand breaks. 2021
The UVSSA complex alleviates MYC-driven transcription stress. 2021
Evidence for CAT gene being functionally involved in the susceptibility of COVID-19. 2021
Increased chromosomal instability characterizes metastatic renal cell carcinoma. 2021
Germline variants in UNC13D and AP3B1 are enriched in COVID-19 patients experiencing severe cytokine storms. 2021
miR-218-2 regulates cognitive functions in the hippocampus through complement component 3-dependent modulation of synaptic vesicle release. 2021
Computing the Role of Alternative Splicing in Cancer. 2021
Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers. 2021
Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis. 2021
Genomic Analysis Revealed a Convergent Evolution of LINE-1 in Coat Color: A Case Study in Water Buffaloes (Bubalus bubalis). 2021
Single-cell transcriptome profiling of the vaginal wall in women with severe anterior vaginal prolapse. 2021
Genome sequences reveal global dispersal routes and suggest convergent genetic adaptations in seahorse evolution. 2021 | {
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6,726,079,749,692,720,000 | Bio 172 GSI: Mackenzie Mosera
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Room: SLC - Alcove 6
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Type: Bio GSI
Created by: barboliv
Last updated: 09:26:10am - Tuesday 02 January 2018
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Repeat day: Thursday
Repeat end date: Thursday 26 April 2018
Edit Entry - Edit Series
Delete Entry - Delete Series
Copy Entry - Copy Series
Export Entry - Export Series
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-3,692,714,238,624,185,300 | Please login to your online account to display your discounted pricing
Mouse anti-MyoD, Clone: SPM427, Novus Biologicals™
Manufacturer: novus biologicals canada NBP23288210ML
View all options for this product
Disclaimers
For Research Use Only
Catalog No. NBP23288210
Description & Specifications
Specifications
Antigen MyoD
Applications Flow Cytometry
Applications Immunocytochemistry
Applications Immunofluorescence
Applications Immunohistochemistry (Frozen)
Applications Immunohistochemistry (Paraffin)
Applications Immunoprecipitation
Applications Western Blotting
Clone SPM427
Concentration 0.2mg/mL
Conjugate Unlabeled
Cross Reactivity Chicken
Cross Reactivity Human
Cross Reactivity Mouse
Cross Reactivity Rat
Format Purified
Formulation PBS with 0.05% BSA.
Gene Accession No. P15172
Host Species Mouse
Immunogen Recombinant mouse MyoD1 protein
Isotype IgG1, κ
Purification Method Purified
Quantity 1.0mL
Regulatory Status RUO
Storage Requirements Store at 4°C short term. Aliquot and store at -20°C long term. Avoid freeze-thaw cycles.
Primary or Secondary Primary
Monoclonal or Polyclonal Monoclonal
Gene ID (Entrez) 4654
Reconstitution Protein A purified | {
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8,606,700,411,733,157,000 | Navigation Links
AGU journal highlights -- Feb. 26, 2008
Date:2/26/2008
agu.org/sci_soc/prrl/2008-05.html)
Title: Potential role of the ocean thermostat in determining regional differences in coral reef bleaching events
Authors: Joan A. Kleypas and Gokhan Danabasoglu: National Center for Atmospheric Research, Boulder, Colorado, U.S.A.;
Janice M. Lough: Australian Institute of Marine Science, Townsville, Queensland, Australia.
Source: Geophysical Research Letters (GRL) paper 10.1029/2007GL032257, 2008; http://dx.doi.org/10.1029/2007GL032257
6. The dynamics of North American monsoons
The North American Monsoon Experiment is an international research program aimed at learning more about summertime precipitation over North America to improve precipitation prediction in models. In particular, several scientists interested in understanding more about summer precipitation over southwestern North America conducted a field study during the summer of 2004. For this study, scientists used GPS receivers, surface barometers, and surface thermometers to calculate the daily precipitable water vapor (PWV) content over northwestern Mexico. Through analyzing these data, Kursinski et al. find that the onset of the monsoon season can be seen by a large increase in PWV over several days, beginning in early July. Data from the Sierra Madre Occidental foothills reveal a dynamical transition in mid-August from smaller local convection patterns to larger, more regional scales. During the small-scale phase, a positive feedback helps precipitation-supplied moisture to initiate more moist convection. The authors note that precipitation is usually preceded by a rapid PWV rise and a sharp surface temperature decrease, implying that models must include moist convective downdrafts in the NAM area.
Title: Water vapor and surface observations in northwestern Mexico during the 2004 NAME Enhanced Observing Period
Autho
'/>"/>
Contact: Peter Weiss
[email protected]
202-777-7507
American Geophysical Union
Source:Eurekalert
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504,140,855,765,169,340 | [Home ] [Archive] [ فارسی ]
:: Main :: About :: Current Issue :: Archive :: Search :: Submit :: Contact ::
:: Volume 20, Issue 5 (8-2015) ::
__Armaghane Danesh__ 2015, 20(5): 393-403 Back to browse issues page
Effects of ethanolic Chavill extract on growth of lactobacillus and salmonella bacteria, in skimmed milk and imaging gastric-intestine media in vitro
R Naghiha 1, AN Keshtkaran 1, H Hosseini 1
1- Department of Animal Sciences, Yasuj University, Yasuj, Iran
Abstract: (1583 Views)
Introduction & aim: To achieve high performance and health, it’s better to use additives in the human diet which have beneficial effects on good bacteria and damaging effect on the harmful bacteria. For this purpose, effects of Chavill extract on growth, viability and death of lactobacillus and salmonella, in skimmed milk and imaging gastric-intestine media were studied in vitro conditions. Methods: This study was investigated in two completely randomized experiments with three levels of Chavill extract. In the first experiment, ability of the Chavill extract in Skim Milk medium was examined to survey survival, proliferation and death of beneficial and pathogenic gut bacteria. The second experiment which was down in the simulation of simulated gastric juice and simulated small intestine juice, the effect of Chavill extract on survival, proliferation and death of the bacteria were investigated. Treatments in both of experiments were three levels of Chavill extract (0, 1, and 3 %) for three probiotic bacteria species. Data were analyzed with SAS 9.1 software and their means were compared by Duncan’s Multiple Range test at a significance level of 5 %. Results: By increasing of Chavill extract concentration to 1%, probiotic bacterial counts significantly increase compared to control treatment and the differences were significant and the count of Salmonella typhimurium difference with control significantly decreased. Using 3% Chavill extract compared to 1% extract, increased number of Lactobacillus acidophilus and Lactobacillus plantarum, decreased number of Lactobacillus casei, inhibit growth of Salmonella typhimurium bacterium and block growth of this bacterium. The second experiment on simulated gastric juice showed that numbers of Lactobacillus acidophilus and Lactobacillus plantarum bacteria increased and Lactobacillus casei and Salmonella typhimurium decreased. Also, findings of bacterial survival on simulated small intestine juice showed that there was no significant difference in bacterial on Lactobacillus acidophilus and Lactobacillus plantarum. Conclusion: Results showed that Chevill have good effects on binifical bacteria of digestive system and increases the number of beneficial bacteria and have harmful effects on pathogenic bacteria. It seemed that this plant could be used in diets and also for diseases causing imbalances of normal flora in the gastrointestinal tract. .
Keywords: probiotic bacteria, Chavill, Salmonella typhimurium, gastric juice, small intestine juice.
Full-Text [PDF 190 kb] (597 Downloads)
Type of Study: Research | Subject: Microbiology
Received: 2015/02/3 | Accepted: 2015/06/29 | Published: 2015/08/8
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naghiha R, keshtkaran A, hosseini H. Effects of ethanolic Chavill extract on growth of lactobacillus and salmonella bacteria, in skimmed milk and imaging gastric-intestine media in vitro . Armaghane danesh. 2015; 20 (5) :393-403
URL: http://armaghanj.yums.ac.ir/article-1-48-en.html
Volume 20, Issue 5 (8-2015) Back to browse issues page
ارمغان دانش Armaghane danesh
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-4,843,561,030,295,195,000 | Register or Login
All
• All
• Uniprot Id
• Catalog #
• Peptide Sequence
> home > Products > Primary Antibodies > ZNF37A Antibody (N-term)
ZNF37A Antibody (N-term)
Peptide Affinity Purified Rabbit Polyclonal Antibody (Pab)
• WB - ZNF37A Antibody (N-term) AP18996a
ZNF37A Antibody (N-term) (Cat. #AP18996a) western blot analysis in NCI-H460 cell line lysates (35ug/lane).This demonstrates the ZNF37A antibody detected the ZNF37A protein (arrow).
• SPECIFICATION
• CITATIONS
• PROTOCOLS
• BACKGROUND
Product Information
Application
• Applications Legend:
• WB=Western Blot
• IHC=Immunohistochemistry
• IHC-P=Immunohistochemistry (Paraffin-embedded Sections)
• IHC-F=Immunohistochemistry (Frozen Sections)
• IF=Immunofluorescence
• FC=Flow Cytopmetry
• IC=Immunochemistry
• ICC=Immunocytochemistry
• E=ELISA
• IP=Immunoprecipitation
• DB=Dot Blot
• CHIP=Chromatin Immunoprecipitation
• FA=Fluorescence Assay
• IEM=Immunoelectronmicroscopy
• EIA=Enzyme Immunoassay
WB, E
Primary Accession P17032
Other Accession NP_003412.1
Reactivity Human
Host Rabbit
Clonality Polyclonal
Isotype Rabbit Ig
Calculated MW 65418 Da
Antigen Region 71-100 aa
Additional Information
Gene ID 7587
Other Names Zinc finger protein 37A, Zinc finger protein KOX21, ZNF37A, KOX21, ZNF37
Target/Specificity This ZNF37A antibody is generated from rabbits immunized with a KLH conjugated synthetic peptide between 71-100 amino acids from the N-terminal region of human ZNF37A.
Dilution WB~~1:1000
Format Purified polyclonal antibody supplied in PBS with 0.09% (W/V) sodium azide. This antibody is purified through a protein A column, followed by peptide affinity purification.
StorageMaintain refrigerated at 2-8°C for up to 2 weeks. For long term storage store at -20°C in small aliquots to prevent freeze-thaw cycles.
PrecautionsZNF37A Antibody (N-term) is for research use only and not for use in diagnostic or therapeutic procedures.
Protein Information
Name ZNF37A
Synonyms KOX21, ZNF37
Function May be involved in transcriptional regulation.
Cellular Location Nucleus.
Citations (0)
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Background
ZNF37A may be involved in transcriptional regulation.
References
Deloukas, P., et al. Nature 429(6990):375-381(2004)
Guy, J., et al. Genome Res. 13(2):159-172(2003)
Tunnacliffe, A., et al. Nucleic Acids Res. 21(6):1409-1417(1993)
Huebner, K., et al. Am. J. Hum. Genet. 48(4):726-740(1991)
Thiesen, H.J. New Biol. 2(4):363-374(1990)
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If you have any additional inquiries please email technical services at [email protected].
$ 295.00
$ 99.00
Cat# AP18996a
Size:
Quantity:
(40 western blots)
Availability: In Stock
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-7,855,463,939,120,279,000 | Full Record Display for the EPA National Library Catalog
RECORD NUMBER: 29 OF 676
OLS Field Name OLS Field Data
Main Title An assessment of the current status of living resources, wetland areas and critical habitat in the Pawcatuck River estuary and Little Narragansett Bay /
Author Abrams, Rush
Publisher State of Rhode Island Coastal Resources Management Council ; State of Connecticut Dept. of Environmental Protection, Coastal Resources Management Division,
Year Published 1991
OCLC Number 828028464
Subjects Estuarine area conservation--Rhode Island. ; Estuarine area conservation--Connecticut. ; Estuarine area conservation--Pawcatuck River (R.I. and Conn.) ; Coastal zone management--Rhode Island--Little Narragansett Bay. ; Pawcatuck River Estuary (R.I. and Conn.) ; Little Narragansett Bay (R.I.)
Holdings
Library Call Number Additional Info Location Last
Modified
Checkout
Status
EHBM QH76.5.R4A27 1991 CEMM/ACESD Library/Narragansett,RI 02/26/2013
Collation v, 117 p. : ill., maps ; 28 cm.
Notes Cover title. Technical report #1. "April 1991." Includes bibliographical references (P. 85-91).
Place Published Wakefield, R.I. Hartford, Conn.
Corporate Au Added Ent Pawcatuck Estuary Interstate Management Project. Citizen's Advisory Committee.; Connecticut. Department of Environmental Protection. Coastal Resources Management Division.; Rhode Island. Coastal Resources Management Council.
PUB Date Free Form 1991
BIB Level m
Cataloging Source OCLC/T
OCLC Time Stamp 20130219145841
Language eng
Origin OCLC
Type CAT
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1,289,901,835,954,692,900 | Print
Minor in Biochemistry & Biotechnology {21-22}
Minor in Biochemistry and Biotechnology
Description
Biochemistry and Biotechnology Minor - 22 credits
Core Requirements ( 22 credits )
BIOL 385/385L Molecular Biology with lab (4cr)
CHEM 400/405 Biochemistry I with lab (4cr)
CHEM 410 Biochemistry II (3cr)
Biotechniques elective (Choose 1)
BCBT 461 Nucleic Acids & Bioinformatics (3cr)
BCBT 462 Cell Culture & Immunochemistry (3cr)
BCBT 463 Proteomics & Advanced Chromatography (3cr)
BCBT elective - at least 8 additional credits, no more than 1 credit from any combination of 397/497 courses
Additional Biotechnique elective (BCBT 461, BCBT 462, BCBT 463)
BCBT Certificate course (BCBT 420, BCBT 425, BCBT 430, BCBT 435)
Physiology elective (BIOL 347 or BIOL 349 or BIOL 360, 4cr)
BCBT 469 Internship
TOTAL BIOCHEMISTRY & BIOTECHNOLOGY MINOR REQUIREMENTS = 22cr
BIOL 385/BIOL 385L Molecular Biology with lab (4)
CHEM 400/CHEM 405 Biochemistry I with lab (4)
CHEM 410 Biochemistry II (3)
BCBT 461 Nucleic Acids & Bioinformatics (3) or
BCBT 462 Cell Culture & Immunochemistry (3) or
BCBT 463 Proteomics & Advanced Chromatography (3)
At least 8 additional credits from the following list:
(no more than 3 credits from any combination of 394/494/469 courses)
BCBT 394 BCBT Research (1) *was BCBT 397
BCBT 494 Senior Thesis (1) *was BCBT 497
BCBT 461 Biotechniques: Nucleic Acids and Bioinformatics (3)
BCBT 462 Cell Culture and Immunochemistry (3)
BCBT 463 Proteomics & Advanced Chromatography (3)
BCBT 469 Internship (1)
BIOL 347/BIOL 347L Plant Physiology with lab (4)
BIOL 349/BIOL 349L Human Physiology with lab (4)
BIOL 360/BIOL 360L Cellular and Molecular Physiology with lab (4) | {
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6,686,460,426,533,042,000 | Journal Articles
Differential Expression of Virulence Genes and Motility in Ralstonia (Pseudomonas) solanacearum during Exponential Growth.
Author
S J Clough, A B Flavier, M A Schell, T P Denny
Journal
Cited Count
4
Partners
MEDLINE®/PubMed®
Category
Natural Sciences > Biology , Medicine > Biotechnology
References 31
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-4,801,653,863,688,873,000 | Lineage for d1r7aa1 (1r7a A:435-504)
1. Root: SCOPe 2.06
2. 2017114Class b: All beta proteins [48724] (177 folds)
3. 2066963Fold b.71: Glycosyl hydrolase domain [51010] (1 superfamily)
folded sheet; greek-key
4. 2066964Superfamily b.71.1: Glycosyl hydrolase domain [51011] (6 families) (S)
this domain is C-terminal to the catalytic beta/alpha barrel domain
5. 2066965Family b.71.1.1: alpha-Amylases, C-terminal beta-sheet domain [51012] (22 protein domains)
this domain follows the catalytic beta/alpha barrel domain
6. 2067372Protein Sucrose phosphorylase [101920] (1 species)
single beta-sheet; probable result of a decay of the common-fold
7. 2067373Species Bifidobacterium adolescentis [TaxId:1680] [101921] (2 PDB entries)
8. 2067374Domain d1r7aa1: 1r7a A:435-504 [97192]
Other proteins in same PDB: d1r7aa2, d1r7ab2
complexed with trs
Details for d1r7aa1
PDB Entry: 1r7a (more details), 1.77 Å
PDB Description: Sucrose Phosphorylase from Bifidobacterium adolescentis
PDB Compounds: (A:) sucrose phosphorylase
SCOPe Domain Sequences for d1r7aa1:
Sequence; same for both SEQRES and ATOM records: (download)
>d1r7aa1 b.71.1.1 (A:435-504) Sucrose phosphorylase {Bifidobacterium adolescentis [TaxId: 1680]}
afdgtfsyttdddtsisftwrgetsqatltfepkrglgvdnttpvamlewedsagdhrsd
dlianppvva
SCOPe Domain Coordinates for d1r7aa1:
Click to download the PDB-style file with coordinates for d1r7aa1.
(The format of our PDB-style files is described here.)
Timeline for d1r7aa1:
View in 3D
Domains from same chain:
(mouse over for more information)
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3,183,635,952,325,350,400 | Tag Archives: DNA compaction
DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices
MeCP2 and MBD2 are members of a family of proteins that possess a domain that selectively binds 5-methylcytosine in a CpG context. Members of the family interact with other proteins to modulate DNA packing. Stretching of DNA–protein complexes in nanofluidic channels with a cross-section of a few persistence lengths allows us to probe the degree of compaction by proteins.*
In the article “DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices” Ming Liu, Saeid Movahed, Saroj Dangi, Hai Pan, Parminder Kaur, Stephanie M. Bilinovich, Edgar M. Faison, Gage O. Leighton, Hong Wang, David C. Williams Jr. and Robert Riehn demonstrate DNA compaction by MeCP2 while MBD2 does not affect DNA configuration. By using atomic force microscopy (AFM), they determined that the mechanism for compaction by MeCP2 is the formation of bridges between distant DNA stretches and the formation of loops.*
Despite sharing a similar specific DNA-binding domain, the impact of full-length 5-methylcytosine-binding proteins can vary drastically between strong compaction of DNA and no discernible large-scale impact of protein binding. The authors of the article demonstrate that ATTO 565-labeled MBD2 is a good candidate as a staining agent for epigenetic mapping.*
For atomic force microscopy (AFM), the authors used a 7,163-bp linear DNA substrate which contains a 1,697-bp methylated CpG-rich region that is flanked by 2,742-bp and 2,724-bp CpG-free regions. For MeCP2, the DNA substrate and the protein were diluted in AFM imaging buffer (HEPES 20 mM, Mg(OAc)210mM, NaCl 100mM, pH 7.5), mixed together and deposited on freshly peeled mica. For MBD2FLsc, the authors describe how they first mixed the protein and DNA and then diluted the sample in AFM buffer before deposition. The final MeCP2 concentration deposited on mica was 7.5nM, and the MBD2FLsc concentration was 14nM. The mica samples were then washed with filtered deionized water and dried with nitrogen.*
NANOSENSORS™ PointProbe® Plus PPP-FMR AFM probes ( ≈2.8N/m) were used to image the sample at a scan resolution of 5.9nm and a scan rate of 3μm/s.*
Figure 6 from “DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices “ by Ming Liu et al.:
Atomic force microscopy (AFM) of methylated substrates under various conditions. AFM of bare methylated dsDNA oligomer a, the same oligomer with MBD2Flsc b, and with MeCP2 c. Scale bars are 200nm. The green arrows point at ends, and cyan arrows point at loops. The inset in d illustrates the counting method for loops. The distribution of number of free ends (d) and the distribution of number of loops (e) for DNA or DNA–protein complexes was determined from such images (bare DNA N=118, MBD2FLsc N=98, MeCP2 N=108). f Height of isolated DNA–DNA crossings (bare DNA N=52, MBD2FLsc N=68, MeCP2 N=83)
*Ming Liu, Saeid Movahed, Saroj Dangi, Hai Pan, Parminder Kaur, Stephanie M. Bilinovich, Edgar M. Faison, Gage O. Leighton, Hong Wang, David C. Williams Jr. and Robert Riehn
DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices
Epigenetics & Chromatin volume 13, Article number: 18 (2020)
DOI: https://doi.org/10.1186/s13072-020-00339-7
Please follow this external link to read the full article: https://rdcu.be/b3iTm
Open Access: The article “DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices” by Ming Liu, Saeid Movahed, Saroj Dangi, Hai Pan, Parminder Kaur, Stephanie M. Bilinovich, Edgar M. Faison, Gage O. Leighton, Hong Wang, David C. Williams Jr. and Robert Riehn is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | {
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1,258,906,933,073,048,300 | Page Banner
United States Department of Agriculture
Agricultural Research Service
Title: Beta-D-xylosidase from Selenomonas ruminantium: thermodynamics of enzyme-catalyzed and noncatalyzed reactions
Authors
item JORDAN, DOUGLAS
item Braker, Jay
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: July 18, 2008
Publication Date: N/A
Technical Abstract: Beta-D-xylosidase/alpha-L-arabinofuranosidase from Selenomonas ruminantium (SXA) is the most active enzyme known for catalyzing hydrolysis of 1,4-beta-D-xylooligosaccharides to D-xylose. Temperature dependence for hydrolysis of 4-nitrophenyl-beta-D-xylopyranoside (4NPX), 4-nitrophenyl-alpha-L-arabinofuranoside (4NPA), and 1,4-beta-D-xylobiose (X2) was determined on and off (knon) the enzyme at pH 5.3, which lies in the pH-independent region for kcat and knon. Rate enhancements (kcat/knon) for 4NPX, 4NPA, and X2 are 4.3 x 10**11, 2.4 x 10**9, and 3.7 x 10**12, respectively, at 25 deg C and increase with decreasing temperature. Relative parameters kcat**4NPX/kcat**4NPA, kcat**4NPX/kcat**X2, and (kcat/Km)**4NPX/(kcat/Km)**X2 increase and (kcat/Km)**4NPX/(kcat/Km)**4NPA, (1/Km)**4NPX/(1/Km)**4NPA, and (1/Km)**4NPX/(1/Km)**X2 decrease with increasing temperature.
Last Modified: 9/29/2014
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4,484,205,542,659,622,000 | A novel method of thermal activation and temperature measurement in the microscopic region around single living cells
Vadim Zeeb, Madoka Suzuki, Shin'ichi Ishiwata
Research output: Contribution to journalArticlepeer-review
31 Citations (Scopus)
Abstract
We present a simple approach to bring fast and reversible temperature steps of a wide range of amplitudes from the temperature of the experimental chamber up to the boiling point of water in a desired position, with rise and fall times of around 10 ms in a microvolume of μm in size, such as in a single cell. For this purpose, we applied a technique for illuminating a metal aggregate (1-2 μm in diameter) placed at the tip of a glass micropipette with a focused infrared (1064 nm) laser beam under an optical microscope. Stable temperature gradients were created around the metal aggregate using an appropriate neutral density filter set for the laser output. To monitor the local temperature, we devised a new microthermometer composed of the tip of a micropipette filled with thermosensitive fluorescent dye Europium-TTA possessing steep temperature-dependent phosphorescence upon 365 nm excitation. The μm size of the tip of this pipette was able to measure the local temperature with 0.1°C precision and μm spatial resolution. This new approach is compatible with standard electrophysiological and imaging techniques.
Original languageEnglish
Pages (from-to)69-77
Number of pages9
JournalJournal of Neuroscience Methods
Volume139
Issue number1
DOIs
Publication statusPublished - 2004 Oct 15
Keywords
• Europium-TTA
• Fluorescence imaging
• Infrared laser
• Microheater
• Micropipette
• Microthermometer
• Optical microscope
ASJC Scopus subject areas
• Neuroscience(all)
Fingerprint Dive into the research topics of 'A novel method of thermal activation and temperature measurement in the microscopic region around single living cells'. Together they form a unique fingerprint.
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4,807,084,280,999,457,000 | Ecosystem of Ponds for Kids
Ecosystem of Ponds for Kids
••• Comstock Images/Comstock/Getty Images
Take almost any child to water and she'll want to peer inside, look for fish, watch ducks and splash the surface. Ponds are intriguing and near mystical in certain conditions, like when mist settles over them or when they reflect the colors of an autumn afternoon. Life at a pond is varied and can be most exciting to children, especially when guided carefully by parents or teachers who are informed about the delicate environs and the interdependency of life forms.
Basics
Ecosystems are the biological organism communities that rely upon one another for continued life. These can be pristine settings where reeds grow, breezes create ripples and many types of animals thrive. Or they can be dank, polluted and nearly lifeless. If you have a pond near your home or school, take children down to the pond's edges to explore. Discuss the importance of the sun to plant life, the bacteria or algae that grow naturally and how air quality and temperature affect what kinds of plants and animals can grow and thrive in the area. Each pond's specific ecosystem takes all of these into account.
Critters
Trails near the ponds, bridges and piers can offer lookout stations to hunt for all kinds of "critters." Ask the the children to point out and list the types and colors of water bugs, dragonflies, ladybugs, beetles, spiders and other insects. The kids may find them directly on the water or on plants nearby. Point out the cattails and water irises and any wild plants that may be floating in areas -- like loosestrife, mallow, milfoil and water lilies -- all of which provide shelter, food sources and security to various bugs and other creatures. You might see tiny fishes and tadpoles, or hear toads and frogs, which are especially exciting for children to actually discover or find hopping around. Talk about the life cycles as observers so as not to disrupt any habitats.
Birds and Wildlife
Ecosytems at ponds are affected by many factors, including human contact.
••• Polka Dot Images/Polka Dot/Getty Images
Numerous birds make homes and nests around ponds. In winter, try to find higher nests in deciduous trees when leaves have fallen. In spring, ducklings often appear with their mothers, sneaking out from reeds or darting behind them when afraid. Respect nesting areas for ducks, herons, egrets and other birds, so don't let children poke sticks or cause any harm. The presence of birds helps to contribute to the ecosystems balance. Discuss how birds help keep down mosquito populations or how their food comes from plants nearby. Watch what the various birds eat. (A pair of binoculars is a good item to carry along.) Raccoons, deer, coyotes and other wildlife visit ponds for water or for resting places and food sources, too. Bird and wildlife waste contributes to reseeding and nourishment of plants. Find tracks in mud and identify them.
Human Effects
Talk to children about how humans rely on clear water, but so do animals and plants. The effects of pollution aren't always obvious, but close investigation by sampling water will yield a lot of information. Avoid throwing trash into ponds; recycle plastic and metal containers. if you and the children are using sunscreen and you touch or wash your hands in the pond, you will likely notice a film that floats off. This can harm the ecosystem. Fishing at a pond might be educational in some ways, but using nets will cause fewer damaging results -- especially if you release the fish. Utilize resource centers and nature exhibits at pond sites. Take along cameras and sketch pads for children to record moments and sightings, but leave the area as undisturbed as possible.
References
Resources
About the Author
Debra J. Rigas, a professional writing coach, has been a writer and editor since 1975. She is the author of the nonfiction book "Everyone's A Guru" and has edited novels ("The Woman Pope") and worked in arts and sciences as a filmmaker, boat captain, landscaper, counselor, theater administrator and licensed midwife.
Photo Credits
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5,554,607,223,215,736,000 | Anti-extracellular matrix protein 2, female organ and adipocyte specific Antibody Products from Atlas Antibodies
Listed below are anti-Extracellular matrix protein 2, female organ and adipocyte specific antibodies from multiple suppliers. Extracellular matrix protein 2, female organ and adipocyte specific is a reported alias name for the human gene ECM2, or 'extracellular matrix protein 2'. The 699-amino acid protein is a member of the Small leucine-rich proteoglycan (SLRP) family, SLRP class I subfamily. The cellular localization is predicted to be secreted. Glycosylation sites have been reported. See the supplier page to learn important antibody details, such as target specificity and designated applications.
Anti-extracellular matrix protein 2, female organ and adipocyte specific Antibody Products from Atlas Antibodies
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• Applications:
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• Reactivity:
Human (Hu)
• Conjugate/Tag:
unconjugated
• Quantity:
100 µl
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-4,675,313,086,800,719,000 | Protocol Online logo
Top : New Forum Archives (2009-): : Biochemistry
241. looking for kinase inhibitor to study phosphatase - kinase inhibitor (Inhibit phosphorylation on transmembrane receptor) (reply: 4)
242. Quantification of total lipids in tisuue - (reply: 1)
243. enzymatic inhibition assay - (reply: 5)
244. boiling point of allicin, diallyl sulphide, diallyl disulphide and ajoene - (reply: 2)
245. How did they know what we knew? like in the case of TCA cycle - (reply: 3)
246. phage display - peptide differentiation (reply: 1)
247. Detection of phosphorylation site - (reply: 23)
248. Protease Assay - (reply: 4)
249. Strip and Reprobe ELISA - (reply: 2)
250. Lipid raft extraction HELP! - (reply: 2)
251. Reversing crosslinks - (reply: 3)
252. measurement of reactive oxygen species - (reply: 1)
253. What is the solution when tween80 or DMSO is not enough to dissolve plant extrac - (reply: 1)
254. dna loading dye for proteins - (reply: 2)
255. protein optimization - (reply: 3)
256. pectinase assay - pectinase acitvity (reply: 5)
257. TBARS assay - (reply: 2)
258. silver stain of immunoprecipitate - (reply: 2)
259. immunoprecipitation: beads-antibody incubation - (reply: 3)
260. Protein at low PH - Strange behavior of His-tagged protein at low PH (reply: 1)
261. Clinical question - For a friend whose child has a developmental delay (reply: 5)
262. which is the best lysis buffer for whole cell extracts? - (reply: 1)
263. formamide loading buffer - storage? (reply: 2)
264. inhibitors - (reply: 1)
265. Neuraminidase Kinetic Assay - (reply: 1)
266. what's wrong with my anthrone reagent? - (reply: 1)
267. Method to measure enzyme activity - GSS (reply: 2)
268. Protein elution from amylose resin - (reply: 1)
269. Hey guys，what do you think the Anti-Flag M2 agarose beads is made of? - Well,actually I want to make some homemade agarose beads,which haven't (reply: 5)
270. GAPDH activity assay - (reply: 9)
Pages: 1 2 3 4 5 6 7 8 9 10 11 12 | {
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
7,081,170,499,991,197,000 |
Annotation Overview for fig|451515.3.peg.1795 in Staphylococcus aureus subsp. aureus USA300 FPR3757:
Pyruvate kinase (EC 2.7.1.40) / Phosphohistidine swiveling domain
[to old protein page]
current assignment
This feature plays multiple roles which are implemented by distinct domains within the feature. The roles are:
Pyruvate kinase (EC 2.7.1.40)EC Number 2.7.1.40
Phosphohistidine swiveling domain
taxonomy id451515contig
internal linksgenome browser | feature evidence | sequenceACH [?]show essentially identical genes
annotation historyrun tool
FigFamFIG00000043CDD linkshow cdd
PATtyfamPGF_00045994: Pyruvate kinase (EC 2.7.1.40) / Phosphohistidine swiveling domain
PLF_1279_00000772: Pyruvate kinase (EC 2.7.1.40) / Phosphohistidine swiveling domain
alignments and trees4 alignments and treesPATRIC link19592731
edit functional rolePyruvate kinase (EC 2.7.1.40)
Phosphohistidine swiveling domain
aliases
propagation lock
Unlocked Toggle lock
This feature is part of a subsystem
• In Glycerate metabolism its role is Pyruvate kinase (EC 2.7.1.40).
• In Pyruvate metabolism I: anaplerotic reactions, PEP its role is Pyruvate kinase (EC 2.7.1.40).
• In Protein Carbonylation its role is Pyruvate kinase (EC 2.7.1.40). However, the functionality of this subsystem has not yet been classified for this organism.
• In Glycolysis and Gluconeogenesis its role is Pyruvate kinase (EC 2.7.1.40).
• In Glycolytic pathways PanGenomes its role is Pyruvate kinase (EC 2.7.1.40). However, the functionality of this subsystem has not yet been classified for this organism.
• In Glycerate metabolism its role is Pyruvate kinase (EC 2.7.1.40).
• In Glycolysis and Gluconeogenesis its role is Pyruvate kinase (EC 2.7.1.40).
• In Pyruvate metabolism I: anaplerotic reactions, PEP its role is Pyruvate kinase (EC 2.7.1.40).
• Compare Regions For fig|451515.3.peg.1795
The chromosomal region of the focus gene (top) is compared with four similar organisms. The graphic is centered on the focus gene, which is red and numbered 1. Sets of genes with similar sequence are grouped with the same number and color. Genes whose relative position is conserved in at least four other species are functionally coupled and share gray background boxes. The size of the region and the number of genomes may be reset. Click on any arrow in the display to refocus the comparison on that gene. The focus gene always points to the right, even if it is located on the minus strand. | {
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8,430,642,606,093,069,000 | Journal Articles
Alternative splicing of a neural-specific Src mRNA (Src+) is a rapid and protein synthesis-independent response to neural induction in Xenopus laevis.
Author
J W Collett, R E Steele
Journal
Cited Count
5
Partners
MEDLINE®/PubMed®
Category
Natural Sciences > Biology
Keywords
Alternative Splicing, Animals, Base Sequence, Ectoderm, metabolism, Gene Expression Regulation, Genes, src, Mesoderm, physiology, Molecular Sequence Data, Neurons, Phosphorylation, Protein Biosynthesis, RNA, Messenger, analysis, Tetradecanoylphorbol Acetate, pharmacology, Xenopus laevis
References
No relevant information is available
If you register references through the customer center, the reference information will be registered as soon as possible.
Articles referencing this article
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Top
Biology
Top Journals Cited | {
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-7,446,959,104,403,671,000 | STRING 9.05
ALDH7A1 protein (Homo sapiens) - STRING network view
This is the evidence view. Different line colors represent the types of evidence for the association.
Your Input:
ALDH7A1
aldehyde dehydrogenase 7 family, member A1 (539 aa)
(Homo sapiens)
Predicted Functional Partners:
GAD1
glutamate decarboxylase 1 (brain, 67kDa); Catalyzes the production of GABA (594 aa)
0.948
GAD2
glutamate decarboxylase 2 (pancreatic islets and brain, 65kDa); Catalyzes the production of GAB [...] (585 aa)
0.938
ABAT
4-aminobutyrate aminotransferase; Catalyzes the conversion of gamma-aminobutyrate and L- beta-a [...] (500 aa)
0.935
AASS
aminoadipate-semialdehyde synthase; Bifunctional enzyme that catalyzes the first two steps in l [...] (926 aa)
0.925
HIBADH
3-hydroxyisobutyrate dehydrogenase (336 aa)
0.920
ACSS2
acyl-CoA synthetase short-chain family member 2; Activates acetate so that it can be used for l [...] (701 aa)
0.916
GLYCTK
microRNA 135a-1 (523 aa)
0.915
ACSS1
acyl-CoA synthetase short-chain family member 1; Important for maintaining normal body temperat [...] (689 aa)
0.912
HADH
hydroxyacyl-Coenzyme A dehydrogenase; Plays an essential role in the mitochondrial beta- oxidat [...] (314 aa)
0.909
CHDH
choline dehydrogenase (594 aa)
0.909
Views:
Neighborhood Fusion Occurence Coexpression Experiments Database Textmining Summary Network
Info & Parameters ...
Network Display - Nodes are either colored (if they are directly linked to the input - as in the table) or white (nodes of a higher iteration/depth). Edges, i.e. predicted functional links, consist of up to eight lines: one color for each type of evidence. Hover or click to reveal more information about the node/edge.
Active Prediction Methods:
Neighborhood Gene Fusion Co-occurrence
Co-expression Experiments Databases Textmining
required confidence (score): interactors shown:
or custom value: or custom limit:
additional (white) nodes
Server load: medium (46%)
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
8,084,848,339,056,438,000 | Search results
Map
Choose map: | | Download Centroids / Boundaries / Map (pdf)
Materials presented on this website, particularly maps and territorial information, are as-is and as-available based on available data and do not imply the expression of any opinion whatsoever on the part of the Secretariat of the Ramsar Convention concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries.
List
1. ---
Apsley Marshes
• Country:
Australia
• Designation date:
16-11-1982
• Site number:
255
• Published since:
9 year(s)
880 ha
2. Ramsar logo
Grassland Ecological Area (GEA)
• Country:
United States of America
• Designation date:
02-02-2005
• Site number:
1451
• Published since:
18 year(s)
65,000 ha
3. Alkaline steppes with Avocets in the Kiskunság
Upper Kiskunság alkaline steppes
• Country:
Hungary
• Designation date:
06-10-2006
• Site number:
1646
• Published since:
6 year(s)
13,177 ha
4. View of the Dinnyési-Fertő from the drinking site
Velence and Dinnyés Nature Conservation Area
• Country:
Hungary
• Designation date:
11-04-1979
• Site number:
183
• Published since:
6 year(s)
1,354 ha
5. Tens of thousands of geese and thousands of ducks roost on Lake Öreg, in front of the baroque style Castle of Tata during the migration period
Lakes by Tata
• Country:
Hungary
• Designation date:
17-03-1989
• Site number:
419
• Published since:
6 year(s)
1,897 ha
6. Traversée Parc National d'Azagny
Mangroves
Traversée Parc National d'Azagny
Parc National d’Azagny
• Country:
Côte d'Ivoire
• Designation date:
27-02-1996
• Site number:
790
• Published since:
4 year(s)
19,400 ha
7. The Ugrai Meadow
Biharugra Fishponds
• Country:
Hungary
• Designation date:
26-05-1997
• Site number:
903
• Published since:
6 year(s)
2,791 ha
8. Ramsar logo
Río Matos
• Country:
Bolivia (Plurinational State of)
• Designation date:
02-02-2013
• Site number:
2093
• Published since:
10 year(s)
1,729,788 ha
9. Ramsar logo
Caddo Lake
• Country:
United States of America
• Designation date:
23-10-1993
• Site number:
633
• Published since:
16 year(s)
7,977 ha
10. Ramsar logo
San Francisco Bay/Estuary (SFBE)
• Country:
United States of America
• Designation date:
02-02-2013
• Site number:
2097
• Published since:
10 year(s)
158,711 ha
Pages
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As soon as the list has been generated an e-mail will be sent to you with the link to access the file. | {
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-5,125,849,364,413,302,000 | On the Reception of the 'Origin of Species'
Thomas Henry Huxley
History
On the Reception of the 'Origin of Species'
Free
Description
Contents
Reviews
Language
English
ISBN
Unknown
ON THE RECEPTION OF THE 'ORIGIN OF SPECIES'
by
PROFESSOR THOMAS HENRY HUXLEY
FROM THE LIFE AND LETTERS OF CHARLES DARWIN
EDITED BY FRANCIS DARWIN
EDITED BY FRANCIS DARWIN
ON THE RECEPTION OF THE 'ORIGIN OF SPECIES.'
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-2,542,491,399,646,112,300 | KN314261 Pus3 - mouse gene knockout kit via CRISPR
Search for all "Pus3 - mouse gene knockout kit via CRISPR"
1 kit / €1,290.00
Please visit the country specific website of Acris Antibodies or contact your local Distributor to buy this product.
KN314261
Properties for Pus3 - mouse gene knockout kit via CRISPR
Product Category CRISPR
Quantity 1 kit
Species (CRISPR) Mouse
Donor Vector GFP-Puro
Shipping to Europe, USA/Canada
PDF datasheet View Datasheet
Manufacturer OriGene Technologies, Inc.
Datasheet Extract
Add. information The kit is designed based on the best knowledge of CRISPR technology. The system has been functionally validated for knocking-in the cassette downstream the native promoter. The efficiency of the knock-out varies due to the nature of the biology and the complexity of the experimental process.
Background
Kit Component:
- KN314261G1, Pus3 gRNA vector 1 in pCas-Guide vector
- KN314261G2, Pus3 gRNA vector 2 in pCas-Guide vector
- KN314261D, donor vector containing left and right homologous arms and GFP-Puro functional cassette
- GE100003, scramble sequence in pCas-Guide vector
CRISPR Manual:
CRISPR/CAS9 Genome Editing Manual
• LinkedIn | {
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
7,899,403,168,585,499,000 |
1N4V
ATOMIC RESOLUTION STRUCTURE OF CHOLESTEROL OXIDASE @pH 5.8 (STREPTOMYCES SP. SA-COO)
Experimental Data Snapshot
• Method: X-RAY DIFFRACTION
• Resolution: 1.00 Å
• R-Value Free: 0.147
• R-Value Work: 0.119
wwPDB Validation 3D Report Full Report
This is version 1.2 of the entry. See complete history
Literature
Atomic resolution crystallography reveals how changes in pH shape the protein microenvironment
Lyubimov, A.Y.Lario, P.I.Moustafa, I.Vrielink, A.
(2006) Nat Chem Biol 2: 259-264
• DOI: 10.1038/nchembio784
• Primary Citation of Related Structures:
1N4U, 1N4V, 1N4W, 2GEW
• PubMed Abstract:
• Hydrogen atoms are a vital component of enzyme structure and function. In recent years, atomic resolution crystallography (>or=1.2 A) has been successfully used to investigate the role of the hydrogen atom in enzymatic catalysis. Here, atomic resolution crystallography was used to study the effect of pH on cholesterol oxidase from Streptomyces sp ...
Hydrogen atoms are a vital component of enzyme structure and function. In recent years, atomic resolution crystallography (>or=1.2 A) has been successfully used to investigate the role of the hydrogen atom in enzymatic catalysis. Here, atomic resolution crystallography was used to study the effect of pH on cholesterol oxidase from Streptomyces sp., a flavoenzyme oxidoreductase. Crystallographic observations of the anionic oxidized flavin cofactor at basic pH are consistent with the UV-visible absorption profile of the enzyme and readily explain the reversible pH-dependent loss of oxidation activity. Furthermore, a hydrogen atom, positioned at an unusually short distance from the main chain carbonyl oxygen of Met122 at high pH, was observed, suggesting a previously unknown mechanism of cofactor stabilization. This study shows how a redox active site responds to changes in the enzyme's environment and how these changes are able to influence the mechanism of enzymatic catalysis.
Organizational Affiliation
Department of Molecular, Cell and Developmental Biology, 1156 High Street, University of California, Santa Cruz, California 95064, USA.
Macromolecules
Find similar proteins by: (by identity cutoff) | 3D Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Cholesterol oxidaseA504Streptomyces sp. SA-COOMutation(s): 0
Gene Names: choA
EC: 1.1.3.6 (PDB Primary Data), 5.3.3.1 (UniProt)
UniProt
Find proteins for P12676 (Streptomyces sp. (strain SA-COO))
Explore P12676
Go to UniProtKB: P12676
Entity Groups
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12676
Protein Feature View
Expand
• Reference Sequence
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD
Download Ideal Coordinates CCD File
B [auth A]FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
Ligand Interaction
GOL
Query on GOL
Download Ideal Coordinates CCD File
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Ligand Interaction
Experimental Data & Validation
Experimental Data
• Method: X-RAY DIFFRACTION
• Resolution: 1.00 Å
• R-Value Free: 0.147
• R-Value Work: 0.119
• Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.354α = 90
b = 73.291β = 105.1
c = 63.171γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
SHELXmodel building
SHELXL-97refinement
SHELXphasing
Structure Validation
View Full Validation Report
Entry History
Deposition Data
Revision History (Full details and data files)
• Version 1.0: 2004-04-27
Type: Initial release
• Version 1.1: 2008-04-28
Changes: Version format compliance
• Version 1.2: 2011-07-13
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-6,164,008,315,674,468,000 | @article {4351, title = {CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.}, journal = {PLoS genetics}, volume = {4}, year = {2008}, month = {2008 Nov}, pages = {e1000257}, abstract = {At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting "instability elements," and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF -- a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability.}, keywords = {2008, Animals, Binding Sites, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, GENOMIC INSTABILITY, Human Biology Division, Humans, Male, MICE, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Spinocerebellar Ataxias, Trinucleotide Repeat Expansion}, issn = {1553-7404}, author = {Libby, Randell T and Hagerman, Katharine A and Pineda, Victor V and Lau, Rachel and Cho, Diane H and Baccam, Sandy L and Axford, Michelle M and Cleary, John D and Moore, James M and Sopher, Bryce L and Tapscott, Stephen J and Filippova, Galina N and Pearson, Christopher E and La Spada, Albert R} } | {
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-5,548,710,523,446,323,000 | a
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Mount Hamiguitan
Photo provided by Boj Capati
The Mount Hamiguitan Range Wildlife Sanctuary is a diverse mountain ecosystem with a high number of endemic plant and animal species.
The area lies in the south of Mindanao Island. It is a representation of the Philippines biodiversity hotspot.
The mountain range is home to a number of globally threatened and endemic species, such as the critically endangered Philippine Eagle and the tropical pitcher plant Nepenthes hamiguitanensis.
Mount Hamiguitan is a stratovolcano with an height of 1,620 metres. At its topmost it is covered by a unique 'pygmy' or 'bonsai' forest layer.
Map
Community Reviews
Boj - September 2012
In, 2010, Mt. Hamiguitan was closed to visitors in preparation for its bid to UNESCO World Heritage inscription. During a recent hike (July 2012), the protected area has shown positive signs of recovery. The mountain is indeed a biodiversity/endemism hotspot; its bonsai forest is just one of the many outstanding features of the property.
Also worth noting is the tireless and collective efforts of the concerned local government units in ensuring the protection of the park. Such a practice is rare in the country and very inspiring.
Share your experiences!
Have you been to Mount Hamiguitan? Click here to add your own review.
Site Info
Full name: Mount Hamiguitan Range Wildlife Sanctuary
Site History
• 2014 - Inscribed
Reasons for inscription
•
• 2013 - Referred
•
• 2013 - Advisory Body overruled
Deferral was proposed
•
• 2012 - Incomplete - not examined
•
• 2012 - Revision
Includes part of former TWHS Mount Apo and Mount Hamiguitan: Sanctuaries of Endemism in Mindanao (2008)
•
• 2010 - Incomplete - not examined
As part of former TWHS Mount Apo and Mount Hamiguitan: Sanctuaries of Endemism in Mindanao
•
Locations
The site has 1 locations.
• Mount Hamiguitan
Connections
The site has 12 connections.
Ecology
Geography
Trivia
WHS on Other Lists
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Soror was the name given to the second planet of Betelgeuse, where Ulysse Mérou and his companions landed in Pierre Boulle's novel. Latin for 'Sister', it was so-named because of its generally Earthlike qualities.[1]
Geography Edit
Soror was an Earth sized world, though according to Ulysses Soror is probably older. It contained an atmosphere of oxygen and nitrogen that revolved around Betelguese at a distance equivalent to thirty times the space between the Sun and Earth. The atmosphere was bright, slightly tinged with a pale green color verging from time to time on yellow. The ocean was light blue, also with green tinges. The temperature was high but bearable: about seventy-seven degrees Fahrenheit.
History Edit
Ancient Human Civilization Edit
Over ten thousand years ago, Soror was home to a human civilization similar to twentieth century Earth. The sciences employed by the humans were geared toward the biological disciplines. Apparently the men of Soror were very close to a cure for cancer. The humans employed apes in their culture as pets and servants. At one time the apes were on the verge of extinction, but for some reason spontaneously multiplied outnumbering their human masters. Over the centuries the apes soon began to develop cognitive and speech abilities. Whereas the apes were experiencing an evolutionary awakening, simultaneously the humans began to suffer a cerebral regression.
While the humans stagnated, this evolutionary advantage allowed the apes to slowly take over human civilization, driving many humans to the outskirts or flee deeper into the jungles. The men and women that remained in the cities soon had their roles as masters reversed as pets or animals. The cerebral regression that was affecting the humans caused most men and women to accept the transition with little resistance. According to the memory of a lady animal tamer of orangutans, from her contemporary descendant's testimony, after being caged but pampered she was more than willing to relinquish her role of a sentient being in favor that of a trained animal that performed humiliating tricks at her orangutans leisure. Relieved of the responsibilities and worries, majority humans accepted the regime, further devolving from rational beings.
The humans too lazy to coordinate a response to this revolution remained static on the fringes of their former territories. Some even surrendered themselves to the apes to relive their hunger. However the apes were not content with their former masters being so close to their new domains, that some of the gorillas began to actively hunt humans and drive them further into the jungles with whips.
The memory of the ancient human civilization was eventually lost to time by the apes, who later became the sole masters of Soror. With their innate characteristics of mimicry, the apes produced the humans cultural works and sciences as their own.
At this time, modern simian civilization regarded this era as a dark age that lasted nearly ten thousand years. It became the era of the beginnings of ape civilization. Here no form of scientific progress had been made and curiously no records of any earlier 'older' achievements by apes were found leading to a mystery to many.
'Modern' Simian Civilization Edit
A century before the arrival from Earth, the simian civilization undertook impressive leaps in scientific advances concerning biology and evolution.
64singes2
Human Dissection
Strangely much of their sciences are geared toward biological study, no doubt due to the former role their ancestors played in advancing the ancient humans of Soror knowledge in that field. Using their heighten traits of mimicry, the apes duplicated the medical industry to almost specializing in its roles, from doctors, nurses, etc. The descendants of their former masters however serve the humiliating roles as lab animals and wild game in the pursuit of medical advances.
Currently the apes are at the stage of launching artificial satellites in orbit, with their last satellite containing a living subject.
Man's Resurgence? Edit
After more than a year since his arrival from Earth, Ulysse and his family departed Soror. With the birth of his son it herald the dawn of a new race of intelligent men. His existence had become an unwanted reminder of the apes true origins and had shook simian civilization. However, his influence did not only affect the apes, but his fellow men. Though he had tried and fail to raise majority of them from their savage state, its hinted that the men of Soror could be achieving an evolutionary awakening of its own just as the apes had thousands of years ago. Ulysses' very existence sparked some sort of consciousness among the captive men in the Institute. Seeing a clothed man among the apes caused them to realize that a miracle had happened. According to the ape handlers Ulysse's example had begun to sow unrest among the captive men. In addition as if by some mysterious instinct the captives had greeted Ulysse in a concert of howls after Sirius's birth. Though the apes believe that the threat of a new race of men is gone after Ulysses was supposedly disposed of, Professor Antelle still remains on the planet and has taken a female as a mate, indicating that mankind's resurgence may not be far fetched should she bear his child.
Races Edit
Soror is home to two races man and ape, the latter of the two being the current dominate species reigning the planet.
Humans Edit
81singes5
Man in their Natural State
"Of course. Man's brain, like the rest of his anatomy, is the one that bears the closest resemblance to ours. It's a lucky chance that nature has put at our disposal an animal on whom we can study our own bodies. Man serves us in many other fields of research, as you'll come to realize. ... At this very moment we are undertaking an extremely important series of experiments."
The humans on Soror are indistinguishable from humans from Earth, albeit they possess golden skin and are physically fit, handsome specimens of humanity. Since their ancestors lost the pedestal as Soror’s dominant race, they have been reduced as savage animals, living in the wilds. Trading life in the jungles their descendants are able to move with impunity and agility through the jungles.
Culture Edit
64singes1
Man Hunt
Modern human society on Soror resemble gorilla colonies of Earth, living in nests as naked animals. They are omnivores subsisting on wild fruits, such as bananas, and deer. They live in constant fear of ape hunting drives that raid their colonies at the edges of the jungles.
According to the apes, they believe man's malformation, the lack of four hands, caused man to be pegged on the ground and not evolve as highly as the apes.
Communication Edit
The men on Soror having forgotten the ability to communicate coherently, due to the lack of use of their facial muscles and tongues, they have been reduced to shrill mewing or whining. While unintelligible to higher beings, their grunts allow they to communicate and issue orders amongst themselves. This is not to say they are emotionless, men and women are capable of expressing their feelings for another, physically and animalistically. For example a woman would mark a potential mate by rubbing her nose against her partner and then passing her tongue over his cheek. Likewise the man would imitate her doing the same action.
81singes11
The Gorilla Drives
Exploitation Edit
Man being a similar creature in anatomy close to ape, the apes find it a lucky coincidence that nature has given them a resource which allows them to study their own bodies.
Man serves as a valuable animal that fetches a high price on the market as they play an intricate part in medical sciences conducted by the apes. Unfortunately the apes require a considerable amount of material. This status has also allowed the gorillas to conduct drives into the jungles, capturing specimens but at the same time indulging in horrific slaughter on innocent men and women for entertainment. According to Ulysse there is a study proving that there are more men than apes on Soror. However the ape population is on the rise while former is falling in decline due to over-hunting by the gorilla clan for sport. Scientists are even worried about the future supplies for their laboratories.
71singes6
Human Trophy
Besides being hunted for entertainment and medical purposes, man is also hunted as a trophy animal which hunters proudly display. Human hair especially is prized as a keepsake, similar to the feathers of a rare bird. In a bizarre form of plume hunting hunters are noted to take extra care to smooth down the manes of their kills, particularly women, with the locks of the best specimens being cut to decorate the hats of female apes.
Animal Status Edit
To most of the apes, a man is a man and nothing more. The differences between one individual and another do not strike them. Ape hunters however do make distinctions between men with extremely handsome features. While the elite specimens are taken to the medical industries, the surviving men and women from these drives are then sold to zoos and fairs for exhibition. In other cases they are allowed to be made as pets, but are normally tied up or muzzled. Tame men in clothes, which by the simian's viewpoint was comical.
Humans in the wild have an innate hatred for apes and anything associated with them, clothing, articles of civilization causes agitation and fear in them. The mere sight evoking irrational violence. The apes, attempting to discover their evolutionary origins, once believed that apes were descended from man, however contemporary chimpanzee scientists now know ape and man are two separate branches of evolutionary that had evolved from a common ancestor. The apes' stance on man's evolutionary process is that man was handicapped at birth, bereft with only two clumsy hands and thus unable to visualize and fully utilize tools as compared to apes. According to Zira, the men of Soror may have at one point attempted to relearn tool use, but failed miserably.
81singes31
A Woman Subjected to the Ape's Torturous Experiments
At one point its revealed that the Institute for Advanced Biological Study had succeeded in educating a man to accomplish many things. Sadly however his education was for not when the apes dissected his brain leaving him less than a stupid animal. When Ulysse intelligence was raised into question after he effortlessly succeeded in passing numerous reactionary tests, the orangutans wanted to transfer him to the medical ward dealing with complex brain procedures. He would have most likely suffered the same fate if not for Zira's intervention.
However this would suggest that the men of Soror's failure to regain their status as intelligent beings may not necessarily be attributed to their mental shortcomings. But perhaps due to interference by the apes through not only territorial encroachment and over-hunting, but also through the abuse of their medical sciences. Promising specimens that could encourage the species' gene pool are killed in the wild by overzealous gorilla hunters; those kept in captivity that may show potential are studied until the apes deem their existence a nuisance to simian dominance and are eliminated in the name of science. It is clear that with the right motivation and minimal simian interference, man can rise through from their barbarity on Soror, as was shown with Nova, Soror's only human to be successfully be uplifted.
Mating Habits Edit
Due to the regression from civilized life, man has developed a complex ritual in courtship. Through studies conducted by the chimpanzees at the Institute, it has been observed each man courted his woman before approaching her. He indulged in a display similar in every way to that executed by certain birds: a sort of slow, hesitant dance consisting of steps forward, backward, and sideways. He moved thus in an ever-decreasing circle, a circle whose center was occupied by the woman, who merely pivoted around without shifting from her position awaiting copulation that concluded these preliminaries.
Apes Edit
Book46
"Ape's brain," Zira concluded, "has developed, is complex and organized, whereas man's has hardly undergone any transformation."
The apes on Soror were originally servants and pets of men tens of thousands of years ago. Due to the apes innate mimicry their ancestors imitated the roles of their former master and effectively assumed the roles of rulers of Soror.
Culture Edit
81singes25
Simian culture is remarkably similar to 20th century Earth, albeit for a few cultural differences. Due to the simians arboreal legacies, their society is adapted to their origins: Streets being crossed through the use of overhanging bars, boxing being conducted on springs and in the air; ape lovers making love in the dense boughs of trees; thick gloves instead of shoes; etc. The apes are not divided into nations. The whole planet is administered by a council of ministers, at the head of which is a triumvirate consisting of one gorilla, one orangutan, and one chimpanzee. In conjunction with this government, there is also a parliament composed of three chambers: the Chamber of Gorillas, of Orangutans, and of Chimpanzees, each of which attends to the interests of its respective members. The apes have no military but a global police force that maintains order on the planet.
To explain their evolutionary origins, simian scientists theorize that equipped with four hands may be one of the most important factors in their spiritual evolution. Their innate talents may have helped them to climb trees, and thereby conceive the three dimensions of space. A taste for tools came next due to the potentiality of using four hands with dexterity.
Gorillas Edit
Gorillas are the statesmen of simian civilization. In the past they preserved a lust for power which they maintain as organizer and directors. They love hunting and life in the open air. The poorest of them are engaged on work that requires physical strength. When new discoveries are made by either of the other two ape families, it is usually a gorilla that will exploit the invention to derive every benefit. For the most part the gorillas occupy the roles of hunters. This is a function more or less reserved for them. They capture wild animals and, in particular, men. They act as a whole tribe of hunters, beaters, porters, and tradesmen devoted to this industry. Other apes view them as meat eaters, due to their propensity for killing. Their favorite past-time is shooting, a hobby that has caused the near endangerment for man as a species on their world.
Orangutans Edit
Orangutans occupy and compete with the chimpanzees in matters of intellectual debates. They are traditionalists and looked upon as official ministers of science. But some of them occasionally indulge in politics, the arts, and literature. They possess good memory, and learn an enormous amount by heart and from books. Then they themselves write other books, in which they repeat what they have read, thereby earning the respect of their fellow orangutans.
Chimpanzees Edit
Chimpanzees represent the intellectual element of the planet. It is not an idle boast that all the great discoveries have been made by them. Many chimpanzees are credited to leading reforms in simian society.
External LinksEdit
ReferencesEdit
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8,271,204,414,737,320,000 | EMBL announces ARISE, the Career Accelerator for Research Infrastructure Scientists
EMBL's ARISE fellowship program offers fellowships for experienced professionals with a background in science, technology, engineering, or mathematics who wish to advance technology development in the life sciences and receive training to operate life science research infrastructures, which provide novel technologies as a service for life scientists.
Between 2021 and 2025, ARISE will award 62 three-year fellowships to talented technology experts to develop new technologies for the life sciences that can be included in the service offers of worldwide research infrastructures operating in the fields of imaging, bioinformatics, structural biology, genomics, proteomics, metabolomics and (bio)chemical engineering.
Each ARISE fellow will be hosted by one EMBL group or team at one of EMBL's six sites (Barcelona, Grenoble, Hamburg, Heidelberg, Hinxton, or Rome). Their group and team leaders all have a track record in developing new methods and technologies, providing these as a service, and applying them to answer novel scientific questions.
More information can be found here. | {
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-1,289,368,204,621,510,000 |
University of Cambridge > Talks.cam > Departmental Seminar Programme, Department of Veterinary Medicine > Debunking the Neandertal myth
Debunking the Neandertal myth
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If you have a question about this talk, please contact Fiona Roby.
The publication of the Neandertal and other archaic human genomes has led to the widespread acceptance that inter-breeding occurred and that modern non-African humans carry a few percent of Neandertal DNA . However, the analysis on which this conclusion is based makes a number of assumptions, notably that mutation rate is, and has been, constant. Relaxing this assumption reveals that a better fitting explanation involves mutation rate slowing as humans left Africa.
This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.
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-31,226,920,145,434,760 | Set Analyses:
Advanced Search
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Search By
Section (entire)
for
SLC25A30 Gene
protein-coding GIFtS: 50
GCID: GC13M045967
Solute Carrier Family 25, Member 30
Try our
disease database
(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
About This Section
Aliases
Solute Carrier Family 25, Member 301 2
KMCP12 3 5
Kidney Mitochondrial Carrier Protein 12
Solute Carrier Family 25 Member 303
External Ids: HGNC: 273711 Entrez Gene: 2535122 Ensembl: ENSG000001740327 OMIM: 6107935 UniProtKB: Q5SVS43
Export aliases for SLC25A30 gene to outside databases
Previous GC identifers: GC13M043766 GC13M044865 GC13M026765
(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section
Entrez Gene summary for SLC25A30 Gene:
Although the outer mitochondrial membrane is permeable to many small metabolites, transport of solutes across the
inner mitochondrial membrane is achieved by members of the mitochondrial carrier protein family, such as SLC25A30
(Haguenauer et al., 2005 (PubMed 15809292)).(supplied by OMIM, Mar 2008)
GeneCards Summary for SLC25A30 Gene:
SLC25A30 (solute carrier family 25, member 30) is a protein-coding gene. An important paralog of this gene is UCP3.
UniProtKB/Swiss-Prot: KMCP1_HUMAN, Q5SVS4
Function: Probable transporter (By similarity)
(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
About This Section
RefSeq DNA sequence at NCBI GenBank:
NC_000013.10 NT_024524.15 NC_018924.2
Regulatory elements:
Regulatory transcription factor binding sites in the SLC25A30 gene promoter:
SRF AML1a SRF (504 AA) CUTL1 POU3F2 GATA-2 MEF-2A aMEF-2 ZIC2/Zic2 RSRFC4
Other transcription factors
SwitchGear Promoter luciferase reporter plasmidSLC25A30 promoter sequence
Search Chromatin IP Primers for SLC25A30
Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat SLC25A30
Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track
Entrez Gene cytogenetic band: 13q14.13 Ensembl cytogenetic band: 13q14.13 HGNC cytogenetic band: 13q14
SLC25A30 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
SLC25A30 gene location
GeneLoc information about chromosome 13 GeneLoc Exon Structure
GeneLoc location for GC13M045967: view genomic region (about GC identifiers)
Start:
45,967,451 bp from pter End:
45,992,590 bp from pter
Size:
25,140 bases Orientation:
minus strand
(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, Cloud-Clone Corp., eBioscience, and/or antibodies-online,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, Cloud-Clone Corp., eBioscience, and/or antibodies-online, Antibodies by EMD Millipore, R&D Systems, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, Cloud-Clone Corp, antibodies-online, and/or others.)
About This Section
UniProtKB/Swiss-Prot: KMCP1_HUMAN, Q5SVS4 (See protein sequence)
Recommended Name: Kidney mitochondrial carrier protein 1
Size: 291 amino acids; 32475 Da
Secondary accessions: B2RN96
Explore the universe of human proteins at neXtProt for SLC25A30: NX_Q5SVS4
Explore proteomics data for SLC25A30 at MOPED
Post-translational modifications:
• Modification sites at neXtProt
• Modification sites at PhosphoSitePlus
• See SLC25A30 Protein Expression from SPIRE MOPED, PaxDB, and MaxQB
REFSEQ proteins (3 alternative transcripts):
NP_001010875.1 NP_001273735.1 NP_001273736.1
ENSEMBL proteins:
ENSP00000429168 ENSP00000311856 ENSP00000429308 ENSP00000430687 ENSP00000425603
ENSP00000443542
SLC25A30 Human Recombinant Protein Products:
Browse Purified and Recombinant Proteins at EMD Millipore
Browse R&D Systems for human recombinant proteins
Browse recombinant and purified proteins available from Enzo Life Sciences
Browse OriGene full length recombinant human proteins expressed in human HEK293 cells
OriGene Protein Over-expression Lysate for SLC25A30
OriGene Custom MassSpec
OriGene Custom Protein Services for SLC25A30
GenScript Custom Purified and Recombinant Proteins Services for SLC25A30
Novus Biologicals SLC25A30 Protein
Browse Sino Biological Recombinant Proteins
Browse Sino Biological Cell Lysates
Browse ProSpec Recombinant Proteins
Cloud-Clone Corp. Proteins for SLC25A30
Search eBioscience for Proteins for SLC25A30
antibodies-online proteins for SLC25A30
antibodies-online peptides for SLC25A30
SLC25A30 Antibody Products:
Browse EMD Millipore's Extensive Line of Mono- and Polyclonal Antibodies
Browse R&D Systems for Antibodies
Browse OriGene Antibodies
OriGene Custom Antibody Services for SLC25A30
Novus Biologicals SLC25A30 Antibody
Search for Antibodies for SLC25A30 at Abcam
Cloud-Clone Corp. Antibodies for SLC25A30
Search ThermoFisher Antibodies for SLC25A30
antibodies-online antibodies for SLC25A30 (2 products)
SLC25A30 Assay Products:
Browse Kits and Assays available from EMD Millipore
OriGene Custom Assay Services for SLC25A30
Browse R&D Systems for biochemical assays
GenScript Custom Assay Services for SLC25A30
Browse Enzo Life Sciences for kits & assays
Cloud-Clone Corp. ELISAs for SLC25A30
Cloud-Clone Corp. CLIAs for SLC25A30
Search eBioscience for ELISAs for SLC25A30
antibodies-online kits for SLC25A30 (6 products)
(According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section
HGNC Gene Families:
SLC: Solute carriers
IUPHAR Guide to PHARMACOLOGY protein family classification: KMCP1
Miscellaneous SLC25 mitochondrial transporters
3 InterPro protein domains:
IPR023395 Mt_carrier_dom
IPR002030 Mit_uncoupling
IPR018108 Mitochondrial_sb/sol_carrier
Graphical View of Domain Structure for InterPro Entry Q5SVS4
ProtoNet protein and cluster: Q5SVS4
1 Blocks protein domain: IPB002030 Mitochondrial brown fat uncoupling protein signature
UniProtKB/Swiss-Prot: KMCP1_HUMAN, Q5SVS4
Similarity: Belongs to the mitochondrial carrier (TC 2.A.29) family
Similarity: Contains 3 Solcar repeats
Find genes that share domains with SLC25A30 About GenesLikeMe
(According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, genOway,
transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, Vector BioLabs and/or Addgene, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Flow cytometry from eBioscience, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
About This Section
Molecular Function:
UniProtKB/Swiss-Prot Summary: KMCP1_HUMAN, Q5SVS4
Function: Probable transporter (By similarity)
Gene Ontology (GO): 1 molecular function term: About this table
GO IDQualified GO termEvidencePubMed IDs
GO:0003674molecular_function ND--
Find genes that share ontologies with SLC25A30 About GenesLikeMe
Phenotypes:
1 GenomeRNAi human phenotype for SLC25A30:
Lamellipodia and high actin ra
3 MGI mutant phenotypes (inferred from 1 allele(MGI details for Slc25a30):
adipose tissue growth/size/body skeleton
Find genes that share phenotypes with SLC25A30 About GenesLikeMe
Animal Models:
genOway: Develop your customized and physiologically relevant rodent model for SLC25A30
miRNA
Products:
miRTarBase miRNAs that target SLC25A30:
hsa-mir-335-5p (MIRT018190), hsa-mir-1 (MIRT002777), hsa-mir-192-5p (MIRT026526), hsa-mir-124-3p (MIRT002682), hsa-mir-10b-5p (MIRT047420), hsa-mir-9-5p (MIRT021436), hsa-mir-122-5p (MIRT023277), hsa-mir-26a-5p (MIRT050172)
Block miRNA regulation of human, mouse, rat SLC25A30 using miScript Target Protectors
Selected qRT-PCR Assays for microRNAs that regulate SLC25A30 (see all 34):
hsa-miR-548j hsa-miR-30d hsa-miR-570 hsa-miR-1276 hsa-miR-124 hsa-miR-30a hsa-miR-508-5p hsa-miR-506
Browse SwitchGear 3'UTR luciferase reporter plasmids
Inhib. RNA
Products:
OriGene RNAi products in human, mouse, rat for SLC25A30
Predesigned siRNA for gene silencing in human, mouse, rat SLC25A30
Gene Editing
Products:
DNA2.0 Custom Protein Engineering Service for SLC25A30
Clone
Products:
OriGene clones in human, mouse for SLC25A30 (see all 8)
OriGene ORF clones in mouse, rat for SLC25A30
OriGene custom cloning services - gene synthesis, subcloning, mutagenesis, variant library, vector shuttling
GenScript: all cDNA clones in your preferred vector: SLC25A30 (NM_001010875)
Sino Biological Human cDNA Clone for SLC25A30
DNA2.0 Custom Codon Optimized Gene Synthesis Service for SLC25A30
Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat SLC25A30
Cell Line
Products:
GenScript Custom overexpressing Cell Line Services for SLC25A30
Browse ESI BIO Cell Lines and PureStem Progenitors for SLC25A30
In Situ Assay
Products:
Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for SLC25A30
(According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
About This Section
Subcellular locations from UniProtKB/Swiss-Prot
KMCP1_HUMAN, Q5SVS4: Mitochondrion inner membrane; Multi-pass membrane protein (By similarity)
Subcellular locations from COMPARTMENTS:
CompartmentConfidence
mitochondrion5
cytosol2
peroxisome2
extracellular1
nucleus1
Gene Ontology (GO): 4 cellular component terms: About this table
GO IDQualified GO termEvidencePubMed IDs
GO:0005739mitochondrion ISS15809292
GO:0005743mitochondrial inner membrane IEA--
GO:0016021integral component of membrane IEA--
GO:0031966mitochondrial membrane ----
Find genes that share ontologies with SLC25A30 About GenesLikeMe
(SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
About This Section
Pathway & Disease-focused RT2 Profiler PCR Array including SLC25A30:
Mitochondria in human mouse rat
Interactions:
Search GeneGlobe Interaction Network for SLC25A30
STRING Interaction Network Preview (showing 1 interactants - click image to see more details)
1 Interacting protein for SLC25A30 (ENSP000003118564) via UniProtKB, MINT, STRING, and/or I2D
InteractantInteraction Details
GeneCardExternal ID(s)
UBCENSP000003448184STRING: ENSP00000344818
About this table
Gene Ontology (GO): 3 biological process terms: About this table
GO IDQualified GO termEvidencePubMed IDs
GO:0006810transport ----
GO:0006839mitochondrial transport IEA--
GO:0008150biological_process ND--
Find genes that share ontologies with SLC25A30 About GenesLikeMe
(Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
About This Section
Browse Small Molecules at EMD Millipore
Browse drugs & compounds from Enzo Life Sciences
Browse compounds at ApexBio
Browse Tocris compounds for SLC25A30 (KMCP1)
(Secondary structures according to fRNAdb,
GenBank/EMBL/DDBJ Accessions according to
Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
RefSeq according to Entrez Gene,
DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, and/or Addgene, Primers from OriGene, and/or QIAGEN, Flow cytometry from eBioscience )
About This Section
REFSEQ mRNAs for SLC25A30 gene (3 alternative transcripts):
NM_001010875.3 NM_001286806.1 NM_001286807.1
Unigene Cluster for SLC25A30:
Solute carrier family 25, member 30
Hs.591230 [show with all ESTs]
Unigene Representative Sequence: AL832206
7 Ensembl transcripts including schematic representations, and UCSC links where relevant:
ENST00000523988(uc001vaf.3) ENST00000519676(uc001vag.3 uc010tfs.2 uc010tft.2 uc001vah.3)
ENST00000310862 ENST00000519547 ENST00000522438 ENST00000463262 ENST00000539591
miRNA
Products:
Block miRNA regulation of human, mouse, rat SLC25A30 using miScript Target Protectors
Selected qRT-PCR Assays for microRNAs that regulate SLC25A30 (see all 34):
hsa-miR-548j hsa-miR-30d hsa-miR-570 hsa-miR-1276 hsa-miR-124 hsa-miR-30a hsa-miR-508-5p hsa-miR-506
Browse SwitchGear 3'UTR luciferase reporter plasmids
Inhib. RNA
Products:
OriGene RNAi products in human, mouse, rat for SLC25A30
Predesigned siRNA for gene silencing in human, mouse, rat SLC25A30
Clone
Products:
OriGene clones in human, mouse for SLC25A30 (see all 8)
OriGene ORF clones in mouse, rat for SLC25A30
OriGene custom cloning services - gene synthesis, subcloning, mutagenesis, variant library, vector shuttling
GenScript: all cDNA clones in your preferred vector: SLC25A30 (NM_001010875)
DNA2.0 Custom Codon Optimized Gene Synthesis Service for SLC25A30
Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat SLC25A30
Primer
Products:
OriGene qSTAR qPCR primer pairs in human, mouse for SLC25A30
Pre-validated RT2 qPCR Primer Assay in human, mouse, rat SLC25A30
QuantiTect SYBR Green Assays in human, mouse, rat SLC25A30
QuantiFast Probe-based Assays in human, mouse, rat SLC25A30
Additional mRNA sequence:
AK074457.1 AK094133.1 AK095465.1 AK302967.1 AL832206.1 BC129808.1 BC132739.1 BC136760.1
BC144401.1 CR627474.1
7 DOTS entries:
DT.95366482 DT.410890 DT.40129370 DT.95366479 DT.95200961 DT.91748893 DT.95227324
Selected AceView cDNA sequences (see all 79):
AW195328 AW770026 AI800527 CB850989 BE465815 AK095465 AL832206 BF001919
Z44480 BF194826 BU740496 AI651408 AW338475 AI888763 AI522325 AI767440
AI273581 C04249 AW294068 BF111608 CA422444 F05208 BE048788 BQ000885
GeneLoc Exon Structure
5 Alternative Splicing Database (ASD) splice patterns (SP) for SLC25A30 About this scheme
ExUns: 1a · 1b ^ 2 ^ 3 ^ 4 ^ 5 ^ 6 ^ 7a · 7b ^ 8 ^ 9 ^ 10 ^ 11 ^ 12a · 12b
SP1: - -
SP2: - - -
SP3:
SP4: - - -
SP5:
ECgene alternative splicing isoforms for SLC25A30
(RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
About This Section
SLC25A30 expression in normal human tissues (normalized intensities)
See probesets specificity/sensitivity at GeneAnnot
About this imageBioGPS <intensity>2/3
CGAP TAG: TGCTAGAAAT
SLC25A30 Expression
About this image
SLC25A30 Protein expression data from MOPED1, PaxDb2 and MaxQB3 About this image
SLC25A30 Protein Expression
SOURCE GeneReport for Unigene cluster: Hs.591230
Pathway & Disease-focused RT2 Profiler PCR Array including SLC25A30:
Mitochondria in human mouse rat
Primer
Products:
OriGene qSTAR qPCR primer pairs in human, mouse for SLC25A30
Pre-validated RT2 qPCR Primer Assay in human, mouse, rat SLC25A30
QuantiTect SYBR Green Assays in human, mouse, rat SLC25A30
QuantiFast Probe-based Assays in human, mouse, rat SLC25A30
In Situ
Assay Products:
Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for SLC25A30
(Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
About This Section
This gene was present in the common ancestor of animals.
Orthologs for SLC25A30 gene from Selected species (see all 13) About this table
Organism Taxonomic
classification
Gene Description Human
Similarity
Orthology
Type
Details
mouse
(Mus musculus)
Mammalia Slc25a301 , 5 solute carrier family 25, member 301, 5 85.45(n)1
92.44(a)1
14 (40.29 cM)5
675541 NM_026232.31 NP_080508.11
757619995
chicken
(Gallus gallus)
Aves SLC25A301 solute carrier family 25, member 30 77.09(n)
86.6(a)
418845 XM_417040.4 XP_417040.3
lizard
(Anolis carolinensis)
Reptilia SLC25A306
solute carrier family 25, member 30
75(a)
1 ↔ 1
GL343395.1(773695-790173)
tropical clawed frog
(Xenopus tropicalis)
Amphibia LOC3948402 hypothetical protein LOC394840 79.22(n) BC063207.1
zebrafish
(Danio rerio)
Actinopterygii zgc555962 similar to solute carrier family 25 (mitochondrial more 76.02(n) 393133 BC045395.1
fruit fly
(Drosophila melanogaster)
Insecta Bmcp1 Bmcp 59.57(n)
62.06(a)
39322 NM_140244.5 NP_648501.1
ENSEMBL Gene Tree for SLC25A30 (if available)
TreeFam Gene Tree for SLC25A30 (if available)
(Paralogs according to 1HomoloGene,
2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
About This Section
Paralogs for SLC25A30 gene
UCP32 UCP12 UCP22 SLC25A142 SLC25A112 ENSG000002626602 SLC25A102 SLC25A272
11 SIMAP similar genes for SLC25A30 using alignment to 5 protein entries: KMCP1_HUMAN (see all proteins):
SLC25A14 SLC25A27 UCP2 UCP1 UCP3 SLC25A22
SLC25A11 SLC25A10 SLC25A19 SLC25A34 SLC25A35
Find genes that share paralogs with SLC25A30 About GenesLikeMe
(SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
About This Section
Selected SNPs for SLC25A30 (see all 475) About this table
Genomic DataTranscription Related DataAllele Frequencies
SNP IDValidClinical
significance
Chr 13 posSequence#AA
Chg
TypeMore#Allele
freq
PopTotal
sample
More
----------
rs1817965501,2
C--26792561(+) TGAATG/TTTTTA 1 -- us2k10--------
rs1433137111,2
C--26792611(+) GTGTCC/TATTAT 1 -- us2k10--------
rs1467252131,2
--26792784(+) CTCACA/GTCTAT 1 -- us2k10--------
rs58032961,2
C--45966980(+) ATGCTAA/-AACAG 1 -- ds50011Minor allele frequency- -:0.00NA 2
rs128685921,2
C,F--45967193(+) TTCGAA/GTGCCA 1 -- ds50014Minor allele frequency- G:0.10NA EA 244
rs1910378751,2
--45967539(+) AGCTTC/GAAATA 1 -- ut310--------
rs1149763601,2
C,F--45967610(+) AAATAT/CAAAGG 1 -- ut311Minor allele frequency- C:0.05WA 118
rs788966521,2
C,F--45967673(+) CACAAA/GTCCAT 1 -- ut311Minor allele frequency- G:0.02EA 120
rs1828311791,2
--45967806(+) CCCAAC/TTCCTT 1 -- ut310--------
rs1884837341,2
--45967936(+) GCTTTG/TATCTT 1 -- ut310--------
HapMap Linkage Disequilibrium report for SLC25A30 (45967451 - 45992590 bp)
Structural Variations
Database of Genomic Variants (DGV) 3 variations for SLC25A30: About this table
Variant IDTypeSubtypePubMed ID
dgv250e201CNV Deletion23290073
nsv510579CNV Loss20534489
nsv455875CNV Loss19166990
Site Specific Mutation Identification with PCR Assays
SeqTarget long-range PCR primers for resequencing SLC25A30
DNA2.0 Custom Variant and Variant Library Synthesis for SLC25A30
(in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
About This Section
OMIM gene information: 610793 OMIM disorders: --
Find genes that share disorders with SLC25A30 About GenesLikeMe
Genetic Association Database (GAD): SLC25A30
Human Genome Epidemiology (HuGE) Navigator: SLC25A30 (1 document)
Export disorders for SLC25A30 gene to outside databases
(in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
About This Section
PubMed articles for SLC25A30 gene integrated from 10 sources:
(articles sorted by number of sources associating them with SLC25A30)
Utopia: connect your pdf to the dynamic
world of online information
1. Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression. (PubMed id 20877624)1, 4 Hendrickson S.L....O'Brien S.J. (PLoS ONE 2010)
2. A new renal mitochondrial carrier, KMCP1, is up-regulated during tubular cell regeneration and induction of antioxidant enzymes. (PubMed id 15809292)1, 9 Haguenauer A....Pecqueur C. (J. Biol. Chem. 2005)
3. The mitochondrial transporter family SLC25: identification, properties and physiopathology. (PubMed id 23266187)1 Palmieri F. (Mol. Aspects Med. 2013)
4. Systematic and quantitative assessment of the ubiquitin-modified proteome. (PubMed id 21906983)1 Kim W....Gygi S.P. (Mol. Cell 2011)
5. Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. (PubMed id 16344560)1 Kimura K.... Sugano S. (Genome Res. 2006)
6. The DNA sequence and analysis of human chromosome 13. (PubMed id 15057823)2 Dunham A.... Ross M.T. (Nature 2004)
7. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). (PubMed id 15489334)2 Gerhard D.S.... Malek J. (Genome Res. 2004)
8. Complete sequencing and characterization of 21,243 full-length human cDNAs. (PubMed id 14702039)1 Ota T.... Sugano S. (Nat. Genet. 2004)
9. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. (PubMed id 12477932)1 Strausberg R.L....Marra M.A. (Proc. Natl. Acad. Sci. U.S.A. 2002)
(in PubMed, OMIM, and NCBI Bookshelf)
About This Section
ANDOR
Aliases
Free Text
Query String
PubMed
OMIM
NCBI Bookshelf
(Note: In FireFox, select the above section and copy using Ctrl-C)
(According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
About This Section
Entrez Gene: 253512 HGNC: 27371 AceView: SLC25A30 Ensembl:ENSG00000174032 euGenes: HUgn253512
ECgene: SLC25A30 H-InvDB: SLC25A30
(According to HUGE)
About This Section
--
(According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
About This Section
NameDescription
PharmGKB entry for SLC25A30 Pharmacogenomics, SNPs, Pathways
(Patent information from GeneIP,
Licensable technologies from WIS Yeda, Salk, Tufts,
IP news from LifeMap Sciences, Inc.)
About This Section
Patent Information for SLC25A30 gene:
Search GeneIP for patents involving SLC25A30
GeneCards and IP:
Japan Patent Office Licenses GeneCards European Patent Office Licenses GeneCards Improving the IP Search
(Antibodies, recombinant proteins, and assays from EMD Millipore, R&D Systems, OriGene, QIAGEN, GenScript, Cell Signaling Technology, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Cloud-Clone Corp., Thermo Fisher Scientific, eBioscience, antibodies-online, and/or others, Gene Editing from DNA2.0. Clones from OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Addgene, Cell lines from GenScript, and ESI BIO, Flow cytometery from eBioscience, PCR Arrays from QIAGEN, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, Enzo Life Sciences, and/or ApexBio, In Situ Hybridization Assays from
Advanced Cell Diagnostics, Animal models from genOway)
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Hot genes Disease genes SLC25A30 gene at Home site.
Version: 3.12.314 1 Feb 2015
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-1,341,542,412,116,736,500 | close
800px-2007_WSJ_Prince_William
Revealed: the Indian ancestry of (Prince) William’ claims today’s Times headline. The story, covered over 3 pages, revolves around Eliza Kewark, the future King’s great great great great great grandmother. Kewark (or Kevork) has been described in the past as Armenian, although she was known to reside in India. Here she lived conjugally with a colonial merchant called Theodore Forbes, and produced a daughter Katherine who was eventually raised in Scotland. If we follow Katherine’s maternal line of descent from mother to daughter we reach Diana Spencer.
The science behind the headlines involves mitochondrial DNA. Mitochondria are microscopic structures present in every cell in our bodies, whose principal function is providing energy in the form of ATP. Interestingly, mitochondria have their own genetic heritage. Mitochondria are believed to descend from symbiotic bacteria whose energy providing benefits led to them being taken up by primitive cells 1.5 billion years ago. Traces of the bacterial DNA remain within mitochondria, and genetic differences (mutations) in this DNA allow us track the ancestry of human populations. Mitochondria are always inherited from the mother, since they are present in large numbers in the egg at the time of fertilisation. Thus by investigating mitochondrial DNA we can trace maternal ancestry. It is simple to provide a cheek swab sample suitable for DNA analysis, in fact this is the method commonly used by the police as well as genetics researchers.
Research laboratories use mitochondrial DNA for investigation of the genetics of populations, and these findings often provide evidence for past events that lack tangible written support. People researching their family history are also enthusiastic about the use of genetics, whether it is to formally demonstrate the common ancestry of two relatives, or to pursue links with ancient cultures.
Getting back to Prince William, it seems that he has not personally provided a DNA sample, but instead we are able to infer his mitochondrial DNA result with reasonable certainty from the results of two of his maternal relatives. Through a process of triangulation, these samples can be used to determine the type of mitochondrial DNA carried by Eliza Kewark. The results of these tests appear unequivocal: the two people tested both carry a rare type of mitochondrial DNA called R30b, which has previously only been found in India and Nepal. The Times story states that other genetic markers found in the genomes of the DNA donors also provide evidence for south Asian ancestry. Thus it seems that Eliza Kewark was likely to have Indian maternal ancestry, even if her paternal lineage was Armenian.
It is not surprising that members of the royal family are of foreign descent: after all, William’s other ancestors include dozens of European royals. It is however interesting that the future king can claim Indian ancestry – a reminder perhaps of the interconnections that have long brought the world together. The news therefore shows the potential for historical genetics to enrich our understanding of history, as indeed the Times editorial emphasises, talking about Anglo-Indian relations and the power of genetic research to assist historical investigations.
But there are other reasons why this research is hitting the headlines. Dr Jim Wilson of Edinburgh University is the scientist who conducted the genetic tests. Interestingly, Dr Wilson is scientific director of BritainsDNA, a company providing commercial genetic ancestry testing. The Times is providing excellent publicity for BritainsDNA, including a “Readers offer” on page 4 of the paper. There are a number of companies providing similar genetic ancestry tests, but BritainsDNA seems to have the most efficient media team, making headlines with a number of studies earlier in the year, even if according to geneticists at UCL not all of these stories should be taken at face value.
Dr Andy Grierson is Senior Lecturer in Neuroscience at SiTraN in Sheffield, with an interest in the developing field of historical genetics.
Tags : DNA testingmitochondrial DNAPrince WilliamPrince William's Indian ancestry
Andrew Grierson
The author Andrew Grierson
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443,376,769,012,734,660 | Regular Bio Mid-Term
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Created by:
swimmychick on December 12, 2011
Subjects:
biology
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Regular Bio Mid-Term
hypothesis
wild guess about a specific thing
1/12
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hypothesis wild guess about a specific thing
Hypothesis-->Theory-->Law hypothesis-->....-->...
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reproduce, response to environment, use energy, transport, organizes and complez characteristics of Living things
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9,089,123,604,346,931,000 | The UK's Biotechnology and Biological Sciences Research Council has said that it will invest around £20 million ($32 million) in six synthetic biology research projects in the country, which will focus on global challenges such as producing low-carbon fuels and reducing the cost of industrial raw materials.
The financial support will also help build a synthetic biology research community in the UK, the BBSRC says.
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The New York Times and ProPublica look into the close relationship between a startup and Memorial Sloan Kettering Cancer Center.
Yahoo News reports millions of dollars are being transferred from NIH, CDC, and other programs to pay for the housing of detained undocumented immigrant children.
In Science this week: in vitro generation of human reproductive cells, and more.
Researchers gave a handful of octopuses MDMA to find that they too act more social on the drug, Gizmodo reports. | {
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-3,809,207,462,481,853,000 | Advertisement
Journal of the History of Biology
, Volume 25, Issue 2, pp 307–333 | Cite as
Darwin and domestication: Studies on inheritance
• Mary M. Bartley
Article
Conclusions
While Wallace disagreed with Darwin that domesticates provided a great deal of useful information on wild populations,71 Darwin continued to draw on his domesticated animals and plants to inform him on the workings of his theory. Unlike Wallace, his exposure to natural populations was extremely limited after his return from the Beagle voyage. By the 1850s, he had settled into a life at Down House and was becoming more and more withdrawn from London scientific circles. He turned to his network of informants, visits from colleagues such as Hooker and T. H. Huxley, subscriptions to various journals, and his own experimental studies at Down.
This work on domesticates was clearly related to other natural history studies conducted by Darwin and others during the same period. For example, during the 1850s when Darwin worked on domesticates, he was also engaged in questions of geographic distribution. To study the dispersal and subsequent viability of introduced seeds, he soaked various seeds in a tub filled with seawater and counted which of the seeds floated after a given period; later he planted the seeds in the yard at Down to look for potential viability. There was no attempt at controlled, replicated experiments in these studies, or in his work with domesticates, nor should there have been. To Darwin the results of one experiment represented a potential truth of nature, and he was quick to seize upon these results as supporting evidence for his theory.
I have suggested in this paper that his work on domesticates was not simply meant to provide an analogy for natural selection but rather became a research program to investigate other aspects of his natural selection theory, especially inheritance and variability; these subjects were integral parts of his theory of natural selection, but by 1859 he had not found a mechanism to account for them. The experiments brought home the difficult problems of inheritance, and Darwin specifically formulated pangenesis to account for these problems. Pangenesis was not an afterthought but an integration of several decades of thinking on inheritance. It was a unified theory to explain the complicated results he witnessed in his own experiments.
Much of the Darwin scholarship has focused on Darwin's path toward the discovery of natural selection. Natural selection per se was a major interest, but not the only area of interest to Darwin. Inheritance was an area of serious concern for him both before and after he had formulated natural selection. His experimentation with domesticates was an attempt to look beyond natural selection and to concentrate on the difficult subject of inheritance. He found inheritance especially troublesome, requiring a “provisional hypothesis” to account for it. To see domesticates, as they are described in the Origin, as merely an analogy for natural selection, does not account for the importance Darwin placed on them. For him they were not man's monstrous productions, but worthy experimental subjects providing him with crucial information on inheritance.
Keywords
Natural Selection Wild Population Domesticate Animal Supporting Evidence Unify Theory
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Preview
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Copyright information
© Kluwer Academic Publishers 1992
Authors and Affiliations
• Mary M. Bartley
• 1
1. 1.Section of Ecology and SystematicsCornell UniversityIthacaUSA
Personalised recommendations | {
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4,969,278,549,464,296,000 | Emilio Segrè Visual Archives
More than 30,000 photos of scientists and their work
Harwit Martin C1
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Harwit Martin C1
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Image title:
Martin Harwit with father
Credit line:
Foto Sonmez, Eminonu, Istanbul, courtesy AIP Emilio Segrè Visual Archives, Harwit Collection
Description:
Martin Harwit age 9, with his father, Felix M. Haurowitz in Istanbul. Felix Haurowitz was a Professor of Biochemistry on the Medical Faculty of Istanbul University. The family had left their native Czechoslovakia just after the German occupation of Prague in March 1939.
Photo date:
circa 1940
Person(s):
Haurowitz, Felix, 1896-1987
Harwit, Martin, 1931-
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9 SASI_Hs02_00376883 predicted 90
10 SASI_Hs02_00376884 predicted 15 | {
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"label": "Product Page"
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"label": "No Reasoning"
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-3,464,690,670,409,310,700 | Set Analyses:
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Section (entire)
for
TRAV40 Gene
protein-coding GIFtS: 18
GCID: GC14P022855
T Cell Receptor Alpha Variable 40
See related diseases
at
(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
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Aliases
T Cell Receptor Alpha Variable 401 2
TCRAV31S12
TCRAV40S12
External Ids: HGNC: 121411 Entrez Gene: 286412 Ensembl: ENSG000002118197
Export aliases for TRAV40 gene to outside databases
Previous GC identifers: GC14U990278 GC14P020773 GC14P021852 GC14P022783 GC14P022784
(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
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GeneCards Summary for TRAV40 Gene:
TRAV40 (T cell receptor alpha variable 40) is a protein-coding gene. Diseases associated with TRAV40 include t-cell leukemia, and obesity. An important paralog of this gene is TRAV8-7.
(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
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Regulatory elements:
Search for regulatory transcription factor binding sites for TRAV40
Other transcription factors
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Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat TRAV40
Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track
Entrez Gene cytogenetic band: 14q11 Ensembl cytogenetic band: 14q11.2 HGNC cytogenetic band: 14q11.2
TRAV40 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
TRAV40 gene location
GeneLoc information about chromosome 14 GeneLoc Exon Structure
GeneLoc location for GC14P022855: view genomic region (about GC identifiers)
Start:
22,782,922 bp from pter End:
22,783,351 bp from pter
Size:
430 bases Orientation:
plus strand
(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Cloud-Clone Corp.,
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UniProtKB: --
ENSEMBL proteins:
ENSP00000452585
TRAV40 Human Recombinant Protein Products:
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(According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
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HGNC Gene Families:
TRAS: T cell receptors / TRA locus
--
(According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, inGenious Targeting Laboratory, genOway,
transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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Gene Ontology (GO): 1 molecular function term: About this table
GO IDQualified GO termEvidencePubMed IDs
GO:0005515protein binding ----
TRAV40 for ontologies About GeneDecksing
Animal Models:
inGenious Targeting Laboratory: Let us create your new Knockout/Knockin mouse model for TRAV40
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(According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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--
(SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
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Custom Pathway & Disease-focused RT2 Profiler PCR Arrays for TRAV40
Interactions:
Search GeneGlobe Interaction Network for TRAV40
(Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
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Browse Small Molecules at EMD Millipore
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(Secondary structures according to fRNAdb,
GenBank/EMBL/DDBJ Accessions according to
Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
RefSeq according to Entrez Gene,
DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
Conferences by KenesGroup, exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, Primers from OriGene, and/or QIAGEN )
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1 Ensembl transcript including schematic representation, and UCSC links where relevant:
ENST00000390467(uc001wdq.2)
miRNA
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Primer
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QuantiTect SYBR Green Assays in human, mouse, rat TRAV40
QuantiFast Probe-based Assays in human, mouse, rat TRAV40
1 AceView cDNA sequence:
X70306
GeneLoc Exon Structure
(RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
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TRAV40 expression in normal human tissues (normalized intensities)
See probesets specificity/sensitivity at GeneAnnot
About this imageBioGPS <intensity>2/3
CGAP TAG: --
TRAV40 Expression
About this image
TRAV40 Protein expression data from MOPED1, PaxDb2 and MaxQB3 --
Custom PCR Arrays for TRAV40
Primer
Products:
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In Situ
Assay Products:
Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for TRAV40
(Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
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This gene was present in the common ancestor of chordates.
Orthologs for TRAV40 gene from Selected species (see all 5) About this table
Organism Taxonomic
classification
Gene Description Human
Similarity
Orthology
Type
Details
lizard
(Anolis carolinensis)
Reptilia --
--
(see all 4)
Uncharacterized protein
(see all 4)
29(a)
28(a)
(see all 4)
many ↔ many
many ↔ many
(see all 4)
GL343466.1(631652-633772)
GL343466.1(595325-596224)
Species with no ortholog for TRAV40
ENSEMBL Gene Tree for TRAV40 (if available)
TreeFam Gene Tree for TRAV40 (if available)
(Paralogs according to 1HomoloGene,
2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
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Paralogs for TRAV40 gene
TRAV8-72 TRAV162 TRAV9-12 TRAV8-32 TRAV8-62 TRAV8-42 TRAV32 TRAV8-12
TRAV8-22 TRAV182 TRAV9-22
TRAV40 for paralogs About GeneDecksing
(SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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Site Specific Mutation Identification with PCR Assays
Search QIAGEN SeqTarget long-range PCR primers for resequencing TRAV40
DNA2.0 Custom Variant and Variant Library Synthesis for TRAV40
(in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Conferences by KenesGroup, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
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3 diseases for TRAV40:
About MalaCards
t-cell leukemia obesity leukemia
TRAV40 for disorders About GeneDecksing
Human Genome Epidemiology (HuGE) Navigator: TRAV40 (1 document)
Export disorders for TRAV40 gene to outside databases
(in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
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PubMed articles for TRAV40 gene integrated from 10 sources:
(articles sorted by number of sources associating them with TRAV40)
Utopia: connect your pdf to the dynamic
world of online information
1. Molecular analysis of T-cell receptor transcripts in a human T-cell leukemia bearing a t(1;14) and an inv(7); cell surface expression of a TCR-beta chain in the absence of alpha chain. (PubMed id 8412327)1, 3 Bernard O....Azogui O. (Leukemia 1993)
2. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. (PubMed id 23251661)1 Comuzzie A.G....Butte N.F. (PLoS ONE 2012)
(in PubMed, OMIM, and NCBI Bookshelf)
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ANDOR
Aliases
Free Text
Query String
PubMed
OMIM
NCBI Bookshelf
(Note: In FireFox, select the above section and copy using Ctrl-C)
(According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
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Entrez Gene: 28641 HGNC: 12141 AceView: TRAV40 Ensembl:ENSG00000211819 euGenes: HUgn28641
ECgene: TRAV40 H-InvDB: TRAV40
(According to HUGE)
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--
(According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
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NameDescription
PharmGKB entry for TRAV40 Pharmacogenomics, SNPs, Pathways
IMGT entry for TRAV40 The international ImMunoGeneTics information system® specializing in Immunoglobulins (IG), T cell receptors (TR), Major Histocompatibility Complex (MHC) and related proteins of the immune system (RPI) of human and other vertebrate species.
(Patent information from GeneIP,
Licensable technologies from WIS Yeda, Salk, Tufts,
IP news from LifeMap Sciences, Inc.)
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Patent Information for TRAV40 gene:
Search GeneIP for patents involving TRAV40
GeneCards and IP:
Japan Patent Office Licenses GeneCards European Patent Office Licenses GeneCards Improving the IP Search
(Antibodies, recombinant proteins, and assays from EMD Millipore, R&D Systems, OriGene, QIAGEN, GenScript, Cell Signaling Technology, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Cloud-Clone Corp., Thermo Fisher Scientific, LSBio, Gene Editing from DNA2.0. Clones from OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Cell lines from GenScript, and ESI BIO, PCR Arrays from QIAGEN, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, Enzo Life Sciences, and/or ApexBio, In Situ Hybridization Assays from
Advanced Cell Diagnostics, Animal models from inGenious Targeting Laboratory, genOway)
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GeneCards Homepage - Last full update: 7 May 2014 - Incrementals: 9 May 2014 , 2 Jun 2014 , 26 Jun 2014 , 30 Jun 2014
View Random Gene
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(GIFtS: )
GIFtS Group
The GeneCards human gene database gene index: 1 3 5 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Developed at the Crown Human Genome Center, Department of Molecular Genetics, the Weizmann Institute of Science
Hot genes Disease genes TRAV40 gene at Home site.
Version: 3.12.142 28 July 2014
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Researchers discover two new groups of viruses
02.06.2015
Researchers at the University of Bonn and the German Center for Infection Research (DZIF) have discovered two new groups of viruses within the Bunyavirus family in the tropical forest of Ivory Coast. Previously only five groups responsible for serious illnesses in humans and animals were known. Most are spread through blood-feeding insects. Based on the discovered viruses researchers conclude that the ancester to all bunyaviruses must have existed in arthropods such as insects. The results are now being published in the “Proceedings of the National Academy of Sciences” (PNAS).
The bunyavirus family includes five different groups of viruses which trigger serious illnesses in humans and animals and which can also cause significant damage to vegetables, such as tomatoes. The first viruses of this family were discovered in a place known as Bunyamwera in Uganda, from which they derive their name.
Electron microscope image of the Ferak virus.
Image: Dr. Andreas Kurth/Robert Koch Institute Berlin
Electron microscope image of the Jonchet virus. "Jonchet" means "rod" in French.
© Image: Marco Marklewitz/UKB
"The most well-known bunyaviruses include, for example, the Rift Valley fever virus, which can cause febrile illnesses with severe bleeding in humans," says Dr. Sandra Junglen from the Bonn Institute of Virology, also affiliated with the German Center for Infection Research. In 2011, the "Schmallenberg virus" gained much attention: also a part of the Bunyavirus family and transmitted by gnats, it caused severe fetal malformations in ruminant animals including sheep in the German Sauerland region.
Not in Schmallenberg but instead in the African tropical forest of the Ivory Coast, where the virologist has been conducting research for more than ten years, she set off on the search for new viruses. Because most bunyaviruses are transmitted by blood-sucking insects, Dr. Junglen caught more than 7500 mosquitoes. Sorted according to species and sites of capture, the scientists combined the captured mosquitoes into 432 mixed samples. In 26 of these samples, the researchers discovered particles of unknown bunyaviruses.
Agents of human disease have developed from insect viruses
"These were two groups of as-yet-unknown viruses which we called Jonchet virus and Ferak virus," reports the virologist. The scientists obtained fragments of the viral genetic material from the insect samples and joined these fragments together like a puzzle, thus reconstructing the entire genome sequence. "That alone took four years," reported lead authors Marco Marklewitz and Florian Zirkel. During the comparison of the genetic information with other viruses, it was found that Jonchet and Ferak viruses are two phylogenetically independent bunyavirus lineages.
How dangerous are the two new groups of viruses – can they be easily transmitted to humans and animals? To answer these questions, the scientists went in a new direction: They performed infection trials in a large number of cell cultures at different temperature levels.
While pathogenic bunyaviruses can multiply at temperatures that include the human body temperature, growth of Jonchet and Ferak viruses ceases above 32 degrees Celsius, making it unlikely that the viruses infect humans or other vertebrates. "In addition, we reconstructed the evolutionary history of host associations of the entire family of viruses, demonstrating for the first time that viruses affecting vertebrates developed from arthropod-specific viruses," says the researcher from the University of Bonn Hospital.
Simplified test to test novel viruses for risk of human infection
Triggered by epidemics such as SARS and Ebola, virologists are now reaching out to discover the plethora of unknown viruses lurking in natural reservoirs such as insects, in an attempt to forecast pandemic risks. „We hope our temperature test for estimating the risk of vertebrate infection can be useful for assessing other viruses that keep being discovered," says Dr. Junglen.
Publication: “Evolutionary and phenotypic analysis of live virus isolates suggests arthropod origin of a pathogenic RNA virus family”, Proceedings of the National Academy of Sciences (PNAS), DOI: 10.1073/pnas.1502036112
Media contact information:
Dr. Sandra Junglen
Institute of Virology
University of Bonn Medical Centre
German Center for Infection Research (DZIF)
Tel. 0228/28713068
E-Mail: [email protected]
Weitere Informationen:
http://www.virology-bonn.de Institute of Virology at University of Bonn Medical Centre
Johannes Seiler | idw - Informationsdienst Wissenschaft
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B2B-VideoLinks
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
2,238,105,567,418,554,400 | CSHL Archives Repository
Preserving and promoting the history of molecular biology.
Letter from A. Rossi Fanelli, E. Antonini, M. Brunori, and P. Fasella to James D. Watson
JDW_02_02_0902_090
Collection
Citation
Rossi Fanelli, A. (Alessandro), “Letter from A. Rossi Fanelli, E. Antonini, M. Brunori, and P. Fasella to James D. Watson,” CSHL Archives Repository, Reference JDW/2/2/902/90, accessed January 26, 2022, https://libgallery.cshl.edu/items/show/40795. | {
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-2,640,324,809,912,390,000 | BIOSCI/bionet Frequently Asked Questions
BIOSCI Administrator biosci-help at net.bio.net
Wed Dec 1 04:04:02 EST 1999
BIOSCI/bionet Frequently Asked Questions (FAQ)
----------------------------------------------
This document supplements the BIOSCI Newsgroups Information Sheet and
provides details on how to participate in BIOSCI forums. Both
documents are available for anonymous FTP and gopher retrieval (port
70) from net.bio.net [134.172.2.69]. The text version of the FAQ is
found in pub/BIOSCI/doc/biosci.FAQ. This document is also available
using the World Wide Web at
"http://www.bio.net/BIOSCI/biosci.FAQ.html". This document may also
be requested by e-mail by sending the command
info faq
in the body of an e-mail message addressed to the Internet address
biosci-server at net.bio.net
Any text placed on the Subject: line of your message is ignored, so
please be sure to put the "info faq" command in the main body of your
e-mail message. The FAQ is posted the first of each month to the
BIONEWS/bionet.announce newsgroup along with the BIOSCI information
sheet and the list of changes to the newsgroups during the preceding
month.
----------------------------------------------------------------------
Contents
COMMON QUESTIONS ABOUT BIOSCI/BIONET USAGE
* What is BIOSCI and bionet?
* What newsgroups are available on BIOSCI/bionet?
* Where should I post my messages?
* What are the restrictions on commercial activities in the
BIOSCI/bionet newsgroups?
* How does one post a message?
* Should I post my message to more than one newsgroup?
* Sorting out mail - which newsgroup did an e-mail message come
from?
* Why do all of my postings come from "BIOSCI-REQUEST?"
* How do I reply to a BIOSCI posting?
* What is Usenet?
* How can I get news software at my site?
* How can I test my news or mail software?
* I hear that a new bionet newsgroup was created but why isn't it at
my site yet?
* A new bionet Usenet group has been created at my site but there
are no messages in it. However, I see that messages are being
sent out to the mailing list. Why do the contents differ?
* How do I request or cancel e-mail subscriptions to BIOSCI
newsgroups?
* How can I get a list of newsgroups or my subscriptions?
* How do I find back issues of BIOSCI postings?
* Is there a summary of METHODS-AND-REAGENTS postings?
* What journals are available on BIO-JOURNALS? How can one locate
articles?
* Why are there two BIOSCI sites?
* Why have I stopped getting messages?
* What should I do about mail error messages that come back when I
post?
* How does one start a new BIOSCI newsgroup/mailing list?
* How can I list my address information in the BIOSCI user
directory?
* Why didn't my Usenet posting show up elsewhere?
* Why are my messages are going to bionet.followup?
COMMON QUESTIONS POSTED TO BIOSCI/BIONET NEWSGROUPS
* What are all of these references to FTP, WAIS, Gopher, and WWW?
* Please help me find the e-mail address for Dr. ...
* How do I report a problem in a biological data base?
* What about submitting sequence data to GenBank, EMBL, DDBJ or PIR?
Other questions to add to this list??? Please send them to
biosci-help at net.bio.net. We would also appreciate your sending the
answer to the question if possible. All contributions will be
gratefully acknowledged by including the author's name along with the
answer provided.
----------------------------------------------------------------------
Common Questions about BIOSCI/bionet usage
WHAT IS BIOSCI AND BIONET?
We'll spare you the fascinating historical details and say simply that
BIOSCI is a series of freely accessible electronic communication
forums (i.e., electronic bulletin boards or "newsgroups") for use by
biological scientists worldwide. No fees are charged for the service.
The system is intended to promote communication between professionals
in the biological sciences. All postings to the newsgroups should be
made in that spirit. While the general public may "listen in" to the
discussions, these newsgroups are intended primarily for
communications between researchers. There are other forums on Usenet
such as sci.bio for the asking and answering of biological questions
from lay persons.
BIOSCI messages are distributed without editorial intervention in most
cases. Dissemination is by both electronic mail and over Usenet in the
form of the "bionet" newsgroups (see below for Usenet details). The
contents of the electronic mail distribution is identical to the
Usenet news distribution, but we encourage BIOSCI users to access the
system through Usenet news software whenever possible. E-mail
distributions may eventually be phased out. As of October 1992, 59% of
our readers used Usenet news software instead of e-mail.
You may find much more detailed and up to date information concerning
Usenet in the news.announce.newusers newsgroup. These articles are
also available using anonymous FTP from rtfm.mit.edu [18.181.0.24, but
please always reference the hostname rtfm.mit.edu, as IP addresses and
canonical names will change in the future, but rtfm.mit.edu will
remain correct], in the /pub/usenet/news.announce.newusers directory.
You may be specifically interested in the following articles:
* What_is_Usenet?
* What_is_Usenet?__A_second_opinion.
* Usenet_Software:_History_and_Sources
* How_to_Get_Information_about_Networks
* How_to_become_a_Usenet_site
* Answers_to_Frequently_Asked_Questions_about_Usenet
* Emily_Postnews_Answers_Your_Questions_on_Netiquette
* Hints_on_writing_style_for_Usenet
Detailed starting information on how to get your site connected to the
Internet can be found the file
"How_to_Get_Information_about_Networks".
----------------------------------------------------------------------
WHAT NEWSGROUPS ARE AVAILABLE ON BIOSCI/BIONET?
"THE BIOSCI ELECTRONIC NEWSGROUP NETWORK INFORMATION SHEET" containing
the latest list of newsgroups, e-mail posting addresses, and other
information about subscribing/unsubscribing, etc., to BIOSCI is posted
the first of each month on the BIONEWS/bionet.announce newsgroup along
with this FAQ posting.
Two versions of the BIOSCI info sheet are available, one for the
Americas and the Pacific Rim countries, and the second for Europe,
Africa, and Central Asia. The former may be requested by e-mail to
biosci-help at net.bio.net, while the latter may be requested from
biosci at daresbury.ac.uk.
----------------------------------------------------------------------
WHERE SHOULD I POST MY MESSAGES?
The list of newsgroups in the BIOSCI info sheet gives a brief
description of the purpose of each newsgroup. Please select the
appropriate forum for your posting with the newsgroup's purpose in
mind. The groups designated as "Scientific Interest Group" are for
discussions of professional interest in the area designated by the
newsgroup name, i.e., population biology issues should obviously be
directed to the POPULATION-BIOLOGY newsgroup.
A few guidelines on specific newsgroups:
BIONAUTS/bionet.users.addresses: This newsgroup was designed to help
biologists "voyaging" into the new world of electronic networking.
This is also the appropriate forum for requesting electronic mail
addresses of other biologists if you can not find them in the BIOSCI
user address directory (the address directory is described elsewhere
in this FAQ). Regarding address requests to BIONAUTS, there are no
guarantees that the people in question will respond personally, of
course, but someone else might. In addition, this forum can be used
for asking questions if you need any help with mail and news software
or other aspects of electronic networking, e.g. "What is WAIS, gopher,
and all of these other newfangled things that I have been hearing
about?" (see another FAQ section for answers to this last question!).
BIONEWS/bionet.announce: This is a moderated newsgroup designed to be
low-volume, high content and intended primarily for announcements of
interest to most users on the network, e.g., for general announcements
such as for scientific meetings, courses, etc. We recommend that *ALL*
participants subscribe to this newsgroup to keep up with the items
above and also to receive the latest information about changes to
BIOSCI/bionet.
BIOFORUM/bionet.general: BIOFORUM is intended for discussions on
topics that do not fit in to any of the specialty newsgroups. If you
want to start a new newsgroup, you might begin by trying to raise
interest through a discussion in this forum. Be aware that this
newsgroup is by design one of the most "chatty" forums in the BIOSCI
network.
BIO-JOURNALS/bionet.journals.contents: This newsgroup is not for
postings by readers. It is used to distribute the Table of Contents
for over 30 biological research journals approximately a week or two
in advance of publication (see the latest listing of journals in the
FAQ section about the BIO-JOURNALS newsgroup).
BIO-SOFTWARE: Intended for discussions about software in the
biological sciences. There are other Usenet newsgroups and mailing
lists for questions about word processors, etc., i.e., for general
purpose software. BIO-SOFTWARE is intended for discussions about
software for biologists. For Usenet users only, please note that there
is an accompanying newsgroup bionet.software.sources used for
distributing biological software source code and binaries. This
service is *not* available by e-mail.
COMPUTATIONAL-BIOLOGY: This newsgroup is moderated, i.e., postings
made to the group are reviewed by a moderator before being
distributed.
EMPLOYMENT: These are the posting regulations for
EMPLOYMENT/bionet.jobs as formulated by the U.S. National Science
Foundation. Readers outside of the U.S. should check with their local
network authorities to determine what rules apply to their usage.
EMPLOYMENT/bionet.jobs is to be used for the posting of job openings
in the biological sciences or professional level jobs that support the
work of biological scientists (such as for computer/systems
programming/support). There are no restrictions on the content of the
postings if these jobs are in the non-profit sector. Individuals
regardless of their place of employment may post their CVs/resumes to
this newsgroup or simply place a request for work if they are looking
for jobs in this area of endeavor. Commercial companies can post jobs
intended for professional people in the areas just mentioned provided
that the postings are limited to the format described below. Extended
commercial job/benefit descriptions and promotional material are not
allowed, nor may commercial firms post openings for non-professional
positions (if in doubt about the appropriateness of a posting, please
check with biosci-help at net.bio.net *before* proceeding).
Commercial job posting format
The posting should include
* job title
* one or two line factual description of the position
* an e-mail contact address for further information; a regular
surface mail address and contact telephone number is also
permissible.
To repeat, commercial job postings that do not comply with the above
format or that are for jobs in areas outside of the range described
above are not permissible in this newsgroup. Your cooperation is
greatly appreciated.
SCIENCE-RESOURCES: This newgroup is used solely to distribute funding
agency announcements such as the "NIH Guide for Grants and Contracts"
and is not to be used for postings by readers.
Most other BIOSCI newsgroups are dedicated to professional discussions
in the area defined by the name of the newsgroup. You are free to post
anything of interest within the specialty served by the newsgroup.
Please note that the lack of face-to-face contact often emboldens some
of our readers. While we can wish that everyone learned manners in
grade school or at home, please be aware that discussions can
sometimes become a bit more heated than a new user might be accustomed
to (our readership is usually composed of "sober" Ph.D.s, or so we
used to think, but it appears that perhaps economic hard times have
taken their toll on sobriety 8-).
NOTE: To understand what 8-) means tilt your head to the left; other
variants: :-) and :-(. These symbols try to add emotional connotations
to the electrons such as "that's a joke, son!"
----------------------------------------------------------------------
WHAT ARE THE RESTRICTIONS ON COMMERCIAL ACTIVITIES IN THE BIOSCI/BIONET
NEWSGROUPS?
BIOSCI is funded in part by the National Science Foundation (NSF)
which supports the Internet in the U.S. with U.S. taxpayer dollars.
NSF is responsible for setting Acceptable Use Policy (AUP) for the the
NSFNet backbone section of the Internet of which BIOSCI makes
extensive use. Because of these reasons, BIOSCI users should adhere to
the following guidelines.
Commercial activities on BIOSCI are in general prohibited except as
noted below. People at for-profit organizations are free to read all
postings made to the BIOSCI/bionet newsgroups, but must ensure that
their postings to the newsgroups do not violate our guidelines.
Commercial organizations may post job openings on
EMPLOYMENT/bionet.jobs subject to the format restrictions for that
group. Commercial job posting format restrictions for the
EMPLOYMENT/bionet.jobs newsgroup are described above under the
question "Where should I post my messages?" Users who violate these
format restrictions consciously risk losing their network access.
BIOSCI readers without any financial connections to a company or a
product may discuss and/or post endorsements of a commercial product.
However, it is standard Internet practice to include in the posting a
disclaimer of any financial interest in the product/company. Note that
postings to newsgroups are subject to libel laws. BIOSCI advises
readers to think twice before taking potshots at products that they do
not like.
BIOSCI users often post general questions about problems that might be
solved through the use of a commercial product. It is EXTREMELY
IMPORTANT, however, that such general questions *not* be answered by
people affiliated with the product or company that might stand to gain
a sale as a result. For example, user X may ask, "Is there a product
that will allow me to separate protein A from protein B given the
following properties ...?", but, if user Y works at company Z which
sells a product that can accomplish this task, user Y does *NOT* have
permission to respond to the question. Responses can only be posted by
other scientists who might have experience in solving the problem in
question and who do not stand to gain financially by promoting the
product in question, i.e., they are not employees, consultants, or
connected to the company via other financial ties. As noted above,
postings endorsing commercial products should contain a customary
disclaimer stating the absence of financial ties of the poster to the
product/company.
Commercial companies MAY RESPOND to a public BIOSCI newsgroup if a
BIOSCI user asks a question directly about one of their products,
e.g., mentions it by name. The response should be limited to a factual
answer of the question posed and should avoid any hint of advertising
hype. Comparisons with competitors' products should be avoided
completely.
Finally, as a general rule, if you are unsure about the
appropriateness of your posting, before you post anything please send
a copy of what you propose to post to the BIOSCI adminstrator at
biosci-help at net.bio.net for review.
BIOSCI will takes steps to terminate network access to any reader who
willfully violates our commercial use policies.
----------------------------------------------------------------------
HOW DOES ONE POST A MESSAGE?
If you use Usenet, run your posting program (e.g., postnews or e.g.,
use the ":post" command in nn) and follow the prompts. Please check
with your local systems administrator for details on using your local
news software; general information on Usenet and how to get news
software is provided further below but each news program is different.
When prompted, enter the appropriate newsgroup name from the list of
Usenet names in the BIOSCI info sheet. Be sure to set your news
distribution to "world" (or "bionet" if the option is available) if
you want your message to be seen by others. Some Usenet systems may
default to "local" which means that only people on your local computer
will see the message. You can limit the extent of distribution of your
message by choosing other distribution options, e.g., "usa"
distributes only to the U.S.A. (sometimes! - on occasion these
distribution limiting features don't work for a variety of reasons).
Usually pressing "?" or "h" at the Distribution: prompt will show you
your options. After entering your options, you are usually placed in
an editor to compose your message. After saving it and exiting the
editor, one typically enters a "send" command to complete the posting
process.
If you are using e-mail, first select the newsgroup that you wish to
post to and find the mailing address in the BIOSCI info sheet for your
region. For example, to post to the METHODS-AND-REAGENTS newsgroup you
would use one of the following two addresses depending upon your
location:
Address Serving
------- -------
methods at net.bio.net The Americas and Pacific Rim
methods at daresbury.ac.uk Europe, Africa, and Central Asia
Once you have entered the newsgroup mailing address on the To: line of
your mail message, the rest of the process is the same as composing
and sending any e-mail message. Your message will be automatically
distributed to all mail recipients on the list and also distributed by
Usenet news.
The BIOSCI information sheet containing the latest list of e-mail
addresses for each of the above regions can be requested from
biosci at net.bio.net or biosci at daresbury.ac.uk respectively.
----------------------------------------------------------------------
SHOULD I POST MY MESSAGE TO MORE THAN ONE NEWSGROUP?
Generally only *ONE* copy of a message should be posted to the most
appropriate forum. Crossposting the same message to multiple
newsgroups can aggravate readers who participate by e-mail. These
people will receive multiple copies of a message if they are on the
mailing lists for the groups that receive the crosspostings.
Please note that software safeguards in our system which prevent
mailing loops also make it difficult to use news software to both
crosspost to different newsgroups AND simultaneously mail to all
associated mailing lists. If you *absolutely must* distribute a
message to different newsgroups AND their associated mailing lists,
the way to do this is to e-mail a *separate* copy of your message to
each newsgroup e-mail posting address. Including multiple mailing
addresses on a single e-mail message will not crosspost to all mailing
lists. Please be aware that many people read multiple groups by mail
and be assured that, if two groups are related, many people who are
interested in one will obviously sign up for the other group, too.
Before crossposting, be certain that your message is so important that
it really warrants sending multiple copies to a large number of
people.
----------------------------------------------------------------------
SORTING OUT MAIL - WHICH NEWSGROUP DID AN E-MAIL MESSAGE COME FROM?
If you use Usenet news software, all messages are sorted by newsgroup
so there is no problem identifying the source. If you receive BIOSCI
postings in your mail file, all postings are funneled into your one
mail file merely by chronological order of posting and you must be a
little discerning to follow discussions.
The best way to determine the news forum is to look at the line in the
mail header that starts with "To:". For example, if you see "To:
arab-gen at net.bio.net" or "To: arab-gen at daresbury.ac.uk" then you know
that the address for sending a reply to everyone on the newsgroup is
"arab-gen at net.bio.net" or "arab-gen at daresbury.ac.uk." The "From:" line
in the mail header indicates who sent the message. In most cases, if
you want to reply only to the author of the message, use the address
on the "From:" line, and, if you want to reply to everyone on the
newsgroup, use the address on the "To:" line (but please read the
following sections on the BIOSCI-REQUEST address and replying to
BIOSCI postings for additional information).
Please note that replies to BIOSCI messages are *not* automatically
sent back to the newsgroup address. The default reply on most mail
systems (your local mail configuration may differ) will be to reply to
the address that you see on the "From:" line, i.e., only to the person
who posted the original message. You must consciously decide to send a
copy of your reply to the newsgroup by including the newsgroup posting
address in your e-mail response. This default reply (to the original
sender only) is an Internet newsgroup standard and is the opposite of
that used by the BITNET LISTSERV software (for those who may be
familiar with the latter; the Internet standard is designed to
minimize wasted network bandwidth, i.e., to avoid the *automatic,
unthinking* posting by many people of the same answer to a particular
question).
----------------------------------------------------------------------
WHY DO ALL OF MY POSTINGS COME FROM "BIOSCI-REQUEST?"
Unfortunately some mail systems make all BIOSCI postings appear to
come from someone named "BIOSCI-REQUEST." The
BIOSCI-REQUEST at net.bio.net address was established to trap mailing
error messages ("bouncers"). The address is not normally seen by
BIOSCI readers in the messages that they receive. Unfortunately some
proprietary (read "VMS") and other oddball mail systems misread the
information used to transmit Internet e-mail messages and may end up
putting the BIOSCI-REQUEST address on the From: line in the mail that
you may receive. If this happens at your site and you want to reply to
a message, please use either the newsgroup address on the To: line of
the message or try to find the author's e-mail address elsewhere in
the message (people often append this at the end of their text in
their "signature"). If you send a message back to
BIOSCI-REQUEST at net.bio.net, the BIOSCI managers at net.bio.net will be
the only ones who will see it (we will try to forward it to the
appropriate newsgroup, but would appreciate it if you would determine
the correct address yourself first).
----------------------------------------------------------------------
HOW DO I REPLY TO A BIOSCI POSTING?
If you are using news software, there are usually two types of reply
commands. One command sends a private reply to the author of the
original posting; the second sends a "followup" posting to everyone on
the newsgroup. Press ? or h in your news software to find these
commands. They are often noted by "r" and "R" or "r" and "f"
respectively.
If you are replying to an e-mail message from BIOSCI, be sure to look
carefully at the To: and Cc: lines of your reply message *before*
sending it off. If you want the reply to be PRIVATE, only the address
of the person who posted the original message (and perhaps your
address and/or that of other individuals) should be on the To: and Cc:
address lines. If you want the reply to be PUBLIC, be sure that the
newsgroup posting address appears on either the To: or Cc: line of
your response. If your mail system is a bit unorthodox and puts the
"BIOSCI-REQUEST" address in your response (see the section about
BIOSCI-REQUEST above), please be sure to correct this *before* sending
your message (ask your systems administrator how to edit the To: and
Cc: lines of your mail messages before sending if you do not know how
to do this).
Now that you have read about all of these problems with using e-mail
to participate in BIOSCI, why don't you get news software installed at
your site and make life easy for yourself instead of using e-mail
8-)!! Let's look at Usenet news next!
----------------------------------------------------------------------
WHAT IS USENET?
Usenet (short for Users Network) is an electronic bulletin board
network which utilizes various public domain versions of the "netnews"
software for message transmission. The software can operate over
physical networks ranging from as simple as a telephone UUCP link (via
modem) to networks as sophisticated as the Internet. Netnews has been
optimized to transmit messages without loss and also to avoid possible
mail loops and other errors which plague simple electronic mail
"broadcasting." We strongly encourage our users to adopt netnews
software at their sites as soon as possible. News software also keeps
messages segregated into their respective newsgroups, making it easier
to follow the thread of a discussion. If you only use e-mail, messages
from all of the newsgroups to which you subscribe will be sent to your
one personal e-mail address and will be mixed in with each other and
with your other personal messages. This is obviously a suboptimal
means of organizing messages. With news software, you can browse the
discussion topics easily, read what you want and discard the rest. Why
subject yourself to having to page through a disorganized mail file
message-by-message unless you really have no other choice?? News
software makes the use of BIOSCI pleasant and efficient. It's time to
get your organization "into the 20th Century" before it turns into the
21st Century!
----------------------------------------------------------------------
HOW CAN I GET NEWS SOFTWARE AT MY SITE?
Contact biosci-help at net.bio.net for information on getting started
with Usenet. News software can be obtained free of charge from
anonymous FTP sources. Note, however (yes, here's the unfortunate
catch), that news software should be installed and maintained by a
trained systems administrator in most cases; it is not a task for a
computer novice. You can find detailed information about Usenet using
anonymous FTP from rtfm.mit.edu [18.181.0.24, but please always
reference the hostname rtfm.mit.edu, as IP addresses and canonical
names will change in the future, but rtfm.mit.edu will remain
correct], in the /pub/usenet/news.announce.newusers directory. You may
be specifically interested in the following articles:
* What_is_Usenet?
* What_is_Usenet?__A_second_opinion.
* Usenet_Software:_History_and_Sources
* How_to_Get_Information_about_Networks
* How_to_become_a_Usenet_site
----------------------------------------------------------------------
HOW CAN I TEST MY NEWS OR MAIL SOFTWARE?
Please DO NOT post test messages to any of the BIOSCI/bionet Usenet
newsgroups. If you are unsure about whether or not your mail is
working, please send test mail messages to either of our two
administrative addresses, but NOT to newsgroup mailing addresses:
Address for tests Location
----------------- --------
biosci at daresbury.ac.uk Europe, Africa, and Central Asia
biosci at net.bio.net Americas and the Pacific Rim
If you need to test your Usenet news software, please post test
messages to the Usenet newsgroup misc.test which was created solely
for this purpose.
----------------------------------------------------------------------
I HEAR THAT A NEW BIONET NEWSGROUP WAS CREATED BUT WHY ISN'T IT AT MY SITE
YET?
This could happen for a variety of reasons. When we create a new
Usenet newsgroup, a "newgroup" message is sent out from net.bio.net to
news administrators at Usenet sites around the world. Many sites are
configured so that such newgroup messages are acted upon automatically
and the group is established without human intervention. However, due
to the growing volume of Usenet newsgroups, many sites have turned off
automatic newgroup creation and require human intervention to create a
new Usenet group in response to a newgroup message. If you know from
reading BIONEWS/bionet.announce or from contacting the BIOSCI staff at
biosci-help at net.bio.net that a new bionet newsgroup should be in
existance, please contact your local news administrator and ask them
if they acted on the newgroup message. Newgroup messages can sometimes
be simply overlooked by the news administrator and sometimes they may
not be received if a Usenet site upstream on the net from you had a
problem and did not pass on the message. Please let your news
adminstrator know that a bionet "checkgroup" message is posted on the
first of each month to bionet.announce. Your news administrator can
use the contents of that message to update your local list of bionet
Usenet newsgroups.
Please note that all new BIOSCI/bionet newsgroups are announced on
BIONEWS/bionet.announce as soon as they are ready for use. If you see
this announcement, this means that the BIOSCI staff has tested the
group and is (1) sure that it works, and (2) knows that it has
propagated to at least some other sites in both North America and
Europe. We obviously can not check for propagation to the thousands of
sites on Usenet. Depending upon your source of Usenet news, there may
be a delay of several days before the newgroup message reaches your
site. The announcement of the newsgroup availability, however, is
always sent to bionet.announce *after* the newgroup message has been
sent and after system tests have been run.
----------------------------------------------------------------------
A NEW BIONET USENET GROUP HAS BEEN CREATED AT MY SITE BUT THERE ARE NO
MESSAGES IN IT. HOWEVER, I SEE THAT MESSAGES ARE BEING SENT OUT TO THE
MAILING LIST. WHY DO THE CONTENTS DIFFER?
If you experience the problem above, please contact your local news
administrator and have them check with the site that sends you your
bionet Usenet news feed. We explained in a question above that new
Usenet newsgroups are created in response to a "newgroup" message
which is sent out to all Usenet news administrators. It is possible
that your news administrator acted on the message to create the group,
but that the site which sends you bionet Usenet news did not. Having
your Usenet news administrator contact the administrator at the
upstream site can usually resolve the problem. If you have a problem
getting a reliable bionet Usenet news feed, please contact
biosci-help at net.bio.net.
----------------------------------------------------------------------
HOW DO I REQUEST OR CANCEL E-MAIL SUBSCRIPTIONS TO BIOSCI NEWSGROUPS?
Instructions for subscribing and unsubscribing to the BIOSCI
newsgroups by e-mail are included in the BIOSCI info sheet which can
be obtained from either of the following two addresses:
Administrative Address Location
---------------------- --------
biosci at daresbury.ac.uk Europe, Africa, and Central Asia
biosci at net.bio.net Americas and the Pacific Rim
----------------------------------------------------------------------
HOW CAN I GET A LIST OF NEWSGROUPS OR MY SUBSCRIPTIONS?
Simply send a request to your appropriate BIOSCI distribution site:
Administrative Address Location
---------------------- --------
biosci at net.bio.net The Americas and Pacific Rim
biosci-help at daresbury.ac.uk Europe, Africa, and Central Asia
The most recent list of BIOSCI newsgroups/mailing addresses and the
latest revision of the BIOSCI/bionet FAQ are posted the first of each
month on the BIONEWS/bionet.announce newsgroup. You should save these
postings for future reference.
----------------------------------------------------------------------
HOW DO I FIND BACK ISSUES OF BIOSCI POSTINGS?
The BIOSCI node at net.bio.net maintains the entire collection of
BIOSCI/bionet messages. They are available via WAIS (biosci.src and
biology-journal-contents.src), Gopher (net.bio.net port 70),
anonymous ftp from net.bio.net [134.172.2.69], and Mosaic/WWW (URL is
gopher://net.bio.net/). Contact biosci-help at net.bio.net for further
help. If you are on the Internet but do not have WAIS software running
locally, try
telnet quake.think.com
and login in as "wais" to experiment with the software. All of our
WAIS sources (biosci.src, biology-journal-contents.src, and
biologists-addresses.src) may be selected from the menu for searching.
Please also refer to the FAQ section below entitled "Please help me
find the e-mail address for Dr. ..." for additional uses of our WAIS
sources.
If you are not on the Internet you may search the BIOSCI WAIS archives
by e-mail using our WAISMAIL e-mail server. For instructions on using
WAISMAIL, please send the message
help
in the body of a mail message addressed to the Internet address
waismail at net.bio.net
and be sure to leave the Subject: line of your message blank. Detailed
instructions will be returned to you automatically.
The SERC Daresbury BIOSCI node runs a BIOSCI newsgroups WAIS source
called BIOWAIS. This source can also be searched through their gopher
client at host s-crim1.dl.ac.uk, port 70.
All the Bionet newsgroup postings since December 1991 are stored for
Gopher searching and retrieval and anonymous ftp at
ftp.bio.indiana.edu, the IUBIO Archive maintained by Don Gilbert. The
directory in the anonymous FTP account is usenet/bionet. This gopher
site also contains an outstanding collection of biological software
and databases.
Another excellent gopher server is maintained by Dan Jacobson at
merlot.gdb.org, port 70. In addition to newsgroup archives, many
other information sources of use to biologists are available.
In Europe, Rob Harper runs a full-featured Gopher for biologists at
gopher.csc.fi and Reinhard Doelz maintains a biology gopher at
gopher.embnet.unibas.edu. The number of "gopher holes" on the
network is expanding too rapidly to list them all here.
----------------------------------------------------------------------
IS THERE A SUMMARY OF METHODS-AND-REAGENTS POSTINGS?
Yes. A FAQ for the METHODS newsgroup was created by Paul Hengen of
Frederick Cancer Research and Development Center. It can be obtained
via anonymous FTP from net.bio.net in
pub/BIOSCI/METHDS-REAGNTS/METHODS.FAQ or from ftp.ncifcrf.gov in
pub/methods/FAQlist.
Note, however, that maintaining such a FAQ is a gargantuan task. We
also recommend searching the METHODS archives for keywords through the
use of the WAIS and Gopher software as described in the "archives"
question above.
In each issue of "Trends in Biochemical Sciences" since November 1993,
Dr. Hengen writes a monthly digest column of the METHODS newsgroup.
This column highlights topics of special interest which were discussed
recently on the newsgroup.
----------------------------------------------------------------------
WHAT JOURNALS ARE AVAILABLE ON BIO-JOURNALS? HOW CAN ONE LOCATE ARTICLES?
The following journals appear regularly as of 6/28/94. This list is
constantly expanding and the latest copy can be requested from
biosci-help at net.bio.net.
* Anatomy & Embryology
* Applied Microbiology and Biotechnology
* Applied and Environmental Microbiology
* Binary
* CABIOS
* Cell and Tissue Research
* Chromosoma
* Clinical Chemistry
* Current Genetics
* EMBO Journal
* European Journal of Biochemistry
* European Journal of Physiology
* Experimental Brain Research
* Histochemistry
* Human Genetics
* IEEE Engineering in Medicine and Biology
* Immunogenetics
* Journal of Bacteriology
* Journal of Biological Chemistry
* Journal of Comparative Physiology B: Biochemical, Systemic, and
Environmental Physiology
* Journal of Membrane Biology
* Journal of Molecular Evolution
* Journal of Virology
* MGG - Molecular and General Genetics
* Mammalian Genome
* Microbial Releases
* Molecular Microbiology
* Molecular and Cellular Biology
* Nucleic Acids Research
* Plant Cell Reports
* Planta
* Protein Science
* Roux's Archives of Developmental Biology
* Seminars in Cancer Biology
* Seminars in Cell Biology
* Seminars in Developmental Biology
* Seminars in Immunology
* Seminars in the Neurosciences
* Seminars in Virology
* TAG - Theoretical and Applied Genetics
Table of Contents for the journals above are available for FTP from
net.bio.net in pub/BIOSCI/BIO-JOURNALS and also for searching and
retrieval by Gopher from net.bio.net, port 70. One can use either
gopher or WAIS to search the WAIS source biology-journal-contents.src
at net.bio.net and retrieve individual article references from the
journals above. This can be accessed through WAIS, WAISMAIL, gopher,
and Mosaic as described in the FAQ section entitled "How do I find
back issues of BIOSCI postings?"
----------------------------------------------------------------------
WHY ARE THERE TWO BIOSCI SITES?
Originally there were *four* BIOSCI distribution sites (nodes), but
due to administrative complexities, the number of nodes was scaled
back to two. Although 99% of you never have to pay for any BIOSCI
messages, rest assured that network resources are not free and should
not be squandered. We established BIOSCI distribution sites on each
side of the Atlantic to minimize network e-mail traffic. For example,
if a message is posted to the U.S. site, only one copy is sent on to
the U.K. site *via netnews software, not by mail* before being
"exploded" for mail distribution to all of the final e-mail
destinations on the "other side of the pond." This is more efficient
than sending hundreds of copies of the same message across the
Atlantic. A trade-off for this efficiency is slightly increased
complexity in the distribution network, i.e., the mailing lists for
each newsgroup are split between two sites. In the past BIOSCI
experienced sporadic problems with "bounced" mail, but the reduction
in the number of BIOSCI distribution sites and the implementation of
U.S. to U.K. message transfer via news rather than by e-mail has
eliminated this problem. Everyone would be better served if Usenet
news was used exclusively, and we have the eventual elimination of
e-mail subscriptions as a *long term* goal. Currently, however, too
many biologists still have no other means of access to BIOSCI other
than through e-mail.
----------------------------------------------------------------------
WHY HAVE I STOPPED GETTING MESSAGES?
If your computer or network connection is down, mail sent to your
address will "bounce" back to the sender of the message and often to
the BIOSCI-REQUEST address at net.bio.net. Given the number of people
using BIOSCI around the world, this can become quite a problem, so we
have to take prompt action to eliminate troublesome addresses from our
mailing lists. Offending addresses are "commented out" of the mailing
lists. If your system is down, there may be no way to reach you, so it
is your responsibility to contact your BIOSCI distribution site and
request reinstatement if you notice a lapse in distribution. There is
an automatic reminder system at net.bio.net in the U.S. that sends a
message to all "commented out" addresses on the mailing lists at
net.bio.net each Monday for three weeks. After that if no response is
received to biosci-help at net.bio.net, the bad addresses are completely
removed from the mailing lists.
----------------------------------------------------------------------
WHAT SHOULD I DO ABOUT MAIL ERROR MESSAGES THAT COME BACK WHEN I POST?
It is not uncommon when posting a mail message to a newsgroup to
receive an error message from a "mailer daemon." Don't panic!! The
devil is not in the employ of BIOSCI! It is a rare day when every
single computer and e-mail address in the world is functional. Mail
systems are programmed to alert you if mail does not go through to a
particular address which could be on any of our BIOSCI lists. Rest
assured that your message was received by the *vast majority* of
readers. You may either just delete these "bouncers" or send them on
to your local BIOSCI distribution node (in most cases we will probably
be aware of them already). It is not uncommon to receive one or two
bouncers for any e-mail posting that you make. Note once again that if
everyone used news software and if we didn't have to bridge so many
incompatible e-mail networks to bring the biology community together,
we wouldn't have to deal with this problem.
Note that the BIOSCI-REQUEST address at net.bio.net was established to
trap daemon bouncers instead of passing them back to the person who
posts a message. Unfortunately due to network incompatibilities, the
BIOSCI-REQUEST trapping mechanism is often disabled when the bad
address is not on the Internet.
----------------------------------------------------------------------
HOW DOES ONE START A NEW BIOSCI NEWSGROUP/MAILING LIST?
BIOSCI's goal is to promote the use of electronic communications among
biologists and we are here to assist you in establishing new forums at
no charge. There are currently two options - create a full newsgroup
or a prototype (mailing lists only):
For full-fledged BIOSCI newsgroup status (also see "prototype" rules below)
Proposals for new groups must contain a statement of purpose for the
group and the name of a person designated as discussion leader unless
the group is in the service category such as METHODS, EMPLOYMENT, etc.
Discussion leaders are responsible for ensuring that a reasonable
level of activity is sustained on the newsgroup (see Newsgroup
Termination Policy below). The discussion leader can also propose the
creation of moderated newsgroups if he/she agrees to serve as
moderator (this requires access to Usenet news software at the
moderator's site). Proposals should be sent to
biosci-help at net.bio.net.
When a proposal is received it will be posted on
BIONEWS/bionet.announce. A ten day period for discussion on
BIOFORUM/bionet.general will follow and precede the call for votes.
After the discussion, the person proposing the newsgroup may modify or
withdraw the proposal prior to the call for votes. The modified
proposal will then be included in a call for votes on
BIONEWS/bionet.announce. The proposal must collect 80 YES votes in 30
days and the number of YES votes must exceed the number of NO votes by
at least 40 to pass.
BIOSCI management must be informed in advance of any intended efforts
to advertise the newsgroup proposal in other forums. While BIOSCI
wishes to inform potential users of the creation of newsgroups that
might be of interest to them, promotional efforts should be focussed
in forums likely to be utilized by professionals in the subject area
covered by the newsgroup proposal, and should seek participation in
the discussion of the proposal within bionet.general/BIOFORUM rather
than promoting separate discussions in other forums to which portions
of the BIOSCI readership may not have ready access.
If a proposal is not passed by the readers, there will be a three
month period before it can be brought up for another vote.
Newsgroup Termination Policy
Any group with less than 52 msgs in the previous calendar year will be
put on notice by posting an announcement to the newsgroup (not to
bionet.announce) that it faces cancellation. It can be reprieved if 80
readers respond within two weeks (this policy will be stated in the
termination announcement). It then has two months to reach a usage
level of one message per 3 days or else it will be abolished. Appeals
to the BIOSCI management about high content albeit low volume on the
group will be considered.
Newsgroups for Professional Societies in Biology
BIOSCI will create a moderated newsgroup in the bionet.prof-society
domain without voter approval for any professional society in the
biological sciences which has a membership of at least 500. Smaller
groups must go through the regular BIOSCI/bionet newsgroup creation
process. Because these groups are not discussion forums, they will be
exempted from the 52 message per year minimum posting limit and would
only be discontinued if the society in question no longer wishes to
use them. If usage seems extremely low on any group in the
bionet.prof-society domain, the BIOSCI/bionet staff will contact the
society in question and ensure that the newsgroup is still wanted.
BIOSCI "prototype" newsgroup creation policy
We will be happy to establish and administer a straight *mailing* list
*without* an associated Usenet newsgroup for a six month trial period
for anyone that wants to try to form a new electronic community in the
biological sciences (We stress that the topics are limited to
professional communications though.).
The mailing lists will be maintained *initially* only at net.bio.net
instead of at both BIOSCI sites. It will be the responsibility of the
person who proposes the list to get it up and running within the six
month period. They will have to handle promotion; our involvement at
BIOSCI at net.bio.net will be limited to creating the list, putting
out one announcement about it, and handling subscription requests.
After six months, the list will be put out for discussion and a vote
according to our procedures for full-fledged newsgroups above (unless
the organizer decides to bow out). If it passes it will become a
full-fledged BIOSCI newsgroup at both net.bio.net and daresbury.ac.uk
and will also have a parallel Usenet newsgroup. If it fails, the
prototype mailing list at net.bio.net will be shut down.
Note that this service does not preclude people who have an idea that
has widespread appeal from following our current newsgroup creation
policy and going to a vote after a 10 day discussion.
If you have an idea for a prototype newsgroup, please send it to
biosci-help at net.bio.net.
----------------------------------------------------------------------
HOW CAN I LIST MY ADDRESS INFORMATION IN THE BIOSCI USER DIRECTORY?
Below is the address form that we would like each reader of the
BIOSCI/bionet newsgroups to complete and return if you would like to
be listed in our database. The database serves as a directory that
enables biologists, who are currently using (or even just reading) the
BIOSCI newsgroups, to look up e-mail addresses and other information
about our users.
The address database is reindexed nightly for WAIS, waismail, and
gopher access. If you have access to gopher, connect to net.bio.net to
search the database. If you have access to WAIS, please use our WAIS
source biologists-addresses.src. If you are not on the Internet,
please use our waismail server (send the word "help" to
waismail at net.bio.net to get instructions; any text on the Subject:
line of your message will be ignored, so put the help command in the
body of the mail message.).
Please carefully follow the instructions for completing the form below
and return it to either of the following two addresses (whichever is
more convenient for you). Thanks in advance for taking the time to
complete and return the form.
Addresses for returning forms Location Network
----------------------------- -------- -------
biovote at net.bio.net U.S.A. Internet/BITNET
biovote at daresbury.ac.uk U.K. JANET
Making Sure That Your Information Is Current
This notice will be mailed bimonthly to each newsgroup. You should
check your database entry from time-to-time to see if your address
information is still up-to-date.
Using Gopher to complete the form
If you don't want to use a text editor, you can also use Dan
Jacobson's gopher site to fill out the address database form as
follows. Otherwise skip this section on gopher and proceed to the
instructions for filling out the form below.
> To add yourself to the database just point your
> gopher client at merlot.gdb.org and select the following:
>
> --> 15. Searching For Biologists/
>
> --> 9. E-mail Addresses of Biosci-Bionet Users/
>
>--> 1. Add (or Correct) Your Address to the BIOSCI User Address
> Data..
>
> And fill out the form.
or Rob Harper's gopher site in Europe as follows:
> Europeans can point their gopher client at gopher.csc.fi and add their
> information to the database. All entries will be mailed directly to
> Dave for incorporation in a wais source.
>
> The path to the questionare is as follows.
>
> ---> 10. Finnish EMBnet BioBox/
>
> ---> 8. FAQ Files/
>
> FAQ Files
>
> 1. EMBnet: Information.
> 2. EMBnet: Internet resources guide.
> 3. A Biologist's Guide to Internet Resources/
> 4. All FAQs (Frequently Asked Questions) Searches and Archives/
>--->5. Bionauts Address Database (questionaire) <TEL>
Important Instructions - Please Read Carefully
Please enter all responses after the : on each line, leaving one (1)
blank space after the : (i.e., before the start of your text).
Please do NOT extend your responses past the end of each line (80
characters).
PLEASE DO NOT alter any of the field identifiers such as "first
name:". If you have nothing to enter after a field identifier, PLEASE
LEAVE IT - do not delete it even if there is no data on the line in
question.
Several lines are provided at the end of the form for comments, but,
please adhere to the line length restriction.
On the date: line, please enter the date in the DD-MM-YY format, e.g.,
15-05-93 for 15 May 1993. This line will tell others when the
information was last updated. Please be sure to include the 0's for
single digit days or months, e.g., 15-05-93, not 15-5-93.
Note that the "e-mail network:" line below is for specifying, e.g.,
"Internet," "BITNET," "EARN," "JANET," or whatever other network that
your computer may be on.
If you are uncertain about any field, please feel free to leave it
blank, but please DO NOT DELETE the field identifier from the form!
In the first field below, "New information or Update ...", please
enter "N" if this is the first time that you have registered in the
directory or "U" if you are correcting a listing that you sent to us
previously.
The comment: lines may be used for anything that you like but PLEASE
DO NOT DELETE THEM FROM THE FORM OR ALTER THEM. One suggested use is
to list the names of the newsgroups in which you participate. Please
use the MAILING LIST name (see below - the latest version of the list
can be requested from biosci at net.bio.net) instead of the Usenet name
even if you don't participate by e-mail. WAIS might get confused by
the periods in the Usenet names. This allows one to retrieve via WAIS
or waismail the list of participants in a particular group.
For example:
comment: ARABIDOPSIS PLANT-BIOLOGY BIONEWS
On the comment: lines
use these names below -- NOT the Usenet names below
MAILING LIST NAME Usenet Newsgroup Name
----------------- ---------------------
ACEDB-SOFT bionet.software.acedb
AGEING bionet.molbio.ageing
AGROFORESTRY bionet.agroforestry
ARABIDOPSIS bionet.genome.arabidopsis
BIOFORUM bionet.general
BIO-INFORMATION-THEORY bionet.info-theory
BIONAUTS bionet.users.addresses
BIONEWS bionet.announce
BIO-JOURNALS bionet.journals.contents
BIO-MATRIX bionet.molbio.bio-matrix
BIOPHYSICAL-SOCIETY bionet.prof-society.biophysics
BIOPHYSICS bionet.biophysics
BIO-SOFTWARE bionet.software
BIOTHERMOKINETICS bionet.metabolic-reg
CELL-BIOLOGY bionet.cellbiol
CHLAMYDOMONAS bionet.chlamydomonas
CHROMOSOMES bionet.genome.chromosomes
COMPUTATIONAL-BIOLOGY bionet.biology.computational
CYTONET bionet.cellbiol.cytonet
DROSOPHILA bionet.drosophila
EMBL-DATABANK bionet.molbio.embldatabank
EMPLOYMENT bionet.jobs
GDB bionet.molbio.gdb
GENBANK-BB bionet.molbio.genbank
GENETIC-LINKAGE bionet.molbio.gene-linkage
GRASSES-SCIENCE bionet.biology.grasses
HIV-MOLECULAR-BIOLOGY bionet.molbio.hiv
HUMAN-GENOME-PROGRAM bionet.molbio.genome-program
IMMUNOLOGY bionet.immunology
INFO-GCG bionet.software.gcg
JOURNAL-NOTES bionet.journals.note
METHODS-AND-REAGENTS bionet.molbio.methds-reagnts
MOLECULAR-EVOLUTION bionet.molbio.evolution
MYCOLOGY bionet.mycology
NEUROSCIENCE bionet.neuroscience
N2-FIXATION bionet.biology.n2-fixation
PARASITOLOGY bionet.parasitology
PHOTOSYNTHESIS bionet.photosynthesis
PLANT-BIOLOGY bionet.plants
POPULATION-BIOLOGY bionet.population-bio
PROTEIN-ANALYSIS bionet.molbio.proteins
PROTEIN-CRYSTALLOGRAPHY bionet.xtallography
PROTISTA bionet.protista
RAPD bionet.molbio.rapd
SCIENCE-RESOURCES bionet.sci-resources
STRUCTURAL-NMR bionet.structural-nmr
TROPICAL-BIOLOGY bionet.biology.tropical
VIROLOGY bionet.virology
WOMEN-IN-BIOLOGY bionet.women-in-bio
YEAST bionet.molbio.yeast
Listing newsgroups on the comment: line is optional, of course.
Thanks again for your cooperation!
--------------- please cut here and return portion below ---------------
New information or Update to old record (enter N or U):
date (DD-MM-YY):
first name:
middle initial:
family name:
job title:
e-mail address:
e-mail network:
phone number:
FAX number:
institution:
address1:
address2:
address3:
city:
state/province:
country:
postal code:
research interest:
comment:
----------------------------------------------------------------------
WHY DIDN'T MY USENET POSTING SHOW UP ELSEWHERE?
Your local Usenet software may have defaulted to "local" distribution.
If this option is selected, only other readers of the bionet
newsgroups on your local computer will see your posting. If you want
your message to be delivered to all BIOSCI/bionet readers, please be
sure to specify "world" or "bionet" when prompted for the
Distribution:. Generally, if you press "?" or "h" when prompted, you
will see your options for controlling the distribution of your
messages on Usenet. If your message does not reach one of the two
BIOSCI nodes in the U.S. or the U.K. it will not be distributed to
people who participate in BIOSCI by e-mail.
----------------------------------------------------------------------
WHY ARE MY MESSAGES ARE GOING TO BIONET.FOLLOWUP?
This is a problem that might plague users of older versions of the
"rn" newsreading program when they try to reply to messages on
BIOFORUM/bionet.general. bionet.followup is a non-existent newsgroup.
In the "good old days" there was a newsgroup called "net.general" and
replies to net.general were posted to "net.followup." Unfortunately
the Usenet name of the BIOFORUM newsgroup, bionet.general, contains
the text "net.general" as a subset. Older versions of news software
can latch on to this text string and redirect replies to
bionet.general messages to bionet.followup. If you are plagued by this
problem, please call the following fixes, provided by Roy Smith and
Wayne Rindone, to the attention of your local systems manager:
+++++++++++++++++++++++ The problem is indeed in the rn sources,
specifically in intrp.c. In the version I have (intrp.c,v 4.3.2.11
90/12/31 11:47:44 sob Exp), It's the following code at lines 664-670:
if (h = instr(s,"net.general")) { off = h-s; strncpy(scrbuf,s,off+4);
strcpy(scrbuf+off+4,"followup");
safecpy(scrbuf+off+12,h+11,sizeof(scrbuf)); s = scrbuf; } What's going
on is that there used to be the convention that followups to articles
in the newsgroup net.general (which doesn't exist anymore and hasn't
for something like 5 years) should be placed in net.followup. For
better or for worse, the rn code attempted to enforce this convention.
What's going on in the above code is that the string "net.general" in
the Newsgroups line of an article being follow-ed-up to gets changed
to "net.followup". Unfortunately, that means "bionet.general" gets
changed to "bionet.followup". I would suggest simply deleting the
above code entirely. I'm not even sure why it's still there, other
than nobody bothered to take it out, and until bionet.general came
around, it never bit anybody. Old code never dies. It simply gets
integrated into the host genome of the program it's part of waiting
for the right environmental conditions to appear. --
roy at alanine.phri.nyu.edu (Roy Smith) Public Health Research Institute
455 First Avenue, New York, NY 10016, USA "Arcane? Did you say arcane?
It wouldn't be Unix if it wasn't arcane!" +++++++++++++++++++++++
From: Wayne Rindone <wrindone at BBN.COM> Subject: Another source of
bionet.followup problem Thought you might like to know that there are
other potential reasons for the appearance of the bogus
bionet.followup group name. A couple of months ago, I installed rn 4.4
on my workstation, expecting that to fix the bionet.followup problem,
among other things. I was very surprised to discover that I still had
bionet.followup appearing, even though it was quite clear there was
nothing in the new rn sources to account for that. It turned out that
the following lines were included in /usr/local/news/rn/Pnews.header:
case $ng in *net.general*) follow=`echo "$ng" | sed
's/net\.general/net.followup/g'` ;; *) follow="" ;; esac Once these
were removed the problem disappeared. I have no idea if this logic was
created locally at BBN or not, or if it came from elsewhere or had
wider dissemination beyond BBN. Although the problem is solved for me,
I have a bad feeling that it will turn up many places around the world
for many years to come. Feel free to mention Pnews.header as another
potential source of the problem the next time someone asks if you
think that helpful. Wayne Rindone, BBN +++++++++++++++++++++++ -------
Common questions posted to BIOSCI/bionet newsgroups
WHAT ARE ALL OF THESE REFERENCES TO FTP, WAIS, GOPHER, AND WWW/MOSAIC?
FTP
FTP stands for File Transfer Protocol and is a method for transmitting
files at high speed over the Internet. There are also e-mail servers
at various BITNET sites which provide e-mail access to FTP archives.
Send the word "HELP" to BITFTP at PUCC.BITNET for details. A sample
session of using FTP to access the BIOSCI archives follows. Keyboard
input is underlined. ### highlights comments about the procedure.
net<1>ftp net.bio.net ### connect to the BIOSCI computer
---------------
Connected to net.bio.net.
220 net.bio.net FTP server (SunOS 4.1) ready.
Name (net.bio.net:kristoff): anonymous ### login as anonymous
---------
331 Guest login ok, send ident as password.
Password: ### enter any password; typically your e-mail address
----------
230 Guest login ok, access restrictions apply.
ftp> ls ### display the directories. sometimes "dir" is used here
--
200 PORT command successful.
150 ASCII data connection for /bin/ls (134.172.2.69,3225) (0 bytes).
bin
dev
etc
lost+found
misc
pub
usr
226 ASCII Transfer complete.
72 bytes received in 0.1 seconds (0.7 Kbytes/s)
ftp> cd pub ### change to the "pub" public directory. Most FTP
------ ### sites place public material in this directory
250 CWD command successful.
ftp> ls ### list the files again. BIOSCI archives are in BIOSCI 8-)
-- ### Be sure to strictly follow upper/lower case in filenames
### when accessing FTP sites running UNIX such as net.bio.net
200 PORT command successful.
150 ASCII data connection for /bin/ls (134.172.2.69,3227) (0 bytes).
BIOSCI
README
doc
dos
mac
unix
vms
226 ASCII Transfer complete.
42 bytes received in 0.05 seconds (0.82 Kbytes/s)
ftp> cd BIOSCI
---------
250 CWD command successful.
ftp> ls
--
200 PORT command successful.
150 ASCII data connection for /bin/ls (134.172.2.69,3228) (0 bytes).
ADDRESSES
AGEING
AGROFORESTRY
ARABIDOPSIS
BIO-INFO
BIO-JOURNALS
BIO-MATRIX
BIO-SOFTWARE
BIOFORUM
BIONEWS
CHROMOSOME-22
COMPUTATIONAL-BIOLOGY
EMBL-DATABANK
EMPLOYMENT
GDB
GENBANK-BB
GENETIC-LINKAGE
HIV-BIOL
HUMAN-GENOME
IMMUNOLOGY
JRNLNOTE
METHDS-REAGNTS
MOLECULAR-EVOLUTION
NEUROSCIENCE
PLANT-BIOLOGY
POPULATION-BIOLOGY
PROTEIN-ANALYSIS
PROTEIN-CRYSTALLOGRAPHY
SCIENCE-RESOURCES
TROPICAL-BIOLOGY
VIROLOGY
WOMENINBIOLOGY
biosci-uk.infosheet
biosci-us.infosheet
biosci.FAQ
226 ASCII Transfer complete.
562 bytes received in 0.1 seconds (5.5 Kbytes/s)
ftp> cd PROTEIN-ANALYSIS### We want to look at PROTEIN-ANALYSIS archives
-------------------
250 CWD command successful.
ftp> ls
--
200 PORT command successful.
150 ASCII data connection for /bin/ls (134.172.2.69,3233) (0 bytes).
8912
9001
9002
9003
9004
9005
9006
9007
9008
9009
9010
9011
9012
9101
9102
9103
9104
9105
9106
9107
9108
9109
9110
9111
9112
9201
9202
9203
9204
9205
9206
9207
9208
9209
9210
9211
current
226 ASCII Transfer complete.
225 bytes received in 0.12 seconds (1.8 Kbytes/s)
ftp> get 9211 ### Retrieve the file for November 1992.
--------
200 PORT command successful.
150 ASCII data connection for 9211 (134.172.2.69,3234) (208763 bytes).
226 ASCII Transfer complete.
local: 9211 remote: 9211
213849 bytes received in 1.4 seconds (1.5e+02 Kbytes/s)
ftp> bye ### End the FTP session. Some systems use quit or exit.
---
221 Goodbye.
Liberal use of the ? key and help at the ftp> prompt will provide
information on other options.
WAIS
WAIS stands for Wide Area Information Server. WAIS software allows
information to be stored at many sites around the Internet in to a
particular format. Computers running WAIS software can query these
sources remotely using a standard protocol. Free software is available
for many popular hardware platforms, but requires some systems
expertise to install. Now that you know how to use FTP (above), you
can use anonymous ftp to think.com and cd to the "wais" directory for
software and more information. A public WAIS account is accessible to
Internet users by using the command
telnet quake.think.com
and logging in as "wais" (lowercase).
Gopher
Gopher is both a user-friendly interface to the FTP program described
above and a network searching tool similar to WAIS (which can also
utilize WAIS information sources). Gopher software is available as
described below for many platforms; TurboGopher on the Macintosh is
especially slick! Don Gilbert (gilbertd at silver.ucs.indiana.edu) at
ftp.bio.indiana.edu runs the excellent IUBIO Gopher Hole with many
services of use to biologists, including search and retrieval of
GenBank entries and BIOSCI/bionet newsgroup postings among many other
information resources. Dan Jacobson (danj at gdb.org) runs an excellent
gopher server at merlot.gdb.org with software, database, news, and
government information archives. In Europe Rob Harper
(harper at finsun.csc.fi) has set up a similar gold mine of information
at gopher.csc.fi. Please see the section on searching the BIOSCI
archives for other useful gopher sites.
The following information is excerpted from the Gopher FAQ. Many
questions have been cut out for brevity.
----------------------------------------------------------------------
Common Questions and Answers about the Internet Gopher, a
client/server protocol for making a world wide information service,
with many implementations. Posted to comp.infosystems.gopher and
news.answers every two weeks.
The most recent version of this FAQ can be gotten through gopher, or
via anonymous ftp:
rtfm.mit.edu:/pub/usenet/news.answers/gopher-faq
Those without FTP access should send e-mail to mail-server at rtfm.mit.edu
with "send usenet/news.answers/finding-sources" in the body to find out
how to do FTP by e-mail.
-------------------------------------------------------------------
List of questions in the Gopher FAQ:
Q0: What is Gopher?
Q1: Where can I get Gopher software?
Q2: What do I need to access Gopher?
Q3: Where are there publicly available logins for Gopher?
Q5: Who Develops Gopher Software?
Q12: What is the relationship between Gopher and (WAIS, WWW, ftp)?
Q13: Are papers or articles describing Gopher available?
-------------------------------------------------------------------
Q0: What is Gopher?
A0: The Internet Gopher client/server provides a distributed
information delivery system around which a world/campus-wide
information system (CWIS) can readily be constructed. While
providing a delivery vehicle for local information, Gopher
facilitates access to other Gopher and information servers
throughout the world.
-------------------------------------------------------------------
Q1: Where can I get Gopher software?
A1: via anonymous ftp to boombox.micro.umn.edu. Look in the directory
/pub/gopher
--------------------------------------------------------------------
Q2: What do I need to access Gopher?
A2: You will need a gopher "client" program that runs on your local PC
or workstation
There are clients for the following systems. The directory
following the name is the location of the client on the anonymous
ftp site boombox.micro.umn.edu (134.84.132.2) in the directory
/pub/gopher.
Unix Curses & Emacs : /pub/gopher/Unix/gopher1.03.tar.Z
Xwindows : /pub/gopher/Unix/xgopher1.1a.tar.Z
Macintosh Hypercard : /pub/gopher/Mac_client/
Macintosh Application : /pub/gopher/Macintosh-TurboGopher
DOS w/Clarkson Driver : /pub/gopher/PC_client/
NeXTstep : /pub/gopher/NeXT/
VM/CMS : /pub/gopher/Rice_CMS/ or /pub/gopher/Vienna_CMS/
VMS : /pub/gopher/VMS/
OS/2 2.0 : /pub/gopher/os2/
MVS/XA : /pub/gopher/mvs/
Many other clients and servers have been developed by others, the
following is an attempt at a comprehensive list.
A Macintosh Application, "MacGopher".
ftp.cc.utah.edu:/pub/gopher/Macintosh
Another Macintosh application, "GopherApp".
ftp.bio.indiana.edu:/util/gopher/gopherapp
A port of the UNIX curses client for DOS with PC/TCP
oac.hsc.uth.tmc.edu:/public/dos/misc/dosgopher.exe
A port of the UNIX curses client for PC-NFS
bcm.tmc.edu:/nfs/gopher.exe
A beta version of the PC Gopher client for Novell's LAN Workplace
for DOS
lennon.itn.med.umich.edu:/gopher
A Xwindows/DECwindows client
job.acs.ohio-stat.edu:
Most of the above clients can also be fetched via a gopher client
itself. Put the following on a gopher server:
Type=1
Host=boombox.micro.umn.edu
Port=70
Path=
Name=Gopher Software Distribution.
Or point your gopher client at boombox.micro.umn.edu, port 70 and
look in the gopher directory.
There are also a number of public telnet login sites available.
The University of Minnesota operates one on the machine
"consultant.micro.umn.edu" (134.84.132.4) See Q3 for more
information about this. It is recommended that you run the client
software instead of logging into the public telnet login sites. A
client uses the custom features of the local machine (mouse,
scroll bars, etc.) A local client is also faster.
---------------------------------------------------------------------
Q3: Where are there publicly available logins for Gopher?
A3: Here is a short list, use the site closest to you to minimize
network lag.
Non-tn3270 Public Logins:
Hostname IP# Login Area
------------------------- --------------- ------ -------------
consultant.micro.umn.edu 134.84.132.4 gopher North America
gopher.uiuc.edu 128.174.33.160 gopher North America
panda.uiowa.edu 128.255.40.201 panda North America
gopher.sunet.se 192.36.125.2 gopher Europe
info.anu.edu.au 150.203.84.20 info Australia
gopher.chalmers.se 129.16.221.40 gopher Sweden
tolten.puc.cl 146.155.1.16 gopher South America
ecnet.ec 157.100.45.2 gopher Ecuador
tn3270 Public Logins:
Hostname IP# Login Area
------------------------- --------------- ------ -------------
pubinfo.ais.umn.edu 128.101.109.1 -none- North America
It is recommended that you run the client software instead of
logging into the public login sites. A client uses the
custom features of the local machine (mouse, scroll bars, etc.)
and is local client is also faster.
---------------------------------------------------------------------
Q5: Who Develops Gopher Software?
A5: Gopher was originally developed in April 1991 by the University
of Minnesota Microcomputer, Workstation, Networks Center to help
our campus find answers to their computer questions.
It has since grown into a full-fledged World Wide Information
System used by a large number of sites in the world.
Many people have contributed to the project, too numerous to
count.
The people behind the much of the gopher software can be reached
via e-mail at gopher at boombox.micro.umn.edu, or via paper mail:
Internet Gopher Developers
100 Union St. SE #190
Minneapolis, MN 55455 USA
Or via FAX at:
+1 (612) 625-6817
---------------------------------------------------------------------
Q12: What is the relationship between Gopher and (WAIS, WWW, ftp)?
A12: Gopher is intimately intertwined with these two other systems.
As shipped the Unix gopher server has the capability to:
- Search local WAIS indices.
- Query remote WAIS servers and funnel the results to gopher
clients.
- Query remote ftp sites and funnel the results to gopher
clients.
- Be queried by WWW (World Wide Web) clients (either using
built in gopher querying or using native http querying.
-------------------------------------------------------------------
Q13: Are papers or articles describing Gopher available?
A13: Gopher has a whole chapter devoted to it in :
_The_Whole_Internet_, Ed Kroll, O'Reilly, 1992 (Editors note:
..Great book, go out and buy a bunch!)
Other references include:
_The_Internet_Gopher_, "ConneXions", July 1992, Interop.
_Exploring_Internet_GopherSpace_ "The Internet Society News", v1n2 1992,
(You can subscribe to the Internet Society News by sending e-mail to
isoc at nri.reston.va.us)
_The_Internet_Gopher_Protocol_, Proceedings of the Twenty-Third
IETF, CNRI, Section 5.3
_Internet_Gopher_, Proceedings of Canadian Networking '92
_The_Internet_Gopher_, INTERNET: Getting Started, SRI
International, Section 10.5.5
_Tools_help_Internet_users_discover_on-line_treasures, Computerworld,
July 20, 1992
_TCP/IP_Network_Administration_, O'Reilly.
Balakrishan, B. (Oct 1992)
"SPIGopher: Making SPIRES databases accessible through the
Gopher protocol". SPIRES Fall '92 Workshop, Chapel Hill, North
Carolina.
Tomer, C. Information Technology Standards for Libraries,
_Journal of the American Society for Information Science_,
43(8):566-570, Sept 1992.
-------------------------------------------------------------------
WWW/Mosaic
The World-Wide Web (WWW) has become the latest hot network item,
especially since the advent of the Mosaic software from the National
Center for Supercomputing Applications at the University of Illinois.
In a nutshell, Mosaic is a "hypertext browser," i.e., an application
program that lets you read through the thousands of cross-linked
hypertext documents, pictures and sound bites now available on the
Internet. A more detailed explanation will be included in a future
version of this FAQ. For now, we recommend using FTP to
ftp.ncsa.uiuc.edu to pick up a version of Mosaic for your hardware
platform. Note that to get the most out of Mosaic, your machine needs
a direct and fast Internet connection. 9600 baud links or lower will
not be a happy compromise except possibly for browsing plain text
documents in some cases.
----------------------------------------------------------------------
PLEASE HELP ME FIND THE E-MAIL ADDRESS FOR DR. ...
If you can not get this information by calling the person in question,
there are several other resources that can be of help. As of May 1993,
BIOSCI at net.bio.net began running a BIOSCI user address directory
which can be accessed through gopher to net.bio.net or via WAIS or
waismail. The WAIS source is called biologists-addresses.src and is
updated daily. See the FAQ section entitled "How do I find back issues
of BIOSCI postings?" for information on WAIS and waismail access.
Instructions for using the address source are included in the waismail
help file which can be retrieved by sending the word "help" to
waismail at net.bio.net (leave the Subject: line of your message blank.)
The second easy route is to post your request to the
BIONAUTS/bionet.users.addresses newsgroup managed by Rob Harper. Odds
are that you will get a response fairly promptly, but, if not, there
are other routes described below.
If the person in question has posted to BIOSCI/bionet or another
Usenet newsgroup, they will be listed in the "usenet-addresses" WAIS
source. If you are on the Internet, telnet to quake.think.com and
login as "wais" (lowercase). After entering your terminal type, select
the usenet-addresses source from the list presented to you (use the
up-arrow key to get there more quickly since it is near the end of a
long list). When the source is highlighted, press the return key and
then enter the person's surname at the Keywords: prompt to begin the
search. Available commands are listed at the bottom of the screen.
When finished, press "s" to return to the source menu and then "q" to
quit.
For those who do not have access to the Internet, the usenet-addresses
source can also be accessed by e-mail. Please send mail to
mail-server at rtfm.mit.edu with "help" in the body of the message in
order to receive more information.
Another source of information for finding Internet, but not BITNET,
addresses is netfind. Use the command
telnet bruno.cs.colorado.edu
and login as "netfind" without a password. The program is menu-driven
and pretty self-explanatory. Unfortunately it is not available to
people on BITNET.
Gopher is also useful in the address search. For example, Dan Jacobson
provides access to several directories of biologists at his gopher
hole on merlot.gdb.org.
None of the above methods is guaranteed to return you an answer, so
you may still have to resort to the telephone or (groan) regular mail
to make contact 8-(.
----------------------------------------------------------------------
HOW DO I REPORT A PROBLEM IN A BIOLOGICAL DATA BASE?
(answer contributed by Dr. John Garavelli of PIR)
Brookhaven Protein Data Bank bionet.xtallography
PIR or SWISS-PROT bionet.molbio.proteins
NCBI GenBank DataBank bionet.molbio.genbank
EMBL Databank bionet.molbio.embldatabank
Human Genome Database (GDB) bionet.molbio.gdb
Museums and Herbaria bionet.plants, or private inquiry
to beach at huh.harvard.edu
Since staff members of these databases usually monitor the
corresponding newsgroups fairly closely, a posting about a problem on
the appropriate board will usually get a response from someone on a
database staff fairly quickly. Problems that might not be of general
interest or corrections to particular entries should be directed as
follows.
Database address
-------- -------
Brookhaven pdb at chm.chm.bnl.gov, pdb at bnlchm.bitnet
PIR postmaster at nbrf.georgetown.edu, postmast at gunbrf.bitnet
SWISS-PROT bairoch at cmu.unige.ch
GenBank update at ncbi.nlm.nih.gov
EMBL update at embl-heidelberg.de
GDB help at welch.jhu.edu
Herbaria beach at huh.harvard.edu
----------------------------------------------------------------------
WHAT ABOUT SUBMITTING SEQUENCE DATA TO GENBANK, EMBL, DDBJ OR PIR?
(answer contributed by Dr. John Garavelli of PIR)
Researchers should submit nucleotide sequence data directly to GenBank
or EMBL for assignment of an accession number prior to publication.
Derived amino acid sequence data may also be included at the same
time. Amino acid sequence data submitted in this way to GenBank, EMBL
or DDBJ is eventually passed on to PIR, and need not be submitted
separately to PIR. This is done so correct cross-references can be
made between nucleotide and protein sequence accession numbers. All
other determined amino acid sequences may be submitted directly to PIR
when the authors permit their public release prior to publication.
Authors are strongly urged to use the sequence submission software
package AUTHORIN to submit their sequence data to the databanks; a
free copy (for either the IBM PC or Macintosh) can be obtained by
sending your request and regular postal mailing address to:
authorin at ncbi.nlm.nih.gov
Please be sure to specify the IBM or Mac version when sending your
request.
Japanese authors who use the NEC 9801 PC should communicate directly
with DDBJ, as these machines use a version of DOS that is
significantly different enough to render the discs unreadable on
MS-DOS computers here. The staff at DDBJ will forward the data to the
appropriate databank via electronic mail. DDBJ may be contacted at:
ddbjsubs at flat.nig.ac.jp
The address for GenBank submissions is:
U.S. mail (for submissions on diskette, indicate whether Mac or PC):
GenBank Submissions
National Center for Biotechnology Information
Bldg. 38A, Room 8N-803
8600 Rockville Pike
Bethesda, MD 20894
E-mail submission of new sequences: gb-sub at ncbi.nlm.nih.gov
E-mail submission of updates: update at ncbi.nlm.nih.gov
The address for EMBL submissions is:
EMBL Data Submissions
Postfach 10.2209
D-6900, Heidelburg
Federal Republic of Germany
Telephone (+49) 6221-387-258
Electronic mail: DATASUBS at EMBL-Heidelberg.DE
The address for DDBJ submissions is:
DNA Database of Japan
Center for Genetic Information Research
National Institute of Genetics
111 Yata
Mishima, Shizuoka 411
JAPAN
Telephone (+81) 559-75-3651
Electronic mail: ddbjsubs at flat.nig.ac.jp
The address for PIR submissions is:
PIR Submissions
National Biomedical Research Foundation
3900 Reservoir Road, NW
Washington, DC 20007
U.S.A.
Telephone: (202) 687-2121
Electronic mail: FILESERV at GUNBRF.BITNET, FILESERV at NBRF.Georgetown.EDU
While we would again urge that AUTHORIN be used as the first choice in
data submission tools, the GenBank/EMBL/PIR Data Submission Form can
be obtained by sending a message consisting of the words
SEND SUBFORM
to the PIR FILESERV address. This form can be filled in using any text
editor, saved in ASCII (text) format, and mailed electronically or on
disk to the databanks.
Please, do not submit data either by electronic mail or on disk in
files that are formatted for word processing programs. Such files are
almost always unreadable except by systems with the same configuration
of computer, operating system and word-processing program. For files
sent by disk, either DOS or Mac formatted disks can be used but
regular "double density" disks are preferred to "high density" disks.
More information about the Bionews mailing list | {
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5,541,290,918,778,685,000 | Modified aminoacyl-tRNA synthetase and use thereof
The present invention provides modified aminoacyl-tRNA synthetases (ARSs) having increased reactivity with N-methyl amino acids compared to natural aminoacyl-tRNA synthetases. The modified aminoacyl-tRNA synthetases according to the present invention can aminoacylate tRNAs with their corresponding N-methyl-substituted amino acids such as N-methyl-phenylalanine, N-methyl-valine, N-methyl-serine, N-methyl-threonine, N-methyl-tryptophan, and N-methyl-leucine more efficiently than natural aminoacyl-tRNA synthetases. The present invention enables a more efficient production of polypeptides containing N-methyl amino acids.
Skip to: Description · Claims · References Cited · Patent History · Patent History
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application of PCT/JP2016/057707, filed Mar. 11, 2016, which claims priority from Japanese application JP 2015-051202, filed Mar. 13, 2015, each of which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
The present invention relates to aminoacyl-tRNA synthetases (ARSs) that aminoacylate tRNA with the corresponding N-methyl amino acid more efficiently than natural aminoacyl-tRNA synthetases, and use thereof. More specifically, the present invention relates to aminoacyl-tRNA synthetases that have modified amino acid sequences, which are able to aminoacylate a tRNA with one of six N-methyl-substituted amino acids corresponding to the tRNA, namely, N-methyl-phenylalanine, N-methyl-valine, N-methyl-serine, N-methyl-threonine, N-methyl-tryptophan, and N-methyl-leucine, more efficiently than natural ARSs, and uses thereof. The aminoacyl-tRNA synthetases with modified amino acid sequences according to the present invention can be used to produce peptides that selectively and regioselectively contain N-methyl amino acids with high efficiency.
BACKGROUND ART
Generally in organisms on earth, information stored in DNA (=an information-storing substance) defines, via RNA (=an information-transmitting substance), the structures of proteins (=functional substances) and functions resulting from the structures. Polypeptides and proteins are composed of 20 types of amino acids. The information stored in DNA, which is composed of four kinds of nucleotides, is transcribed into RNA and then translated into amino acids, which make polypeptides and proteins.
During translation, tRNA plays the role of an adaptor that matches a stretch of three nucleotides to one amino acid, and aminoacyl-tRNA synthetase (aminoacyl-tRNA synthetase; ARS) is involved in the attachment of tRNA to its amino acid.
ARSs are enzymes that specifically attach an amino acid to its corresponding tRNA. There are 20 types of ARSs, each corresponding to each of the 20 types of naturally-occurring amino acids with a few exceptions, in every biological species. Of the 20 kinds of proteinaceous amino acids, ARS precisely acylates tRNA having an anticodon corresponding to an arbitrary codon, using the specific amino acid assigned to the codon. In other words, a tRNA synthetase corresponding to a certain amino acid can distinguish a tRNA corresponding to that amino acid from tRNAs corresponding to other amino acids, and does not attach other amino acids.
In translation of an mRNA into a polypeptide chain, a tRNA bound to its corresponding amino acid (aminoacyl-tRNA) pairs with the appropriate codon on the mRNA starting from the initiation codon and form hydrogen bonds with the mRNA on ribosomes. This is followed by peptidyl transfer to the amino acid on the adjacent aminoacyl-tRNA bound corresponding to the next codon. The first tRNA that released the amino acid by the transfer is liberated from the mRNA and can reattach its corresponding amino acid catalyzed by ARS. Translation is terminated upon reaching the mRNA's stop codon and upon arrival of a protein called the termination factor, which releases the polypeptide chain from the ribosome. Proteins within the living body are produced via such processes. The proteins then exert important physiological functions in the living body.
Meanwhile, in the field of pharmaceuticals of which bioactivities are exerted similarly in living bodies, the possibility of creating new pharmaceuticals using compounds having a molecular weight from 500 to 2000, called “middle molecules”, is being anticipated in the field of drug discovery where it was considered difficult to create drugs with conventional low molecular weight compounds having a molecular weight less than 500. A representative example is cyclosporine A, a naturally-derived middle molecule drug, which is a peptide consisting of 11 residues that is produced by microorganisms, inhibits the intracellular target cyclophilin, and can be orally administered.
The Cyclosporine A peptide is characterized by including the non-natural amino acids “N-methyl amino acids” as components. Triggered by this, multiple studies have recently reported that the incorporation of N-methyl amino acids into peptides can increase drug-likeness of the peptides, and this is being further applied to drug discovery (Non Patent Literature 1, 2, 3). Particularly, it has come to be known that the incorporation of N-methyl amino acids leads to decrease in hydrogen bond-donating hydrogens, acquisition of protease resistance, and fixed conformation, and contributes to membrane permeability and metabolic stability (Non Patent Literature 1,4, Patent Literature 1).
This paves way to the conception of drug discovery methods that select pharmaceutical candidate substances from a library of diverse peptides containing multiple N-methyl amino acids. In terms of diversity and ease of screening, much anticipated are mRNA display libraries of N-methyl amino acid-containing peptides, and such, which use a cell-free translation system (Non Patent Literature 9, 10, Patent Literature 1). First, a display library is constructed, which is a collection of molecules forming one-for-one pairs between an enormous variety of RNA or DNA molecules (genotype) or the like and peptides encoded by these molecules (phenotype). The display library is then allowed to bind to a target protein or the like, followed by washing to remove non-bound molecules and selecting a molecule in the library, which is contained scarcely, in extremely small amounts. The selected RNA (DNA) molecule can be then sequenced to easily obtain the sequence information of the bound peptide. Particularly, an mRNA display library and a ribosome display library utilizing a cell-free translation system can be used to easily analyze 1012-14 diverse types of molecules (Non Patent Literature 11). Recently, a method that can prepare peptides containing non-proteinaceous amino acids using a reconstituted cell-free translation system has been also developed, enabling combination with display techniques to construct an N-methyl amino acid-containing peptide display library (Non Patent Literature 10).
Some methods for preparing N-methyl amino acid-containing peptides by translation of mRNAs are known so far. These methods are performed by separately preparing beforehand “N-methyl aminoacyl-tRNAs” and adding these to a translation system.
First, in the pdCpA method developed by Hecht et al. (Non Patent Literature 5), an N-methyl aminoacyl-tRNA is prepared beforehand by ligating pdCpA (5′-phospho-2′-deooxyribocytidylriboadenosine) acylated with a chemically-synthesized non-natural N-methyl amino acid to a tRNA lacking 3′-terminal CA obtained by transcription using T4 RNA ligase. This method has been used to introduce amino acids including N-methylalanine and N-methylphenylalanine (Non Patent Literature 6). However, when the present inventors attempted to introduce multiple N-methyl amino acids by preparing several complexes between non-natural N-methyl amino acids and tRNAs using the pdCpA method and adding the complexes to a cell-free translation system, translational efficiency decreased. Particularly, N-methylvaline could not be introduced (unpublished data).
As a different method, Suga et al. reported a method for aminoacylating tRNAs with N-methyl amino acids activated in advance by esterification using an artificial RNA catalyst (Flexizyme) (Patent Literature 2), and successfully introduced multiple types of N-methyl amino acids by translation. This method can be applied to various side chain structures, but aminoacylation efficiency of amino acids with nonaromatic side chains is in many cases 40 to 60% which is by no means high, and particularly, N-methylvaline introduction has not been confirmed as with the pdCpA method (Non Patent Literature 3).
Moreover, in the method of Szostak et al., aminoacyl-tRNAs are obtained by using tRNAs extracted from Escherichia coli and wild-type ARSs, and then preparing N-methyl aminoacyl-tRNAs via a chemical N-methylation reaction consisting of three steps. However, side chains that are efficiently translated in this method are limited to only the three side chains valine, leucine, and threonine. This method also requires cumbersome operations and further results in contamination of trace amounts of natural amino acids (the starting material) resulting from incomplete progression of the N-methylation reaction. Such difficulties in controlling the reaction directly affect the purity of products (Non Patent Literature 2).
Moreover, since these techniques add N-methyl aminoacyl-tRNAs prepared outside a translation system to a translation reaction solution, N-methyl aminoacyl-tRNAs are not re-produced in the translation system and thus are only consumed in the translation process. This requires addition of large amounts of N-methyl aminoacyl-tRNAs, but this addition itself of large amounts of tRNAs contributes to the reduction of peptide yield (Non Patent Literature 7). Further, instability of aminoacyl-tRNAs in the translation solution becomes problematic. Aminoacyl-tRNAs have been shown to be hydrolyzed under physiological conditions at pH 7.5 due to the presence of ester bonds between amino acids and tRNAs (Non Patent Literature 12). Half-life of aminoacyl-tRNAs depends on amino acid side chains, the shortest being 30 minutes. Hydrolysis of aminoacyl-tRNA is suppressed when it forms a complex with an aminoacyl-tRNA-elongation factor Tu (EF-Tu), but aminoacyl-tRNAs in excess of the concentration of EF-Tu present in the translation system are hydrolyzed. That is to say, as the translation reaction proceeds, deacylation of aminoacyl-tRNAs added at the start of translation proceeds, and at the end, aminoacyl-tRNAs having N-methyl amino acids are exhausted. In fact, Szostak et al. perceived this depletion as a problem and added N-methyl aminoacyl-tRNAs twice, at the start of translation and during the reaction, when synthesizing a polypeptide containing multiple N-methyl amino acids (Non Patent Literature 2).
The above-mentioned problems regarding introduction of N-methyl amino acids can be solved if there are ARSs for N-methyl amino acids having functions similar to natural ARSs for natural amino acids, but ARSs have an ability to precisely recognize their substrates and thus have limitations. As an exception, Murakami et al. reported that natural HisRS and PheRS could be used to introduce N-methylhistidine and N-methylphenylalanine into peptides in a cell-free translation system (Non Patent Literature 8, 13). Also, Szostak et al. confirmed that natural ARSs were used to aminoacylate tRNAs with the six N-methyl amino acids N-methylvaline, N-methylleucine, N-methyl aspartic acid, N-methylhistidine, N-methyllysine, and N-methyltryptophan (Non Patent Literature 14). However, even though a subsequent report using a cell-free translation system and natural ARSs that analyzed translational synthesis of peptides containing N-methylhistidine and N-methyl aspartic acid by mass spectrum reported a certain level of yield, in the case of peptides containing N-methylvaline, N-methylleucine, N-methyllysine, and N-methyltryptophan, it was shown that the efficiency of translational synthesis (ribosomal synthesis) is very low (Non Patent Literature 8). These reports reveal that aminoacylation with N-methyl amino acids and translational introduction of N-methyl amino acids into peptides using natural ARSs has been confirmed substantially in only the three cases of N-methylphenylalanine, N-methylhistidine, and N-methyl aspartic acid.
There are some prior art in which natural ARSs have been modified to give them the function to catalyze the attachment of non-natural amino acids to tRNAs (Patent Literature 3, 4, 5). Even though these are modified ARSs that catalyze the attachment of non-natural amino acids to tRNAs, and substrates of these modified ARSs are amino acids mainly having side chain derivatives of phenylalanine and tyrosine, modified ARSs having N-methyl amino acids as substrates, and modified ARSs that can introduce multiple N-methyl amino acid residues into peptides have not been known.
CITATION LIST Patent Literature
• Patent Literature 1: WO2013/100132
• Patent Literature 2: WO2007/066627
• Patent Literature 3: WO2003/014354
• Patent Literature 4: WO2007/103307
• Patent Literature 5: WO2002/085923
Non Patent Literature
• Non Patent Literature 1: R. S. Lokey et al., Nat. Chem. Biol. 2011, 7(11), 810-817.
• Non Patent Literature 2: J. W. Szostak et al., J. Am. Chem. Soc. 2008, 130, 6131-6136.
• Non Patent Literature 3: T. Kawakami et al., Chemistry & Biology, 2008, Vol. 15, 32-42.
• Non Patent Literature 4: H. Kessler et al., J. Am. Chem. Soc. 2012, 134, 12125-12133.
• Non Patent Literature 5: S. M. Hecht et al., J. Biol. Chem. 253 (1978) 4517-4520.
• Non Patent Literature 6: Z. Tan et al., J. Am. Chem. Soc. 2004, 126, 12752-12753.
• Non Patent Literature 7: A. O. Subtelny et al., Angew Chem Int Ed 2011 50 3164.
• Non Patent Literature 8: M. C. T. Hartman et al., PLoS one, 2007, 10, e972.
• Non Patent Literature 9: S. W. Millward et al., J. Am. Chem. Soc., 2005, 127, 14142-14143.
• Non Patent Literature 10: Y. Yamagishi et al., Chem. Biol., 18, 1562-1570, 2011.
• Non Patent Literature 11: H. R. Hoogenboom, Nature Biotechnol. 23, 1105-1116, 2005.
• Non Patent Literature 12: J. R. Peacock et al., RNA, 20, 758-64, 2014.
• Non Patent Literature 13: T. Kawakami, ACS Chem Biol., 8, 1205-1214, 2013.
• Non Patent Literature 14: M. C. T. Hartman et al., Proc Natl Acad Sci USA., 103, 4356-4361, 2006.
SUMMARY OF THE INVENTION Problems to be Solved by the Invention
An objective of the present invention is to provide modified ARSs that have been modified to increase reactivity, and which use N-methyl amino acids as substrates. More specifically, an objective of the present invention is to provide a novel modified ARS that catalyzes the acylation reaction in which tRNAs attach non-natural N-methyl amino acids, particularly N-methyl-phenylalanine, N-methyl-valine, N-methyl-serine, N-methyl-threonine, N-methyltryptophan, and N-methylleucine, without using large amounts of tRNAs in order to efficiently produce peptides containing multiple N-methyl amino acids, and uses thereof.
Means for Solving the Problems
In order to obtain ARSs having increased reactivity with N-methyl amino acids, the present inventors obtained multiple ARS genes that employ different amino acids as substrates and introduced mutations into the genes to construct mutated ARS genes encoding ARSs with altered amino acid sequences. These modified ARSs were expressed and collected, and were incubated with tRNAs in the presence of unmodified amino acids or N-methyl amino acids to determine aminoacylation reaction. As a result of estimating the conformation formed in the N-methyl amino acid-ARS interaction, and after much trial and error, the present inventors successfully obtained modified ARSs, including multiple ARSs such as phenylalanyl-tRNA synthetase (PheRS), seryl-tRNA synthetase (SerRS), valyl-tRNA synthetase (ValRS), threonyl-tRNA synthetase (ThrRS), leucyl-tRNA synthetase (LeuRS), and tryptophanyl-tRNA synthetase (TrpRS), with increased activity in the aminoacylation reaction with N-methyl amino acids, compared to wild-type ARSs.
For example, 0.1 μM wild-type PheRS hardly incorporated N-methylphenylalanine into ribosomally-synthesized peptides even when 1 mM N-methylphenylalanine was added. On the other hand, 0.1 μM modified PheRS clearly incorporated N-methylphenylalanine into peptides even when 0.25 mM N-methylphenylalanine was added (Example 1). The amount of phenylalanine and N-methylphenylalanine translationally introduced (ribosomally introduced) into peptides were measured by mass spectroscopy using MALDI-TOF MS. The ratio of the peak values (the peak intensity of the peptide containing N-methylphenylalanine/the peak intensity of the peptide containing phenylalanine) at the time of 0.25 mM N-methylphenylalanine addition was 0.8 when using wild-type PheRS, whereas it dramatically increased to 12.4 when using the modified PheRS α subunit (Example 1). When sequences containing two consecutive and three consecutive phenylalanines were allowed to translate, peptides containing two consecutive and three consecutive N-methylphenylalanines were confirmed to be synthesized respectively, and the efficiency was significantly higher than that using the pdCpA method. Also, ValRS was used to perform translational synthesis in the presence of 5 mM N-methylvaline, and the peptide products were analyzed with mass spectroscopy. A peptide incorporated with unmodified valine was detected as the main product when using wild-type ValRS, whereas a peptide incorporated with N-methylvaline was observed as the main product when using modified ValRS (Example 2). Furthermore, the selectivity to N-methylvaline was successfully increased by introducing mutations into the editing domain of ValRS and decreasing aminoacylation activity with unmodified Val (Example 7). When sequences containing two consecutive and three consecutive valines were allowed to translate, peptides containing two consecutive and three consecutive N-methylvalines were confirmed to be synthesized respectively (Example 2). For SerRS, an N-methylserine-incorporated translation product was detected as the main product when modified SerRS was used under conditions in which an unmodified serine-incorporated translation product is detected as the main product when using wild-type SerRS (Example 3). Even for ThrRS, an N-methyl Thr-incorporated translation product was observed when modified ThrRS was used under conditions in which an unmodified Thr-incorporated translation product is detected when using wild-type ThrRS; whereas it was demonstrated that translation products incorporated with unmodified Thr were hardly observed and the peptide with N-methyl Thr introduced was synthesized with higher purity compared to that achieved with wild-type ThrRS (Example 4). For TrpRS, unmodified Trp was detected as a main product in using wild-type TrpRS, whereas the translation product with N-methyl Trp incorporated was observed as a main product using the modified TrpRS (Example 5). For LeuRS, translation products containing N-methyl Leu were not observed in using wild-type LeuRS, whereas it is revealed that translation products with N-methyl Leu incorporated were produced as much as translation products containing unmodified Leu when modified LeuRSs were used (Example 6). Thus, the modified ARSs according to the present invention can be used to introduce N-methyl amino acids into peptides more efficiently than wild-type ARS.
Accordingly, the following inventions are provided.
The present invention provides ARSs having reactivity with N-methyl amino acids. Specifically, the present invention relates to an aminoacyl-tRNA synthetase (aminoacyl-tRNA synthetase; ARS) that has an altered amino acid sequence and is able to incorporate any N-methyl amino acid, particularly the six N-methyl-substituted amino acids of N-methyl-phenylalanine, N-methyl-valine, N-methyl-serine, N-methyl-threonine, N-methyltryptophan, and N-methylleucine more efficiently than natural ARSs and use thereof. The ARS with an altered amino acid sequence according to the present invention can be used to produce peptides selectively and regioselectively containing any N-methyl amino acid from among these N-methyl amino acids with high efficiency.
The present invention further relates to a method for producing polypeptides containing non-natural amino acids using a modified ARS according to the present invention. More specifically, the present invention relates to a method for producing polypeptides containing N-methylphenylalanine, N-methylvaline, N-methylserine, N-methylthreonine, N-methyltryptophan, and N-methylleucine using ARSs for phenylalanine, valine, serine, threonine, tryptophan, and leucine, respectively, with altered amino acid sequences.
Namely, the present invention provides the following inventions:
• [1] A polypeptide comprising a modified aminoacyl-tRNA synthetase (ARS), wherein the ARS is able to incorporate an N-methyl amino acid more efficiently than an original, natural ARS.
• [2] A polypeptide modified to enhance an aminoacylation reaction with an N-methyl amino acid, wherein the polypeptide has aminoacyl-tRNA synthetase (ARS) activity, wherein the modification comprises at least one amino acid substitution that causes a decrease of 10 or more in molecular weight.
• [3] The polypeptide according to [1] or [2], wherein the N-methyl amino acid is selected from the group consisting of valine, serine, phenylalanine, threonine, tryptophan, and leucine.
• [4] The polypeptide according to any one of [1] to [3], wherein the ARS is selected from the group consisting of ValRS, SerRS, PheRS α subunit, ThrRS, TrpRS, and LeuRS.
• [5] The polypeptide according to any one of [l] to [4], wherein the ValRS is modified at a position(s) corresponding to asparagine at position 43 and/or threonine at position 45 and/or threonine at position 279 of ValRS from Escherichia coli.
• [6] The polypeptide according to any one of [1] to [4], wherein the SerRS is modified at a position(s) corresponding to glutamic acid at position 239 and/or threonine at position 237 of SerRS from E. coli.
• [7] The polypeptide according to any one of [1] to [4], wherein the PheRS α subunit is modified at a position corresponding to glutamine at position 169 of PheRS α subunit from E. coli.
• [8] The polypeptide according to any one of [1] to [4], wherein the ThrRS is modified at a position(s) corresponding to methionine at position 332 and/or histidine at position 511 of ThrRS from E. coli.
• [9] The polypeptide according to any one of [1] to [4], wherein the TrpRS is modified at a position(s) corresponding to methionine at position 132 and/or glutamine at position 150 and/or histidine at position 153 of TrpRS from E. coli.
• [10] The polypeptide according to any one of [1] to [4], wherein the LeuRS is modified at a position corresponding to tyrosine at position 43 of LeuRS from E. coli.
• [11] The polypeptide according to any one of [1] to [4], wherein the ValRS has (a) glycine or alanine at a position corresponding to asparagine at position 43 and/or (b) serine at a position corresponding to threonine at position 45 and/or (c) glycine or alanine at a position corresponding to threonine at position 279 of ValRS from E. coli.
• [12] The polypeptide according to any one of [1] to [4], wherein the SerRS has (a) glycine or alanine at a position corresponding to glutamic acid at position 239 and/or (b) serine at a position corresponding to threonine at position 237 of SerRS from E. coli.
• [13] The polypeptide according to any one of [1] to [4], wherein the PheRS α subunit has glycine or alanine at a position corresponding to glutamine at position 169 of PheRS a subunit from E. coli.
• [14] The polypeptide according to any one of [1] to [4], wherein the ThrRS has glycine at a position corresponding to methionine at position 332 and/or histidine at position 511 of ThrRS from E. coli.
• [15] The polypeptide according to any one of [1] to [4], wherein the TrpRS has (a) alanine or valine at a position corresponding to methionine at position 132 and/or (b) alanine at a position corresponding to glutamine at position 150 and/or (c) alanine at a position corresponding to histidine at position 153 of TrpRS from E. coli.
• [16] The polypeptide according to any one of [1] to [4], wherein the LeuRS has glycine at a position corresponding to tyrosine at position 43 of LeuRS from E. coli.
• [17] The polypeptide according to any one of [1] to [16], wherein the ARS is derived from a bacterium.
• [18] The polypeptide according to [17], wherein the bacterium is Escherichia coli.
• [19] The polypeptide according to any one of [1] to [18], wherein the polypeptide is selected from the group consisting of the following (a) and (b):
• (a) a polypeptide comprising amino acids selected from the group consisting of SEQ ID NOs: 1 to 11 and 182 to 187, and
• (b) a polypeptide comprising an amino acid sequence having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11 and 182 to 187.
• [20] An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 11 and 182 to 187.
• [21] A fusion polypeptide of a polypeptide according to any one of [1] to [20] and another polypeptide.
• [22] A polynucleotide encoding a polypeptide according to any one of [1] to [21].
• [23] A vector comprising the polynucleotide according to [22].
• [24] A host cell comprising the polynucleotide according to [22] or the vector according to [23].
• [25] A method for producing a polypeptide according to any one of [1] to [21], comprising the step of culturing the host cell according to [24].
• [26] A method for producing a tRNA acylated with an N-methyl amino acid, comprising the step of contacting the N-methyl amino acid with a tRNA in the presence of the polypeptide according to any one of [1] to [20].
• [27] The method according to [26], wherein the step of contacting is carried out in a cell-free translation system.
• [28] A method for producing a polypeptide comprising an N-methyl amino acid, comprising the step of performing translation in the presence of the polypeptide according to any one of [1] to [20] and the N-methyl amino acid.
• [29] The method according to [28], wherein the step of performing translation is carried out in a cell-free translation system.
Effects of the Invention
The modified ARSs according to the present invention can be used to efficiently attach N-methylphenylalanine, N-methylvaline, N-methylthreonine, N-methylserine, N-methyltryptophan, and N-methylleucine to tRNAs corresponding to natural phenylalanine, valine, threonine, serine, tryptophan, and leucine, respectively, without complicated reactions.
Methods using modified ARSs according to the present invention require no stoichiometric amount of tRNA, can synthesize peptides into which multiple N-methyl amino acids are introduced with a high translational efficiency, and is useful for generating a highly diverse peptide library.
In order to investigate the effect on translational efficiency provided by the ARS's characteristic feature of “providing a continuous supply of aminoacyl-tRNA during the translation reaction”, the present inventors compared the introduction efficiencies of N-methylphenylalanine in two methods: a method using the modified PheRS05 (SEQ ID NO: 2) obtained by the present application invention and the pdCpA method in which aminoacyl-tRNA is not expected to be regenerated during the translation reaction. As a result, the translational efficiency of the method using the modified ARS was higher, and particularly, when two consecutive and three consecutive N-methylphenylalanines were introduced, the target peptide was synthesized approximately 4 to 8 times more (unpublished data). Thus, the present invention enables more efficient production of N-methyl amino acid-containing polypeptides, which were conventionally hard to produce.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows evaluation of aminoacylation activities of modified ARSs. The bands of the synthetic peptide acylated with N-methylphenylalanine using PheRS04 and PheRS05 were detected more strongly than when using wild-type PheRS (lane 8, 9 vs. 12, 13).
FIG. 2 shows the confirmation by electrophoresis of peptides ribosomally synthesized using mutant PheRS. The bands of the N-methylphenylalanine-containing peptide synthesized using the modified PheRS were detected more strongly than that using wild-type PheRS (lanes 2, 3 vs. 5, 6).
FIG. 3-1 shows detection by mass spectroscopy of peptides ribosomally synthesized using the modified PheRS. Mass spectrum of the peptide ribosomally synthesized using (a) 0.1 μM wt PheRS and 0.25 mM Phe, (b) 0.1 μM wt PheRS and 0.25 mM MePhe, or (c) 0.1 μM wt PheRS and 1 mM MePhe.
FIG. 3-2 shows detection by mass spectroscopy of peptides ribosomally synthesized using the modified PheRS. Mass spectrum of the peptide ribosomally synthesized using (d) 0.1 μM PheRS05 and 0.25 mM Phe, (e) 0.1 μM PheRS05 and 0.25 mM MePhe, or (f) 0.1 μM PheRS05 and 1 mM MePhe.
FIG. 4 shows aminoacylation reaction performed using modified ValRSs. tRNA acylated with N-methylvaline using the mutant 13 (ValRS13) was observed more than tRNA acylated using wild-type ValRS (lane 10).
FIG. 5 shows the results of mass spectrometry analysis of peptides translated using the modified ValRSs. Mass spectrum of the peptides translated using (a) wild-type ValRS, (b) ValRS13, or (c) ValRS04. The peptide containing MeVal was observed as a main product when ValRS13 was used.
FIG. 6 shows aminoacylation reaction performed using ValRS13-11. tRNA acylated with N-methylvaline using the mutant 13-11 (ValRS13-11) was observed more than tRNA acylated using wild-type ValRS or the mutant 13 (ValRS13).
FIG. 7 shows comparison of activities between ValRS13 and ValRS13-11. Mass spectra of the N-methyl peptide-containing peptides translated using ValRS13 ((a), (c), (e)) and ValRS13-11 ((b), (d), (f)). It can be seen that the N-methylvaline-containing target peptide translated using ValRS13-11 had higher purity.
FIG. 8 shows aminoacylation reaction performed using modified SerRSs. tRNA acylated with N-methylserine was observed when mutants 03, 35, and 37 were used (lanes 3, 25, 27).
FIG. 9 shows the results of mass spectrometry analysis of peptides ribosomally synthesized using the modified SerRSs. Mass spectrum of the N-methylserine-containing peptide translated using (a) wild-type SerRS, (b) SerRS03, (c) SerRS05, (d) SerRS35, or (e) SerRS37. The MeSer-containing target peptide synthesized using each modified SerRS had higher purity compared to that synthesized using wild-type SerRS.
FIG. 10 shows the results of mass spectrometry analysis of peptides ribosomally synthesized using modified ThrRSs. Mass spectrum of the N-methylthreonine-containing peptide translated using (a) wild-type ThrRS, (b) ThrRS03, or (c) ThrRS14. The MeThr-containing target peptide synthesized using each modified ThrRS had higher purity compared to that synthesized using wild-type ThrRS.
FIG. 11 shows the results of mass spectrometry analysis of peptides ribosomally synthesized using modified TrpRSs. Mass spectrum of the peptide translated using (a) wild-type TrpRS, (b) TrpRS04, (c) TrpRS05, or (d) TrpRS18. The MeW-containing peptide was observed as a main product when TrpRS04, 05, and 18 were used.
FIG. 12 shows the results of mass spectrometry analysis of peptides ribosomally synthesized using the modified LeuRS. Mass spectrum of the peptide translated using (a) wild-type LeuRS or (b) LeuRS02. The MeL-containing peptide was observed as a main product when LeuRS02 was used.
FIG. 13 shows aminoacylation reaction with MeVal using the modified ValRSs having mutation in the editing domain. The activities of three mutants, 13-11, 66, and 67 were not much different (lanes 17, 18, 19).
FIG. 14 shows aminoacylation reaction with Val using the modified ValRSs having mutation in the editing domain. The activities of the mutants 66 and 67 were attenuated compared to the activity of the mutant 13-11 (lane 17 vs 18, 19).
MODE FOR CARRYING OUT THE INVENTION
An objective of the present invention is to provide mutant enzymes with altered enzyme-substrate specificity for aminoacyl-tRNA synthetase. More specifically, the present invention is characterized by the preparation of mutant aminoacyl-tRNA synthetases that can efficiently and selectively produce polypeptides containing N-methyl amino acids in large amounts, by altering the amino acid sequence of natural aminoacyl-tRNA synthetase.
The present invention provides polypeptides including ARSs that can react with N-methyl amino acids. More specifically, the present invention provides polypeptides comprising modified ARSs that can react with N-methyl amino acids more efficiently than the original, natural ARSs. The present invention also provides polypeptides comprising modified ARSs that can incorporate N-methyl amino acids more efficiently than the original, natural ARSs. The polypeptides according to the present invention are polypeptides that have aminoacyl-tRNA synthetase activity and are modified to enhance the aminoacylation reaction with N-methyl amino acids. As used herein, the phrase “incorporate N-methyl amino acids” refers to, for example, aminoacylation of tRNAs with N-methyl amino acids corresponding to the tRNAs and may be attachment of the N-methyl amino acids to the tRNAs or incorporation of N-methyl amino acids to proteins synthesized in a translation reaction using the aminoacyl-tRNA produced in the acylation reaction. The phrase “a polypeptide has aminoacyl-tRNA synthetase activity” includes not only the case in which the polypeptide exhibits aminoacyl-tRNA synthetase activity by itself, but also the case in which the polypeptide exhibits aminoacyl-tRNA synthetase activity together with other factors. For example, when an aminoacyl-tRNA synthetase is composed of multiple subunits, the polypeptide according to the present invention may be one subunit or may exhibit aminoacyl-tRNA synthetase activity as a complex with other subunits. In such a case, when an aminoacyl-tRNA synthetase complex is formed between a modified polypeptide according to the present invention and other wild-type subunits, the aminoacyl-tRNA synthetase complex can enhance aminoacylation reaction with N-methyl amino acids more than an aminoacyl-tRNA synthetase complex consisting of wild-type subunits. That is to say, in the present invention, polypeptides with aminoacyl-tRNA synthetase activity modified to enhance aminoacylation reaction with N-methyl amino acids include a polypeptide that is one modified subunit in an aminoacyl-tRNA synthetase complex consisting of multiple subunits and is modified to enhance aminoacylation reaction with N-methyl amino acids by the aminoacyl-tRNA synthetase complex.
A polypeptide comprising a modified ARS refers to a polypeptide comprising the polypeptide chain of the modified ARS, and specifically the polypeptide is a polypeptide comprising the amino acid sequence of the modified ARS. The original, natural ARS refers to a natural ARS from which modified ARS is derived, may be for example a wild-type ARS, and includes a naturally-occurring polymorphism. The phrase “can react with N-methyl amino acids” means that modified ARSs can perform an enzymatic reaction with N-methyl amino acids as substrates. The reaction may be, for example, an acylation reaction of tRNAs with N-methyl amino acids, and specifically a reaction that catalyzes a coupling reaction between an N-methyl amino acid and a tRNA. For example, depending on an amino acid used as a substrate by an ARS, the reaction is performed in the presence of the appropriate N-methyl amino acid and the appropriate tRNA, and the coupling between the N-methyl amino acid and the tRNA may be detected. Alternatively, a reaction with N-methyl amino acids may be incorporation of N-methyl amino acids into polypeptides in translation. Production of N-methyl amino acid-tRNA by ARSs can be detected by, for example, performing translation in the presence of the modified ARSs and N-methyl amino acids and detecting incorporation of N-methyl amino acids into the polypeptides produced by translation. The reactivity with N-methyl amino acids is considered to be higher when N-methyl amino acids are frequently incorporated into polypeptides.
The phrase “a modified ARS can react more efficiently than the original, natural ARS” may mean that the modified ARS reacts more efficiently than the original, natural ARS at least under a certain condition, or that a reaction or reaction product that cannot be observed when using the original ARS can be observed when using the modified ARS. For example, a modified ARS is considered to react with an N-methyl amino acid more efficiently than the original, natural ARS when the modified ARS produces polypeptides containing the N-methyl amino acid more than the original, natural ARS. A modified ARS is considered to react with its corresponding N-methyl amino acid more efficiently than the original, natural ARS when, for example, production of polypeptides containing the N-methyl amino acid that cannot be observed when using the original, natural ARS can be observed when using the modified ARS. For example, a modified ARS is considered to react with an N-methyl amino acid more efficiently than the original, natural ARS when, for example, production of polypeptides containing 2, 3, or more consecutive N-methyl amino acids cannot be observed when using the original, natural ARS, but can be observed when using the modified ARS.
The phrase “can react more efficiently than the original, natural ARS” may mean that a reactant of interest is purified at least under a certain condition with higher purity compared to the purity achieved with the original, natural ARS. For example, a modified ARS is considered to react with its corresponding N-methyl amino acid more efficiently than the original, natural ARS when the modified ARS produces polypeptides containing its corresponding N-methyl amino acid more than the original, natural ARS, relative to natural amino acids derived as a result of contamination, Alternatively, a modified ARS is considered to react with N-methyl amino acids more efficiently than the original ARS when it is confirmed that reaction efficiency of the modified ARS for the N-methyl amino acid remains unchanged and reaction efficiency of the modified ARS for natural amino acids decreases. For example, a modified ARS is considered to react with its corresponding N-methyl amino acid more efficiently than the original, natural ARS when reactivity of the modified ARS to the N-methyl amino acid is relatively higher than reactivity of the modified ARS to natural amino acids.
N-methyl amino acids are not particularly limited, but are appropriately selected based on ARSs. For example, when the modified ARS is valine ARS (ValRS), N-methyl amino acid is N-methylvaline; when the modified ARS is threonine ARS (Thr), N-methyl amino acid is N-methylthreonine; when the modified ARS is serine ARS (SerRS), N-methyl amino acid is N-methylserine; when the modified ARS is phenylalanine ARS α subunit (PheRS), N-methyl amino acid is N-methylphenylalanine; when the modified ARS is tryptophan ARS (TrpRS), N-methyl amino acid is N-methyltryptophan; when the modified ARS is leucine ARS (LeuRS), N-methyl amino acid is N-methylleucine.
For example in ValRS, modified sites of ARS are preferably the position(s) corresponding to asparagine at position 43 and/or threonine at position 45 and/or threonine at position 279 of ValRS from E. coli. Modified sites of ARS are preferably a combination of any two positions selected from the positions corresponding to asparagine at position 43, threonine at position 45, and threonine at position 279 (e.g., a combination of position 43 and position 45, position 43 and position 279, or position 45 and position 279), and more preferably a combination of positions corresponding to asparagine at position 43, threonine at position 45, and threonine at position 279. SerRS can be modified at the position(s) corresponding to glutamic acid at position 239 and/or threonine at position 237 of SerRS from E. coli, and more preferably, can be modified at a combination of the positions corresponding to glutamic acid at position 239 and threonine at position 237. PheRS α subunit is preferably modified at the position corresponding to glutamine at position 169 of PheRS from E. coli. ThrRS can be modified at the position(s) corresponding to methionine at position 332 and/or histidine at position 511 of ThrRS from E. coli. TrpRS can be modified at the position(s) corresponding to methionine at position 132 and/or glutamine at position 150 and/or histidine at position 153 of TrpRS from E. coli, preferably can be modified at a combination of any two positions selected from positions corresponding to methionine at position 132, glutamine at position 150, and histidine at position 153 (e.g., a combination of position 132 and position 150, position 132 and position 153, or position 150 and position 153), and more preferably can be modified at a combination of the positions corresponding to methionine at position 132, glutamine at position 150, and histidine at position 153. LeuRS can be modified at the position corresponding to tyrosine at position 43 of LeuRS from E. coli. It should be noted that these modified ARSs may be further modified at other positions. The position numbers in each ARS are indicated taking the position number of the starting methionine in each ARS from E. coli as 1. Specifically, the position numbers in each ARS are indicated taking the position number of the first methionine in the sequences of P07118 (SEQ ID NO: 24) for ValRS, P08312 (SEQ ID NO: 28) for PheRS α subunit, P0A8M3 (SEQ ID NO: 29) for ThrRS, P0A8L1 (SEQ ID NO: 26) for SerRS, P00954 (SEQ ID NO: 188) for TrpRS, and P07813 (SEQ ID NO: 189) for LeuRS (UniProt (http://www.uniprot.org/) as 1. In a certain ARS, a position corresponding to a certain amino acid in ARS from E. coli refers to the amino acid located in the site corresponding to the amino acid in ARS from E. coli and can be identified based on structural similarity between the certain ARS and ARS from E. coli. For example, the corresponding amino acid can be identified as the amino acid aligned at the position of the amino acid in ARS from E. coli when the amino acid sequences of an ARS of interest and ARS from E. coli are aligned. As used herein, a position corresponding to a certain amino acid in ARS from E. coli is preferably the position sterically corresponding to the certain amino acid in ARS from E. coli. The sterically corresponding position refers to the position of an amino acid corresponding to the position of the certain amino acid in ARS from E. coli in the conformation of ARS.
Those skilled in the art can easily identify the sterically corresponding position by aligning ARS from E. coli with all known ARSs from other biological species for example using Multiple Sequence Alignment with default parameters in ClustalW ver2.1 (http://clustalw.ddbj.nig.ac.jp). Particularly, ARSs of interest are not limited to those from prokaryotes. Generally, sequences of ARSs in eukaryotes comprise various functional domains in addition to catalytic domain, and the sequence identity between ARSs from eukaryotes and ARSs from prokaryotes is not always high. In contrast, sequences of catalytic sites, including amino acid recognition site, and editing domain are highly conserved, and the sterically corresponding position in ARSs from eukaryotes can be easily identified using publicly-available alignment techniques.
For example, the sites corresponding to positions 43 and 45 of E. coli ValRS may be respectively amino acid sites of “N/Y/T” and “T/S” in PPP(N/Y/T)X(T/S)G motif (SEQ ID NO: 180; “N/Y/T” is preferably N; X is any amino acid, preferably V, I, or P, and more preferably V; “T/S” is preferably T) present in ValRS from other organisms. More preferably, the sites corresponding to positions 43 and 45 of E. coli ValRS may be amino acids at N and T respectively in PPPNXTG motif (SEQ ID NO: 181; X is any amino acid, preferably V, I, or P, and more preferably V) present in ValRS from other organisms. For example, the position corresponding to asparagine at position 43 of E. coli ValRS is asparagine at position 345 in human (Uniprot P26640) and asparagine at position 191 in Saccharomyces cerevisiae (Uniprot P07806).
Modifications of ARSs include preferably at least one substitution with an amino acid that causes a decrease of 10 or more in molecular weight. Such modifications include, for example, a modification of an amino acid selected from the group consisting of amino acids other than Thr (T), such as Gln (Q), Asn (N), Glu (E), Met (M), Tyr (Y), and His (H), into Ala (A) or Gly (G) (preferably into Gly), for example, a modification of Thr (T) into Ser (S), and for example, a modification of Met (M) into Val (V).
Amino acids to be modified may be appropriately selected. For example in ValRS, the position corresponding to asparagine at position 43 of ValRS from E. coli is preferably modified into glycine or alanine, the position corresponding to threonine at position 45 of ValRS from E. coli is preferably modified into serine, and the position corresponding to threonine at position 279 of ValRS from E. coli is preferably modified into glycine or alanine. In SerRS, the position corresponding to glutamic acid at position 239 of SerRS from E. coli is preferably modified into glycine or alanine, and the position corresponding to threonine at position 237 of SerRS from E. coli is preferably modified into serine. In PheRS, the position corresponding to glutamine at position 169 of PheRS α subunit from E. coli is preferably modified into glycine or alanine. In ThrRS, the position corresponding to methionine at position 332 of ThrRS from E. coli is preferably modified into glycine, and the position corresponding to histidine at position 511 of ThrRS from E. coli is preferably modified into glycine. In TrpRS, the position corresponding to methionine at position 132 of TrpRS from E. coli is preferably modified into valine or alanine, the position corresponding to glutamine at position 150 of TrpRS from E. coli is preferably modified into alanine, and the position corresponding to histidine at position 153 of TrpRS from E. coli is preferably modified into alanine. In LeuRS, the position corresponding to tyrosine at position 43 of LeuRS from E. coli is preferably modified into glycine.
Specifically, the present invention includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 3-5, 182, and 183 (ValRS04, ValRS13, ValRS13-11, ValRS66, and ValRS67); and
(b) a polypeptide that has reactivity with N-methyl Val, has at least 90% identity to the amino acid sequence of any of SEQ ID NOs: 3-5, 182, and 183, and comprises at least one amino acid of the following (i) to (iii):
(i) Gly or Ala at the amino acid position corresponding to position 43 of SEQ ID NOs: 3-5, 182, and 183;
(ii) Ser at the amino acid position corresponding to position 45 of SEQ ID NOs: 3-5, 182, and 183; and
(iii) Gly or Ala at the amino acid position corresponding to position 279 of SEQ ID NOs: 3-5, 182, and 183.
Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide having (i) Asn at the amino acid position corresponding to position 43 and/or (ii) Thr at the amino acid position corresponding to position 45 and/or (iii) Thr at the amino acid position corresponding to position 279. For example, the ValRS according to the present invention preferably has a reactivity with N-methyl Val higher than the reactivity of a ValRS having Asn at the amino acid position corresponding to position 43, Thr at the amino acid position corresponding to position 45, and Thr at the amino acid position corresponding to position 279 of the ValRS.
The present invention also includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 6-9 (SerRS03, SerRS05, SerRS35, and SerRS37) and
(b) a polypeptide that has reactivity with N-methyl Ser, has at least 90% identity to the amino acid sequence of any of SEQ ID NOs: 6-9, and comprises at least one amino acid of the following (i) and (ii);
(i) Ser at the amino acid position corresponding to position 237 of SEQ ID NOs: 6-9, and
(ii) Gly or Ala at the amino acid position corresponding to position 239 of SEQ ID NOs: 6-9.
Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide having (i) Thr at the amino acid position corresponding to position 237 and/or (ii) Glu at the amino acid position corresponding to position 239. For example, the SerRS according to the present invention preferably has a reactivity with N-methyl Ser higher than the reactivity of a SerRS having Thr at the amino acid position corresponding to position 237 of the SerRS and Glu at the amino acid position corresponding to position 239 of the SerRS.
The present invention also includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 1-2 (PheRS05 and PheRS04); and
(b) a polypeptide that has reactivity with N-methyl Phe, has at least 90% identity to the amino acid sequence of any of SEQ ID NOs: 1-2, and comprises an amino acid sequence in which the amino acid at the position corresponding to position 169 of any of SEQ ID NOs: 1-2 is Gly or Ala. Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide in which the amino acid at the above-mentioned position is Gln. The polypeptides as described above represent ARS α subunit, and therefore the polypeptides can form a complex with β subunit to result in a functional ARS. β subunit is not particularly limited, but may be, for example, a desired wild-type subunit. As an example, β subunit that can be used is one comprising the amino acid sequence of NCBI Reference Sequence WP_000672380 (e.g., WP_000672380.1) (wherein the base sequence represents 1897337-1899721 of GenBank CP009685 (e.g., CP009685.1)).
The present invention also includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 10-11 (ThrRS03 and ThrRS14); and
(b) a polypeptide that has reactivity with N-methyl Thr, has at least 90% identity to the amino acid sequence of any of SEQ ID NOs: 10-11, and comprises at least one amino acid of the following (i) and (ii):
(i) Gly at the amino acid position corresponding to position 332 of SEQ ID NOs: 10-11; and
(ii) Gly at the amino acid position corresponding to position 511 of SEQ ID NOs: 10-11.
Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide having (i) Met at the amino acid position corresponding to position 332 and/or (ii) His at the amino acid position corresponding to position 511. For example, the ThrRS according to the present invention preferably has a reactivity with N-methyl Thr higher than the reactivity of a ThrRS having Met at the amino acid position corresponding to position 332 of the ThrRS and His at the amino acid position corresponding to position 511 of the ThrRS.
The present invention also includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 184-186 (TrpRS04, TrpRS05, and TrpRS18), and
(b) a polypeptide that has reactivity with N-methyl Trp, has at least 90% identity to the amino acid sequence of any of SEQ ID NOs: 184-186, and comprises at least one amino acid according to any of the following (i) to (iii):
(i) Val or Ala at the amino acid position corresponding to position 132 of SEQ ID NOs: 184-186;
(ii) Ala at the amino acid position corresponding to position 150 of SEQ ID NOs: 184-186; and
(iii) Ala at the amino acid position corresponding to position 153 of SEQ ID NOs: 184-186.
Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide having (i) Met at the amino acid position corresponding to position 132 and/or (ii) Gln at the amino acid position corresponding to position 150 and/or (iii) His at the amino acid position corresponding to position 153. For example, the TrpRS according to the present invention preferably has a reactivity with N-methyl Trp higher than the reactivity of a TrpRS having Met at the amino acid position corresponding to position 132 of the TrpRS, Gln at the amino acid position corresponding to position 150 of the TrpRS, and His at the amino acid position corresponding to position 153 of the TrpRS.
The present invention also includes the following polypeptides:
(a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 187 (LeuRS02); and
(b) a polypeptide that has reactivity with N-methyl Leu, has at least 90% identity to the amino acid sequence of SEQ ID NO: 187, and comprises an amino acid sequence in which the amino acid at the position corresponding to position 43 of SEQ ID NO: 187 is Gly.
Furthermore, the above-mentioned reactivity is preferably higher than the reactivity of a polypeptide having (i) Tyr at the amino acid position corresponding to position 43.
The identity of amino acid sequence is preferably 93% or more, more preferably 95% or more, more preferably 97% or more, 98% or more, or 99% or more.
The N-methyl aminoacyl-tRNA synthetases according to the present invention are characterized by the ability to efficiently acylate tRNAs with N-methyl amino acids, which are non-natural amino acids known to enhance drug-likeness of peptides. The N-methyl aminoacyl-tRNA synthetases according to the present invention may be derived from any organism including bacteria such as E. coli, yeast, animals, or plants, but, because of their versatility, preferable are those that have high sequence conservation with aminoacyl-tRNA synthetases exemplified in the Examples herein (SEQ ID NOs: 1-11, 182-187), and thus have mutation site(s) easily identified in other biological species. For example, polypeptides comprising the modified ARSs according to the present invention may be derived from ARSs from eukaryotes or prokaryotes. Eukaryotes include protists (including protozoan and unicellular green algae), fungi (including ascomycetes and basidiomycetes), plants (including bryophytes, pteridophytes, and seed plants (gymnosperms and angiosperms)), and animals (including invertebrates and vertebrates). Prokaryotes include archaebacteria (including thermophiles and methane bacteria) and eubacteria (including cyanobacteria and E. coli). Polypeptides comprising the modified ARSs according to the present invention may be derived from mammals (such as human, mouse, rat, guinea pig, rabbit, sheep, monkey, goat, donkey, cattle, horse, and pig). Polypeptides comprising the modified ARSs according to the present invention may be derived from, for example, E. coli or yeast, and preferably derived from prokaryotes, for example bacteria. The polypeptides according to the present invention are derived from, for example, bacteria of the family Enterobacteriaceae, for example, E. coli, including, but are not limited to, for example, the genera Escherichia (including E. coli, E. albertii, E. fergusonii), Shigella (including S. dysenteriae, S. flerneri, S. boydii, S. sonnei, S. enterica, S. bongori), Citrobacter (including C. rodentium, C. koseri, C. farmeri, C. youngae), Kluyvera (including K. ascorbata), Tabulsiella (including T. guamensis), Klebsiella, and the like.
N-methyl aminoacyl-tRNA synthetases from E. coli were used in the Examples herein as one example, and therefore the modified positions indicated herein are positions in E. coli. When N-methyl aminoacyl-tRNA synthetases from other organisms are used, positions to be modified are amino acids at positions corresponding to those in the amino acid sequence of N-methyl aminoacyl-tRNA synthetases from E. coli based on sequence homology. ARSs are generally very highly conserved because they are enzymes playing an essential part in the translation mechanism that exists in all organisms. Accordingly, a desired ARS can be modified based on the method according to the present invention to obtain a modified ARS with an increased ability to incorporate an N-methyl amino acid.
Amino acids to be newly introduced into N-methyl aminoacyl-tRNA synthetases are selected based on hydrophilicity, hydrogen bonds, and side chain size of amino acids in consideration of the distance to and interaction with N-methyl group. For example, when avoiding the steric repulsion between the amino acid at the position and an N-methyl group, the distance to the N-methyl amino group can be adjusted by, for example, substituting a high molecular weight amino acid with a low molecular weight amino acid. Specifically, the distance can be adjusted by reducing the molecular weight, for example, by substituting threonine (Thr) with serine (Ser).
For example, when an amino acid to be modified in an N-methyl aminoacyl-tRNA synthetase is asparagine, the low molecular weight amino acids can include, but are not limited to, for example, serine, valine, glycine, aspartic acid, and alanine. When an amino acid to be modified is glutamic acid, the low molecular weight amino acids can include, but are not limited to, for example, alanine, valine, serine, alanine, and aspartic acid. Moreover, for example, when an amino acid to be modified is Thr, the low molecular weight amino acids include preferably, for example, Ser. When an amino acid to be modified is an amino acid other than the amino acids as described above, the low molecular weight amino acids include preferably, for example, glycine (Gly) and alanine (Ala), and more preferably glycine (Gly). To give one specific example, Thr can be substituted with Ser; Gln, Glu, and Asn can be substituted with Gly or Ala: and Met, His, Gln, and the like can be substituted with Gly, but the substitutions are not limited thereto.
To give a more specific example, modification of valine aminoacyl-tRNA synthetase (ValRS) includes, for example, modification of amino acid(s) at position 43 and/or position 45 and/or position 279 of SEQ ID NO: 24 (natural ValRS), or amino acids at positions corresponding to these positions. Amino acids selected for substitution are not limited, but as mentioned above, for example, Thr can be substituted with Ser, Ala, or Gly, and amino acids (e.g., Asn) other than Thr can be substituted with Gly or Ala. For example, preferred are substitution of the amino acid at position 43 of SEQ ID NO: 24 or an amino acid at a position corresponding to position 43 of SEQ ID NO: 24 with Gly or Ala, and/or substitution of the amino acid at position 45 of SEQ ID NO: 24 or an amino acid at the position corresponding to position 45 of SEQ ID NO: 24 with Ser, and/or substitution of the amino acid at position 279 or an amino acid at a position corresponding to position 279 with Gly or Ala. These substitutions may be any one of the substitutions, a combination of any of these substitutions (e.g., substitutions at position 43 and position 45, substitutions at position 43 and position 279, or substitutions at position 45 and position 279), or all of the substitutions. Other substitutions may be further combined. As a more specific illustration, N43 and/or T45 and/or T279 of SEQ ID NO: 24, or amino acids at the positions corresponding to these, are preferably substituted, and preferably substituted to N43G and/or T45S and/or T279A.
Modification of serine aminoacyl-tRNA synthetase (SerRS) includes, for example, modification of amino acid(s) at position 237 and/or position 239 of SEQ ID NO: 26 (natural SerRS), or amino acids at the positions corresponding to these positions. Amino acids selected for substitution are not limited, but as mentioned above, for example, Thr can be substituted with Ser, and amino acids (e.g., Glu) other than Thr can be substituted with Gly or Ala. For example, preferred are substitution of the amino acid at position 237 of SEQ ID NO: 26 or an amino acid at the position corresponding to position 237 of SEQ ID NO: 26 with Ser, and/or substitution of the amino acid at position 239 of SEQ ID NO: 26 or an amino acid at the position corresponding to position 239 of SEQ ID NO: 26 with Gly or Ala. These substitutions may be any one or both of the substitutions. Other substitutions may be further combined. As a more specific illustration, T237 and/or E239 of SEQ ID NO: 26, or amino acids at positions corresponding to these, are preferably substituted, and preferably substituted to T237S and/or E239G (or E239A).
Modification of phenylalanine aminoacyl-tRNA synthetase α subunit (PheRS α) includes, for example, modification of amino acid at position 169 of SEQ ID NO: 28 (natural PheRS α subunit), or an amino acid at a position corresponding to position 169 of SEQ ID NO: 28. Amino acids selected for substitution are not limited, but as mentioned above, for example, Thr can be substituted with Ser, and amino acids other than Thr can be substituted with glycine (Gly) or alanine (Ala) (more preferably Gly). For example, preferred is substitution of the amino acid at position 169 of SEQ ID NO: 28 or an amino acid at the position corresponding to position 169 of SEQ ID NO: 28 with Gly. Other substitutions may be further combined. As a more specific illustration, Q169 of SEQ ID NO: 28, or an amino acid at the position corresponding to Q169 of SEQ ID NO: 28, is preferably substituted, and preferably substituted to Q169G (or Q169A).
Modification of threonine aminoacyl-tRNA synthetase (ThrRS) includes, for example, modification of amino acid(s) at position 332 and/or position 511 of SEQ ID NO: 29 (natural ThrRS), or amino acids at positions corresponding to these positions. Amino acids selected for substitution are not limited, but as mentioned above, for example, Thr can be substituted with Ser, and amino acids (e.g., Met and His) other than Thr can be substituted with Gly. For example, preferred is/are substitution of the amino acid at position 332 of SEQ ID NO: 29 or an amino acid at a position corresponding to position 332 of SEQ ID NO: 29 with Gly and/or substitution of the amino acid at position 511 of SEQ ID NO: 29 or an amino acid at a position corresponding to position 511 of SEQ ID NO: 29 with Gly. These substitutions may be any one or both of the substitutions. Other substitutions may be further combined. As a more specific illustration, M332 and/or H511 of SEQ ID NO: 29, or amino acids at positions corresponding to these, are preferably substituted, and preferably substituted to M332G and/or H511G.
Modification of tryptophan aminoacyl-tRNA synthetase (TrpRS) includes, for example, modification of amino acid(s) at position 132 and/or position 150 and/or position 153 of SEQ ID NO: 188 (natural TrpRS), or amino acids at a position corresponding to these positions. Amino acids selected for substitution are not limited, but as mentioned above, for example, Met can be substituted with Val or Ala, and amino acids (e.g., Gln) other than Met can be substituted with Ala. For example, preferred is/are substitution of the amino acid at position 132 of SEQ ID NO: 188 or an amino acid at a position corresponding to position 132 of SEQ ID NO: 188 with Val or Ala, and/or substitution of the amino acid at position 150 of SEQ ID NO: 188 or an amino acid at a position corresponding to position 150 of SEQ ID NO: 188 with Ala, and/or substitution of the amino acid at position 153 or an amino acid at a position corresponding to position 153 with Ala. These substitutions may be any one of the substitutions, a combination of any of these substitutions (e.g., substitutions at position 132 and position 150, substitutions at position 132 and position 153, or substitutions at position 150 and position 153), or all of the substitutions. Other substitutions may be further combined. As a more specific illustration, M132 and/or Q150 and/or H153 of SEQ ID NO: 188, or amino acids at positions corresponding to these, are preferably substituted, and preferably substituted to M132V and/or Q150A and/or H153A.
Modification of leucine aminoacyl-tRNA synthetase (LeuRS) includes, for example, modification of the amino acid at position 43 of SEQ ID NO: 189 (natural LeuRS), or an amino acid at a position corresponding to position 43 of SEQ ID NO: 189. Amino acids selected for substitution are not limited, but as mentioned above, for example, Thr can be substituted with Gly. For example, preferred is substitution of the amino acid at position 43 of SEQ ID NO: 189 or an amino acid at a position corresponding to position 43 of SEQ ID NO: 189 with Gly. Other substitutions may be further combined. As a more specific illustration, Y43 of SEQ ID NO: 189, or an amino acid at a position corresponding to Y43 of SEQ ID NO: 189, is preferably substituted, and preferably substituted to Y43G.
A method for producing a mutant N-methyl aminoacyl-tRNA synthetase, which is modified by substituting an amino acid at a specific position with another amino acid, according to the present invention, can be performed using any known genetic engineering technique. For example, DNA fragments having base sequences encoding amino acid sequences comprising amino acids at positions of interest are amplified using primers having base sequences substituted with base sequences encoding amino acid sequences comprising modified amino acids, resulting in base sequences encoding amino acid sequences comprising modified amino acids. The amplified DNA fragments are ligated together to obtain a full-length DNA encoding the mutant aminoacyl-tRNA synthetase. This full-length DNA can be expressed using a host cell such as E. coli to easily produce the mutant N-methyl aminoacyl-tRNA synthetase. Primers used in the method are 20 to 70 bases in length, and preferably about 20 to 50 bases in length. The primers have 1 to 3 base mismatches with the original unmodified base sequence, and therefore relatively long primers, for example, primers of 20 bases or more in length are preferably used.
A method for producing a mutant N-methyl aminoacyl-tRNA synthetase, which is modified by substituting an amino acid at a specific position with another amino acid, according to the present invention, is not limited to the method as described above, and various genetic engineering techniques, such as known point mutation techniques and gene synthesis techniques, and methods for introducing modified fragments using restriction enzymes, can be utilized. Expression hosts are not limited to E. coli, and animal cells and cell-free translation systems may also be used.
Modified ARSs according to the present invention include a polypeptide comprising an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187 (PheRS05, PheRS04, ValRS04, ValRS13, ValRS13-11, SerRS03, SerRS05, SerRS35, SerRS37, ThrRS03, ThrRS14, ValRS66, ValRS67, TrpRS04, TrpRS05, TrpRS18, and LeuRS02) and polypeptides functionally equivalent to the polypeptide. “Functionally equivalent polypeptides” are ARSs with a high structural identity to a polypeptide comprising an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187 and have reactivity with N-methyl amino acids. More specifically, “functionally equivalent polypeptides” are polypeptides that have amino acids modified according to the above description in ARSs with a high structural identity to a polypeptide comprising an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187, thereby having increased reactivity with N-methyl amino acids compared to unmodified ARSs. Increased reactivity with N-methyl amino acids may be, for example, increased substrate specificity to N-methyl amino acids (e.g., increased value of reactivity with N-methyl amino acids/reactivity with unmodified amino acids).
Such polypeptides include, for example, a polypeptide in which one or more amino acids (preferably 1 to 20 amino acids, for example, 1 to 10 amino acids, 1 to 7 amino acids, 1 to 5 amino acids, 1 to 3 amino acids, 1 to 2 amino acids, or 1 amino acid) are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187. Such polypeptides may also be, for example, a polypeptide in which one to several amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187.
A polypeptide functionally equivalent to a modified ARS comprising an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187 typically has a high identity to an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187. A polynucleotide encoding a functionally equivalent polypeptide also typically has a high identity to a base sequence (e.g., SEQ ID NOs: 12-22 and 190-195) encoding an amino acid sequence set forth in any of SEQ ID NOs: 1-11 and 182-187. High identity (sequence identity) specifically refers to 70% or more, preferably 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, or 99% or more identity.
The identity of amino acid sequences or base sequences can be determined using the BLAST algorithm by Karlin and Altschul (Proc. Natl. Acad. Sci. USA (1993) 90: 5873-7). Programs called BLASTN and BLASTX have been developed based on the algorithm (Altschul et al., J. Mol. Biol. (1990) 215: 403-10). When a base sequence is analyzed using BLAST-based BLASTN, parameters are set as, for example, score=100 and wordlength=12. When an amino acid sequence is analyzed using BLAST-based BLASTX, parameters are set as, for example, score=50 and wordlength=3. When BLAST and Gapped BLAST programs are used, default parameters of each program are used. Specific procedures of these analysis methods are known (see, information at the website of Basic Local Alignment Search Tool (BLAST) in National Center for Biotechnology Information (NCBI).
The polypeptides according to the present invention include any polypeptide of the following (a) to (d), wherein the amino acid corresponding to position 43 of SEQ ID NO: 24 (ValRS) is other than Asn, and/or the amino acid corresponding to position 45 of SEQ ID NO: 24 (ValRS) is other than Thr and/or the amino acid corresponding to position 279 of SEQ ID NO: 24 (ValRS) is other than Thr (i.e., a polypeptide in which the amino acid at at least one of these 3 positions is other than the indicated respective amino acid) and wherein the polypeptide has increased reactivity to N-methyl Val compared to a polypeptide in which the amino acids corresponding to position 43, position 45, and position 279 are Asn, Thr, and Thr, respectively:
(a) a polypeptide comprising an amino acid sequence having a high identity to an amino acid sequence set forth in any of SEQ ID NOs: 3-5, 182, and 183 (ValRS04, ValRS13, ValRS13-11, ValRS66, and ValRS67);
(b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NOs: 3-5, 182, and 183;
(c) a polypeptide encoded by a base sequence with high identity to a base sequence set forth in any one of SEQ ID NOs: 14-16, 190, and 191 (DNA encoding ValRS04, ValRS13, ValRS13-11, ValRS66, and ValRS67); or
(d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to a base sequence set forth in any one of SEQ ID NOs: 14-16, 190, and 191 under stringent conditions.
The above-mentioned polypeptides preferably have (i) Gly or Ala at the amino acid position corresponding to position 43 and/or (ii) Ser at the amino acid position corresponding to position 45 and/or (iii) Gly or Ala at the amino acid position corresponding to position 279. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which (i) the amino acid at the position corresponding to position 43 is substituted with Gly or Ala and/or (ii) the amino acid at the position corresponding to position 45 is substituted with Ser and/or (iii) the amino acid at the position corresponding to position 279 is substituted with Gly or Ala.
The polypeptides according to the present invention include any polypeptide of the following (a) to (d), wherein the amino acid corresponding to position 237 of SEQ ID NO: 26 (SerRS) is other than Thr and/or the amino acid corresponding to position 239 of SEQ ID NO: 26 (SerRS) is other than Glu (i.e., a polypeptide in which the amino acid at at least one of these 2 positions is other than the indicated respective amino acid) and wherein the polypeptide has increased reactivity with N-methyl Ser compared to a polypeptide in which the amino acids corresponding to position 237 and position 239 are Thr and Glu respectively:
(a) a polypeptide comprising an amino acid sequence having a high identity to an amino acid sequence set forth in any one of SEQ ID NOs: 6-9 (SerRS03, SerRS05, SerRS35, and SerRS37);
(b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NOs: 6-9;
(c) a polypeptide encoded by a base sequence having a high identity to a base sequence set forth in any one of SEQ ID NOs: 17-20 (DNA encoding SerRS03, SerRS05, SerRS35, and SerRS37); or
(d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to a base sequence set forth in any one of SEQ ID NOs: 17-20 under stringent conditions.
The above-mentioned polypeptides preferably have (i) Ser at the amino acid position corresponding to position 237 and/or (ii) Gly or Ala at the amino acid position corresponding to position 239. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which (i) the amino acid at the position corresponding to position 237 is substituted with Ser and/or (ii) the amino acid at the position corresponding to position 239 is substituted with Gly or Ala.
Such polypeptides according to the present invention include any polypeptide of the following (a) to (d), wherein the polypeptide has any amino acid other than Gln at the position corresponding to position 169 of SEQ ID NO: 28 (PheRS) and has increased reactivity with N-methyl Phe compared to a polypeptide in which the amino acid at position 169 of SEQ ID NO: 28 (PheRS) is Gln:
(a) a polypeptide comprising an amino acid sequence having a high identity to an amino acid sequence set forth in any one of SEQ ID NOs: 1-2 (PheRS05 and PheRS04);
(b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NOs: 1-2;
(c) a polypeptide encoded by a base sequence having a high identity to a base sequence set forth in any one of SEQ ID NOs: 12-13 (DNA encoding PheRS05 and PheRS04); or
(d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to a base sequence set forth in any one of SEQ ID NOs: 12-13 under stringent conditions.
The above-mentioned polypeptides preferably have Gly or Ala at the amino acid position corresponding to position 169. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which the amino acid at the position corresponding to position 169 is substituted with Gly or Ala.
The polypeptides according to the present invention include any polypeptide of the following (a) to (d), wherein the amino acid corresponding to position 332 of SEQ ID NO: 29 (ThrRS) is other than Met and/or the amino acid corresponding to position 511 of SEQ ID NO: 29 (ThrRS) is other than His (i.e., a polypeptide in which the amino acid at at least one of these 2 positions is other than the indicated respective amino acid) and wherein the polypeptide has increased reactivity with N-methyl Thr compared to a polypeptide in which the amino acids corresponding to position 332 and position 511 are Met and His, respectively:
(a) a polypeptide comprising an amino acid sequence having a high identity to an amino acid sequence set forth in any one of SEQ ID NOs: 10-11 (ThrRS03 and ThrRS14);
(b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NOs: 10-11;
(c) a polypeptide encoded by a base sequence having a high identity to a base sequence set forth in any one of SEQ ID NOs: 21-22 (DNA encoding ThrRS03 and ThrRS14); or
(d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to a nucleotide sequence set forth in any one of SEQ ID NOs: 21-22 under stringent conditions.
The above-mentioned polypeptides preferably have (i) Gly at the amino acid position corresponding to 332 and/or (ii) Gly at the amino acid position corresponding to position 511. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which the amino acid at the position corresponding to position 332 is substituted with Gly and/or the amino acid at the position corresponding to position 511 is substituted with Gly.
The polypeptides according to the present invention include a polypeptide that is any polypeptide of the following (a) to (d), wherein the amino acid corresponding to position 132 of SEQ ID NO: 188 (TrpRS) is other than Met and/or the amino acid corresponding to position 150 of SEQ ID NO: 188 (TrpRS) is other than Gln and/or the amino acid corresponding to position 153 of SEQ ID NO: 188 (TrpRS) is other than His (i.e., a polypeptide in which the amino acid at at least one of these 3 positions is other than the indicated respective amino acid) and wherein the polypeptide has increased reactivity with N-methyl Trp compared to a polypeptide in which the amino acids corresponding to position 132, position 150, and position 153 are Met, Gln, and His, respectively:
• (a) a polypeptide comprising an amino acid sequence having a high identity to an amino acid sequence set forth in any one of SEQ ID NOs: 184-186 (TrpRS04, TrpRS05, and TrpRS18);
• (b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NOs: 184-186;
• (c) a polypeptide encoded by a base sequence having a high identity to a base sequence set forth in any one of SEQ ID NOs: 192-194 (DNA encoding TrpRS04, TrpRS05, and TrpRS18); or
• (d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to a base sequence set forth in any one of SEQ ID NOs: 192-194 under stringent conditions.
The above-mentioned polypeptides preferably have (i) Val or Ala at the amino acid position corresponding to position 132 and/or (ii) Ala at the amino acid position corresponding to position 150 and/or (iii) Ala at the amino acid position corresponding to position 153. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which (i) the amino acid at the position corresponding to position 132 is substituted with Val or Ala and/or (ii) the amino acid at the position corresponding to position 150 is substituted with Ala and/or (iii) the amino acid at the position corresponding to position 153 is substituted with Ala.
The polypeptides according to the present invention include any polypeptide of the following (a) to (d), wherein the polypeptide has any amino acid other than Tyr at the position corresponding to position 43 of SEQ ID NO: 189 (LeuRS) and has increased reactivity with N-methyl Leu compared to a polypeptide in which the amino acid corresponding to position 43 is Tyr:
• (a) a polypeptide comprising an amino acid sequence having a high identity to the amino acid sequence set forth in SEQ ID NO: 187 (LeuRS02);
• (b) a polypeptide comprising an amino acid sequence in which one or more amino acids are substituted, deleted, inserted, and/or added in an amino acid sequence set forth in any one of SEQ ID NO: 187;
• (c) a polypeptide encoded by a base sequence having a high identity to the base sequence set forth in SEQ ID NO: 195 (DNA encoding LeuRS02); or
• (d) a polypeptide encoded by a DNA fragment hybridizing with a strand complementary to the base sequence set forth in SEQ ID NO: 195 under stringent conditions.
The above-mentioned polypeptides preferably have Gly at the amino acid position corresponding to position 43. Such polypeptides include natural polypeptides and artificially-modified polypeptides, and preferably include polypeptides in which the amino acid at the position corresponding to position 43 is substituted with Gly.
In the case of polypeptides obtained by modifying natural ARSs, polypeptides according to the present invention are those with increased reactivity to N-methyl amino acids compared to unmodified ARSs. When the polypeptides are natural ARSs or artificially produced polypeptides, the polypeptides according to the present invention are those with reactivity to N-methyl amino acids, namely those having an activity to acylate tRNAs with N-methyl amino acids. When comparing the reactivities of modified ARSs and natural ARSs, and the ARSs are made up of multiple subunits, subunit(s) other than that/those compared is/are the same is/are used. These subunits may be natural (or wild-type) or a modified as long as they are the same in both ARSs.
High identity (or high sequence identity) refers to, as mentioned above, for example, 70% or more, preferably 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, or 99% or more identity. The number of amino acids substituted, deleted, inserted, and/or added may be one or several, for example, 1 to 20, preferably 1 to 15, more preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 7, more preferably 1 to 6, more preferably 1 to 5, more preferably 1 to 4, more preferably 1 to 3, more preferably 1 to 2, and more preferably 1. Stringent hybridization conditions refer to, for example, conditions of about “1×SSC, 0.1% SDS, at 37° C.”, more strictly conditions of about “0.5×SSC, 0.1% SDS, at 42° C.”, further more strictly conditions of about “0.2×SSC, 0.1% SDS, at 65° C.”, and yet more strictly conditions of about “0.1×SSC, 0.1% SDS, at 65° C.”. It is noted that the conditions of SSC, SDS, and temperature as described above are only examples of combinations. Those skilled in the art can achieve stringency similar to those described above by appropriately combining the above-mentioned or other factors that determine hybridization stringency (such as probe concentration, probe length, and duration of hybridization).
The present invention also relates to polynucleotides encoding the polypeptides according to the present invention. The polynucleotides according to the present invention comprise any polynucleotide as long as it comprises a sequence encoding a polypeptide according to the present invention as described above. The polynucleotides according to the present invention also comprise any one of genomic DNA, cDNA, and DNAs artificially produced based on the genomic DNA or cDNA. Genomic DNA comprises exons and introns. That is to say, genomic DNA may or may not comprise introns, and may or may not comprise untranslated regions (5′ UTR and/or 3′ UTR), transcription control elements, and the like. cDNA is a nucleic acid sequence derived from a portion of intronic sequence and may comprise a nucleic acid sequence encoding an amino acid sequence.
The polynucleotides also comprise degenerate polynucleotides comprising any codon that encodes the same amino acid. The polynucleotides according to the present invention may also be a polynucleotide derived from desired organisms.
The polynucleotides according to the present invention may be obtained using any method. For example, a complementary DNA (cDNA) prepared from mRNA, a DNA prepared from genomic DNA, a DNA obtained by chemical synthesis, a DNA obtained by amplifying RNA or DNA as a template using PCR, and a DNA constructed by appropriately combining these techniques are all included. The polynucleotides according to the present invention can be produced by cloning the genomic DNA or RNA encoding the polypeptide according to the present invention according to conventional methods and introducing mutations into the cloned genomic DNA or RNA.
For example, in a method for cloning cDNA from mRNA encoding a polypeptide according to the present invention, first, the mRNA encoding the polypeptide according to the present invention is prepared according to conventional methods from any tissue or cell where the polypeptide according to the present invention is expressed and produced. For example, total RNA prepared using a method such as the guanidine thiocyanate method, hot-phenol method, or AGPC method can be subjected to affinity chromatography on oligo (dT) cellulose, poly U-Sepharose, or the like.
The obtained mRNA is then used as a template to synthesize a cDNA strand by using a known method (Mol. Cell. Biol., Vol. 2, p. 161, 1982; Mol. Cell. Biol., Vol. 3, p. 280, 1983; Gene, Vol. 25, p. 263, 1983), for example, by using reverse transcriptase. The cDNA strand is converted into a double-stranded cDNA and incorporated into a plasmid vector, phage vector, cosmid vector, or the like. The vector is used to transform E. coli or to perform in vitro packaging followed by transfection of E. coli to generate a cDNA library.
The cDNA library can be screened using a polynucleotide according to the present invention (e.g., SEQ ID NOs: 12-22, 190-195) or a portion thereof as a probe to obtain a gene of interest. Alternatively, the cDNA library can be directly amplified by PCR using a polynucleotide according to the present invention (e.g., SEQ ID NOs: 12-22, 190-195) or a portion thereof as a primer. The sites and lengths of probes and primers may be appropriately determined.
The present invention also relates to vectors (recombinant vectors) comprising polynucleotides encoding the polypeptides according to the present invention as described above. The vectors according to the present invention are not particularly limited as long as they can replicate and can be maintained or can self-proliferate in any host prokaryotic and/or eukaryotic cell. The vectors include plasmid vectors, phage vectors, viral vectors, and the like.
Examples of vectors for cloning include, for example, pUC19, λgt10, λgt11, and the like. Furthermore, the vectors preferably have a promoter that can express the polypeptide according to the present invention when cells that can express the polynucleotide in host cells are isolated.
The recombinant vectors according to the present invention can be prepared by simply ligating a polynucleotide encoding a polypeptide according to the present invention into a vector for recombination (a plasmid DNA and bacteriophage DNA) available in the art according to conventional methods.
Examples of recombinant vectors that can be used include, for example, plasmids from E. coli (such as pBR322, pBR325, pUC12, pUC13, and pUC19), plasmids from yeast (such as pSH19 and pSH15), and plasmids from Bacillus subtilis (such as pUB110, pTP5, and pC194).
Examples of phages include bacteriophage such as λ phage, and further animal and insect viruses such as retrovirus, vaccinia virus, nucleopolyhedrovirus, and lentivirus (pVL1393, from Invitrogen).
Expression vectors are useful for expressing polynucleotides encoding the polypeptides according to the present invention and production of the polypeptides according to the present invention. The expression vectors are not particularly limited as long as they have functions to express polynucleotides encoding the polypeptides according to the present invention and produce the polypeptides in any host prokaryotic and/or eukaryotic cell.
For example, expression vectors include pMAL C2, pEF-BOS (Nucleic Acid Research, Vol. 18, 1990, p. 5322, and the like), or pME18S (“Idenshi Kougaku Handbook (Genetic Engineering Handbook)”, supplementary volume of Jikken Igaku (Experimental Medicine), 1992, and the like).
The present invention also relates to fusion between polypeptides according to the present invention with another protein/other proteins. A fusion polypeptide according to the present invention is a fusion polypeptide between a polypeptide having reactivity with N-methyl amino acids according to the present invention and another polypeptide. The fusion polypeptide itself may have no reactivity with N-methyl amino acids as long as it comprises a polypeptide chain having reactivity with N-methyl amino acids according to the present invention. When prepared as a fusion protein with, for example, Glutathione S-transferase (GST), the fusion polypeptide according to the present invention can be prepared by subcloning a cDNA encoding the polypeptide according to the present invention into, for example, plasmid pGEX4T1 (from Pharmacia), transforming E. coli DH5α or the like with the plasmid, and culturing the transformant.
Alternatively, a fusion polypeptide according to the present invention can be prepared as a fusion with HA (influenza agglutinin), immunoglobulin constant region, β-galactosidase, maltose-binding protein (MBP), or the like. Moreover, a fusion polypeptide can be prepared as a fusion with, for example, any known peptide such as FLAG (Hopp, T. P. et al., BioTechnology (1988) 6, 1204-1210), a tag consisting of several (e.g., six) histidine (His) residues (such as 6×His, 10×His), influenza agglutinin (HA), a human c-myc fragment, a VSV-GP fragment, a p18HIV fragment, T7-tag, HSV-tag, E-tag, a SV40T antigen fragment, lck tag, an α-tubulin fragment, B-tag, a Protein C fragment, Stag, StrepTag, and HaloTag.
The vectors according to the present invention preferably comprise at least a promoter-operator region, the initiation codon, a polynucleotide encoding the polypeptide according to the present invention, a termination codon, a terminator region, and a replicable unit when bacteria, particularly E. coli, are used as host cells.
The expression vectors preferably comprise at least a promoter, the initiation codon, a polynucleotide encoding a polypeptide according to the present invention, and a termination codon when yeast, animal cells, or insect cells are used as hosts.
The vectors may also comprise DNA encoding a signal peptide, an enhancer sequence, 5′ and 3′ untranslated regions of the gene encoding a polypeptide according to the present invention, a splicing junction, a polyadenylation site, a selection marker region, a replicable unit, or the like.
The vectors may also comprise, if desired, a marker gene (such as a gene amplification gene, a drug-resistant gene) that allows selection of hosts in which gene amplification and transformation have been achieved.
Examples of marker genes include, for example, dihydrofolate reductase (DHFR) gene, thymidine kinase gene, neomycin resistant gene, glutamic acid synthetase gene, adenosine deaminase gene, ornithine decarboxylase gene, hygromycin B phosphotransferase gene, aspartate transcarbamylase gene, and the like.
The promoter-operator region for expressing a polypeptide according to the present invention in bacteria can include, a promoter, an operator, and Shine-Dalgarno (SD) sequence (such as AAGG).
An example of a promoter-operator region includes one comprising, for example, Trp promoter, lac promoter, recA promoter, λPL promoter, lpp promoter, tac promoter, or the like when the host is a bacterium of the genus Escherichia, for example.
Promoters for expressing a polypeptide according to the present invention in yeast include PH05 promoter, PGK promoter, GAP promoter, and ADH promoter.
The promoters include SL01 promoter, SP02 promoter, penP promoter, and the like when the host is a bacterium of the genus Bacillus.
The promoters also include promoters derived from SV40, retroviral promoters, heat shock promoters, and the like when the hosts are eukaryotic cells such as mammalian cells. The promoters are preferably those derived from SV40 and retroviral promoters. However, the promoters are not particularly limited to those described above. Also, enhancers can be effectively used for expression.
An example of a suitable initiation codon includes the methionine codon (ATG). Examples of termination codons include common termination codons (e.g., TAG, TGA, and TAA). Terminator regions that can be used include natural or synthetic terminators generally used.
The replicable unit refers to DNA having an ability to replicate the full DNA sequence of the replicable unit in host cells, and includes natural plasmids, artificially modified plasmids (DNA fragments prepared from natural plasmids), synthetic plasmids, and the like. Suitable plasmids include plasmid pBR322 or an artificially modified pBR322 (a DNA fragment obtained by digesting pBR322 with a suitable restriction enzyme) for E. coli; yeast 2p plasmid or yeast chromosomal DNA for yeast; and plasmid pRSVneo (ATCC 37198), plasmid pSV2dhfr (ATCC 37145), plasmid pdBPV-MMTneo (ATCC 37224), plasmid pSV2neo (ATCC 37149), and the like for mammalian cells.
Enhancer sequence, polyadenylation site, and splicing junction that can be used are those commonly used by those skilled in the art, such as for example those derived from SV40.
The expression vectors according to the present invention can be prepared by ligating at least a promoter as described above, an initiation codon, a polynucleotide encoding a polypeptide according to the present invention, a termination codon, and a terminator region to a suitable replicable unit continuously and circularly. Suitable DNA fragments (e.g., a linker, other restriction enzyme cleavage sites, and the like) can also be used in conventional techniques such as digestion with restriction enzymes and ligation with T4 DNA ligase, if desired.
The present invention also relates to recombinant cells transformed with the vectors according to the present invention as described above, and the recombinant cells according to the present invention can be prepared by introducing the expression vectors as described above into host cells.
Host cells used in the present invention are not particularly limited as long as they are compatible with the expression vectors described above and can be transformed. Examples of host cells include various cells including natural cells and artificially-established recombinant cells commonly used in the technical field of the present invention, for example, bacteria (Escherichia bacteria, Bacillus bacteria), yeast (such as Saccharomyces, Pichia), animal cells, insect cells, and the like.
The host cells are preferably E. coli or animal cells, and examples include, for example, E. coli (such as DH5α, TB1, HB101), mouse-derived cells (such as COP, L, C127, Sp2/0, NS-1, or NIH3T3), rat-derived cells (PC12, PC12h), hamster-derived cells (such as BHK and CHO), monkey-derived cells (such as COS1, COS3, COS7, CV1, and Velo), human-derived cells (such as Hela, diploid fibroblast-derived cells, myeloma cells, and HepG2), and the like.
Introduction of expression vectors into host cells (transformation (transfection)) can be performed according to conventional methods ([for E. coli, Bacillus subtilis, and the like]: Proc. Natl. Acad. Sci. USA., Vol. 69, p. 2110, 1972; Mol. Gen. Genet., Vol. 168, p. 111, 1979; J. Mol. Biol., Vol. 56, p. 209, 1971; [for Saccharomyces cerevisiae]: Proc. Natl. Acad. Sci. USA., Vol. 75, p. 1927, 1978; J. Bacteriol., Vol. 153, p. 163, 1983); [for animal cells]: Virology, Vol. 52, p. 456, 1973; [for insect cells]: Mol. Cell. Biol., Vol. 3, p. 2156-2165, 1983).
The polypeptides according to the present invention can be produced by culturing recombinant transformed cells including expression vectors prepared as described above (hereinafter used to mean inclusion of an inclusion body) in a nutrient medium according to any conventional method.
The polypeptides according to the present invention can be produced such as by culturing recombinant cells as described above, particularly animal cells and allowing the recombinant cells to secrete the polypeptides into culture supernatant.
The obtained culture is subjected to filtration, centrifugation, or any other similar technique to obtain a culture filtrate (supernatant). The polypeptides according to the present invention are purified and isolated from the culture filtrate according to any conventional method commonly used to purify and isolate natural or synthetic proteins.
Isolation and purification methods include, for example, methods utilizing solubility such as salt precipitation and solvent precipitation, dialysis, ultrafiltration, gel filtration, methods utilizing the difference in molecular weight such as sodium dodecyl sulphate-polyacrylamide gel electrophoresis, methods utilizing electric charge such as ion exchange chromatography and hydroxylapatite chromatography, methods utilizing specific affinity such as affinity chromatography, methods utilizing the difference in hydrophobicity such as reversed-phase high-performance liquid chromatography, methods utilizing the difference in isoelectric point such as isoelectric focusing, and the like.
Meanwhile, when a polypeptide according to the present invention is present in periplasm or cytoplasm of cultured recombinant cells (e.g., E. coli), the culture is subjected to any conventional method such as filtration or centrifugation to collect bacterial pellets or cells. The collected bacterial pellets or cells are suspended in a suitable buffer, and cell wall and/or cytoplasmic membrane is/are disrupted by any method such as for example sonication, lysozyme, and freeze-thawing. Any method such as centrifugation or filtration is then performed to obtain membrane fraction containing the protein according to the present invention. The membrane fraction is solubilized with any surfactant such as Triton™-X100 to give a crude solution. Then, the crude solution can be isolated and purified using any conventional method as described previously.
The present invention also relates to a polynucleotide (cDNA or genomic DNA) encoding a polypeptide according to the present invention as described above or an oligonucleotide hybridizing with a strand complementary to the polynucleotide. For example, the oligonucleotide is a base sequence at least comprising modified sites of ARSs according to the present invention or an oligonucleotide hybridizing with a strand complementary to the base sequence. An oligonucleotide according to the present invention is also a partial fragment of polynucleotides encoding a modified ARS according to the present invention, and is preferably a fragment comprising bases in modified sites of the modified ARSs or a strand complementary to the fragment.
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Val, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon(s) for an amino acid corresponding to position 43, and/or an amino acid corresponding to position 45, and/or an amino acid corresponding to position 279 of the amino acid sequences set forth in SEQ ID NOs: 3-5, 182, and 183 (ValRS04, ValRS13, ValRS13-11, ValRS66, and ValRS67), or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 43 is preferably Gly or Ala (more preferably Gly), and an amino acid corresponding to position 45 is preferably Ser, and an amino acid corresponding to position 279 is preferably Gly or Ala (more preferably Ala).
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Ser, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon(s) for an amino acid corresponding to position 237 and/or an amino acid corresponding to position 239 of the amino acid sequences set forth in SEQ ID NOs: 6-9 (SerRS03, SerRS05, SerRS35, and SerRS37), or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 237 is preferably Ser, and an amino acid corresponding to position 239 is preferably Gly or Ala (more preferably Gly).
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Phe, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon for an amino acid corresponding to position 169 of the amino acid sequences set forth in SEQ ID NOs: 1-2 (PheRS04 and PheRS05) or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 169 is preferably Gly or Ala.
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Thr, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon(s) for an amino acid corresponding to position 332 and/or an amino acid corresponding to position 511 of the amino acid sequences set forth in SEQ ID NOs: 10-11 (ThrRS03 and ThrRS14), or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 332 is preferably Gly, and an amino acid corresponding to position 511 is preferably Gly.
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Trp, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon(s) for an amino acid corresponding to position 132, and/or an amino acid corresponding to position 150, and/or an amino acid corresponding to position 153 of the amino acid sequences set forth in SEQ ID NOs: 184-186 (TrpRS04, TrpRS05, and TrpRS18), or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 132 is preferably Val or Ala (more preferably Val), an amino acid corresponding to position 150 is preferably Ala, and an amino acid corresponding to position 279 is preferably Ala.
For example, for a polynucleotide encoding a polypeptide according to the present invention having reactivity with N-methyl Leu, the oligonucleotide according to the present invention may be an oligonucleotide comprising bases encoding the codon for an amino acid corresponding to position 43 of the amino acid sequence set forth in SEQ ID NO: 187 (LeuRS02) or an oligonucleotide consisting of a sequence complementary to the oligonucleotide. In this case, an amino acid corresponding to position 43 is preferably Gly.
Length of a partial fragment of polynucleotides encoding the polypeptides according to the present invention having reactivity with N-methyl amino acids is not particularly limited, but is for example, at least 15 consecutive bases, preferably 16 or more consecutive bases, more preferably 17 or more consecutive bases, more preferably 18 or more consecutive bases, more preferably 20 or more consecutive bases, more preferably 25 or more consecutive bases, more preferably 28 or more consecutive bases, more preferably 30 or more consecutive bases, more preferably 32 or more consecutive bases, more preferably 35 or more consecutive bases, more preferably 40 or more consecutive bases, and more preferably 50 or more consecutive bases.
In addition to the partial fragment of polynucleotides encoding ARSs according to the present invention as described above, oligonucleotides according to the present invention may also further comprise (an) oligonucleotide(s) consisting of other sequences at its/their both or either end(s) (5′ and/or 3′ end). An oligonucleotide according to the present invention is, for example, 500 bases or less in length, more preferably 300 bases or less in length, more preferably 200 bases or less in length, more preferably 100 bases or less in length, more preferably 70 bases or less in length, more preferably 60 bases or less in length, and more preferably 50 bases or less in length.
Oligonucleotides according to the present invention are useful for producing nucleic acids encoding the polypeptides according to the present invention (e.g., useful for introducing mutations), and also useful for detecting nucleic acids encoding the polypeptides according to the present invention. For example, an oligonucleotide according to the present invention can also be used as a probe in DNA hybridization or RNA hybridization operations. An example of a DNA for the purpose of using as a probe include a partial base sequence of 20 or more consecutive bases hybridizing with a polynucleotide according to the present invention, preferably, a partial base sequence of 30 or more consecutive bases, more preferably a partial base sequence of 40 or 50 or more consecutive bases, more preferably a partial base sequence of 100 or more consecutive bases, more preferably a partial base sequence of 200 or more consecutive bases, and particularly preferably a partial base sequence of 300 or more consecutive bases.
Polypeptides, polynucleotides, and oligonucleotides according to the present invention can be included in compositions in combination with carriers or vehicles, appropriately. The compositions can be produced using any method known to those skilled in the art. The polypeptides, polynucleotides, and oligonucleotides according to the present invention can be appropriately combined with, for example, pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oil, emulsifying agents, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, bonding agents, or the like. These can be mixed together to be formulated in unit dosage form required by generally-accepted pharmaceutical practices.
The present invention also provides cells transformed with a polynucleotide (including DNA and RNA) encoding a mutant N-methyl aminoacyl-tRNA synthetase as described above. Such cells may be prokaryotic cells or eukaryotic cells.
When a mutant N-methyl aminoacyl-tRNA synthetase according to the present invention expressed in cells is directly used for protein synthesis in the cells, cells depending on the intended use can be used. Any known method can be adopted for the transformation.
The present invention also provides a method for producing polypeptide containing N-methyl amino acids using the ARS with an altered amino acid sequence according to the present invention as described above.
The ARSs with altered amino acid sequences according to the present invention are used not only in cells but also in vitro (in a cell-free system).
In either case, unlike prior art using chemical synthesis such as the pdCpA method, tRNAs can be acylated repeatedly during a translation reaction, and therefore N-methyl aminoacyl-tRNAs can be supplied continuously, and addition of a large amount of tRNAs, which may inhibit translation, can be avoided.
Accordingly, the present invention provides a method for producing non-natural amino acids efficiently, selectively, in particular regioselectively, and in large amounts.
General Method for Preparing a Modified ARS According to the Present Invention
A modified ARS according to the present invention can be produced using any known genetic recombination technique as mentioned above, and generally can be prepared as follows: first, site-directed mutation is introduced into a specific position or a specific amino acid by PCR using a plasmid comprising the natural ARS gene as a template with appropriate primers. The template plasmid is digested with a restriction enzyme, and then E. coli or the like is transformed with the digested plasmid. The plasmid into which the desired mutation has been introduced is cloned.
If a second amino acid mutation is introduced, subsequently the introduction of site-directed mutation using the plasmid having the mutation introduced into the specific position as a template with appropriate primers is repeated as with the description above, which results in the construction of a plasmid DNA encoding the polypeptide in which the two amino acids are substituted. A similar procedure can be followed when introducing further amino acid mutations.
E. coli BL21 strain or the like is co-transformed with the constructed DNA and the plasmid pREP4 encoding lac repressor (LacI) or the like, and the obtained transformed strain is isolated and cultured followed by expression induction with IPTG. The obtained strain is then disrupted, and the supernatant is passed through an affinity column for His-tag to purify the mutant ARS.
Alternatively, the following method can be used to prepare a mutant ARS. Specifically, a sequence of a certain mutant ARS is genetically synthesized and inserted into an expression vector, and proteins are allowed to be expressed. Affinity columns for different purification tags are used to purify the protein of interest.
Methods for producing a mutant N-methyl aminoacyl-tRNA synthetase according to the present invention, which is modified by substituting an amino acid at a specific position with another amino acid, are not limited to the methods as described above, and various genetic engineering techniques including known point mutation techniques and gene synthesis techniques, methods for introducing modified fragments using restriction enzymes, and the like may be used. Also, expression is not limited to expression in E. coli, and animal cells and cell-free translation systems may also be used. Purification methods are also not limited to methods in an affinity column for polyhistidine, and various peptide-tags and purification columns may be used.
Method for Confirming Substrate Specificity of the Obtained Modified ARS According to the Present Invention
Substrate specificity of the obtained modified products can be confirmed by any of the following three assay methods, for example.
The first method can confirm by mass spectroscopy that N-methyl amino acids corresponding to codons on mRNA are introduced into a peptide by performing a translation reaction in a cell-free translation system reconstituted with the modified ARS rather than wild-type ARS and further N-methylated amino acids rather than natural amino acids, and performing aminoacylation with N-methyl amino acids in the translation system.
In the second method, peptides to be produced are labeled in a translation experiment using amino acids labeled with radioactive isotopes or fluorescent molecules, and the peptides are separated and visualized by electrophoresis or an analytical column to estimate yield of the peptides. In this method, translational introduction efficiency of corresponding N-methyl amino acids provided by using the modified ARS is increased compared to that provided by using wild-type ARS, and therefore the radioactivity or fluorescence, which is observed by electrophoresis or chromatogram, of the peptide produced using the modified ARS is observed more strongly than that of the peptide produced using wild-type ARS.
In the third method, three molecules, a modified ARS, a tRNA and an N-methyl amino acid corresponding to the modified ARS are reacted together in vitro, and the resulting N-methyl aminoacyl-tRNA is separated from unreacted tRNA by electrophoresis to quantify efficiency of the acylation reaction. The acylated tRNA produced using the modified ARS is detected more than that produced using wild-type ARS.
As mentioned above, the modified ARSs according to the present invention have increased reactivity with N-methyl amino acids compared to unmodified ARSs. The increased reactivity with N-methyl amino acids may be an increase in reaction rate, an increase in the amount of reaction products acylated with N-methyl amino acids, or an increase in substrate specificity to N-methyl amino acids. The increased reactivity with N-methyl amino acids may also be qualitative or quantitative. For example, the reactivity with N-methyl amino acids is considered to have increased in a reaction performed under the same conditions except for the use of an unmodified ARS or a modified ARS when the reactivity (such as reaction rate or the amount of reaction products) of the modified ARS to the substrate N-methyl amino acid is significantly increased compared to the reactivity of the unmodified ARS to N-methyl amino acids. Even if the reaction rate or reaction product amount in a reaction using the modified ARS and an N-methyl amino acid as substrate does not significantly increase compared to that in a reaction using the unmodified ARS, the reactivity of the modified ARS to N-methyl amino acids is considered to have increased when substrate specificity of the modified ARS to the N-methyl amino acid is increased relative to that in a reaction using unmodified amino acids. Preferably, the modified ARSs according to the present invention increase reaction rate or reaction product amount in a reaction using N-methyl amino acids as substrates compared to unmodified ARSs.
For example, the modified ARSs according to the present invention significantly increase the amount of tRNA aminoacylated with N-methyl amino acids or the amount of peptides incorporating N-methyl amino acids, as measured under the same conditions except for using either unmodified ARS or modified ARS, preferably by at least 10%, preferably by 20%, preferably by 1.3 times or more, preferably by 1.5 times or more, preferably by 2 times or more, preferably by 3 times or more, further preferably by 5 times or more, further preferably by 10 times or more, further preferably by 20 times or more, further preferably by 30 times or more, further preferably by 50 times or more, and further preferably by 100 times or more. Alternatively, the modified ARSs according to the present invention significantly increase the amount ratio of “products of the reaction with N-methyl amino acids/products of the reaction with unmodified amino acids”, as measured under the same conditions except for using either unmodified ARS or modified ARS, preferably by at least 10%, preferably by 20%, preferably by 1.3 times or more, preferably by 1.5 times or more, preferably by 2 times or more, preferably by 3 times or more, further preferably by 5 times or more, further preferably by 10 times or more, further preferably by 20 times or more, further preferably by 30 times or more, further preferably by 50 times or more, further preferably by 100 times or more compared to unmodified ARSs. Alternatively, when a nucleic acid encoding a polypeptide containing consecutive N-methyl amino acids is allowed to be translated, the modified ARSs according to the present invention significantly increase the production amount of the polypeptide containing consecutive N-methyl amino acids, as measured under the same conditions except for using either unmodified ARS or modified ARS, preferably by at least 10%, preferably by 20%, preferably by 1.3 times or more, preferably by 1.5 times or more, preferably by 2 times or more, preferably by 3 times or more compared to unmodified ARSs. The consecutive N-methyl amino acids may be, for example, two and/or three consecutive N-methyl amino acids.
The reactivity with N-methyl amino acids can be determined according to a confirmation method as described above. Specifically, for example, ribosomally-produced peptides are electrophoresed, and band intensity of peptides that have incorporated N-methyl amino acids and peptides that have not incorporated N-methyl amino acids can be measured qualitatively or quantitatively to determine the reactivity. Alternatively, mass spectral peaks can be measured, and peaks of peptides that have incorporated N-methyl amino acids and peaks of peptides that have not incorporated N-methyl amino acids can be measured to determine the reactivity.
For example, substrate specificity of a modified ARSs according to the present invention is significantly increased, preferably by at least 10%, preferably by 20%, preferably by 1.3 times or more, preferably by 1.5 times or more, preferably by 2 times or more, preferably by 3 times or more, further preferably by 5 times or more, further preferably by 10 times or more, and further preferably by 20 times or more compared to unmodified ARSs when peptides are synthesized in the presence of unmodified amino acids or N-methyl amino acids and the amount ratio of “products of the reaction with N-methyl amino acids/products of the reaction with unmodified amino acids” is measured.
The reaction conditions may be appropriately determined as long as the conditions used for unmodified ARSs and for modified ARSs are the same. The substrate concentration of unmodified amino acids and N-methyl amino acids at the reaction may be appropriately adjusted, and may be any concentration condition as long as reactivity with N-methyl amino acids is increased. Preferably, unmodified amino acids may not be added (may be only endogenous amino acids originally contained in a cell-free translation system), or may be appropriately adjusted in the range from 0.1 μM to 1 mM, for example, 0.1 μM to 500 μM, 0.1 μM to 250 μM, 0.1 μM to 100 μM, or 0.1 μM to 50 μM for reactions. N-methyl amino acids may be appropriately adjusted in the range from, for example, 50 μM to 10 mM, for example, 100 μM to 5 mM, 200 μM to 2 mM, or 500 μM to 1 mM for reactions.
Modified ARSs obtained by the preparation method as described above can be used to produce peptides and peptide-mRNA fusions that have incorporated N-methyl amino acids in a site-specific manner.
Moreover, ARSs used herein are highly conserved among biological species. Therefore, it is clear that the method according to the present invention can be generally applied to modification of N-methyl amino acid-tRNA synthetases from other biological species.
The modified ARS according to the present invention can be used to produce peptides having a particular amino acid substituted with its non-natural, N-methylated amino acid, in a prokaryotic translation. Such peptides can be produced using ARSs that are derived from other organisms and modified in a similar way as the present invention.
Acylation Reaction of tRNAs Using the Modified ARSs According to the Present Invention
Use of the modified ARSs according to the present invention makes it possible to employ N-methyl amino acids as substrates in acylation of tRNAs. The modified ARSs according to the present invention can acylate tRNAs with N-methyl amino acids and to ribosomally produce N-methyl amino acid-containing peptides.
In order to produce N-methyl aminoacyl-tRNAs using the modified ARSs according to the present invention, the modified ARSs, N-methyl amino acids corresponding to the modified ARSs, and tRNAs may be reacted in vitro as in chemical synthesis such as the pdCpA method. The products, N-methyl aminoacyl-tRNAs may be isolated using any known nucleic acid purification technique such as ethanol precipitation, and the isolated product may be added to a translation system. This leads to production of polypeptides or polypeptide-mRNA fusions that have introduced N-methyl amino acids at the intended positions.
Unlike chemical synthesis which requires reactions performed in a reaction solution comprising only a particular tRNA and the N-methyl amino acid corresponding to the tRNA as substrates, three molecules, a modified ARS, N-methyl amino acid, and tRNA are used to precisely and efficiently produce the intended N-methyl aminoacyl-tRNA even in a mixture of translation reaction solution comprising other tRNAs and other amino acids because the modified ARSs according to the present invention have high substrate specificity for tRNAs and amino acids. Accordingly, the isolation and purification steps as described above are not essential. A reaction solution in which tRNAs have been acylated with N-methyl amino acids can be directly used in a translation reaction, or a translation reaction can be performed at the same time as an acylation reaction of tRNAs with N-methyl amino acids. The modified ARSs according to the present invention are very convenient because the reactions using the modified ARSs require no chemical synthesis of substrates such as pdCpA amino acids and activated amino acids and can be performed using commercially available reagents.
The most important characteristics include no requirement of stoichiometric consideration for a tRNA of interest in performing peptide translation (peptide expression) using a modified ARS according to the present invention. In chemical synthesis in which aminoacyl-tRNAs are supplied, N-methyl aminoacyl-tRNAs are consumed during the reaction, decreasing the reaction efficiency. However, if ARSs are used, translational efficiency is good even in peptide synthesis in which multiple N-methyl amino acids are introduced. Aminoacyl-tRNAs are constantly deacylated in hydrolytic reactions or transpeptidation reactions in translation systems, but the modified ARSs according to the present invention recognize released tRNAs and newly acylate the tRNAs with N-α amino acids, which results in a constant supply of N-α aminoacyl-tRNAs in the translation system. Therefore, the amount of tRNA required is less than the amount of produced polypeptide. Addition of large amounts of tRNA itself contributes to reduction of peptide yield. Therefore, the modified ARSs according to the present invention are useful for producing N-α amino acid-containing peptides at a high translational efficiency and producing highly diverse peptide libraries.
Moreover, because the modified ARSs according to the present invention have increased reactivity with N-methyl amino acids compared to natural ARSs, the modified ARSs can acylate tRNAs in the presence of N-methyl amino acids at a concentration lower than a concentration of N-methyl amino acids used for natural ARSs. In other words, the absolute amount of N-methyl amino acids required for peptide expression using the modified ARSs is not as much as that of N-methyl amino acids required for peptide expression using natural ARSs.
In addition, the modified ARSs according to the present invention can be used to translate N-methyl amino acid-containing peptides at a concentration lower than a concentration of natural ARSs used for translating N-methyl amino acid-containing peptides. In other words, the absolute amount of the modified ARS according to the present invention required for peptide expression is significantly less than in translation of N-methyl amino acid-containing peptides using natural ARSs.
These characteristics are important for improving orthogonality of aminoacylation reaction. Namely, in order to translate N-methyl amino acid-containing peptides, the more the substrate N-methyl amino acid, or an ARS corresponding to the N-methyl amino acid, is needed at a concentration higher than other natural amino acids, or ARSs corresponding to the other natural amino acids, the more it makes it easier for non-specific reactions to happen, such non-specific reactions being: ARS that should be normally using an N-methyl amino acid as a substrate may use other natural amino acids for acylation reaction; or an N-methyl amino acid that is present in excess may be used in acylation reactions by ARSs corresponding to other natural amino acids. This results in the obtained translated peptides being a mixture of N-methyl amino acid-containing peptides and peptides containing corresponding natural amino acid, which may cause issues for peptide libraries. However, it is expected that this issue can be minimized by using the modified ARSs according to the present invention.
Accordingly, the characteristics of the modified ARSs according to the present invention can be described as follows:
modified ARSs that catalyze acylation of tRNAs and comprise
• (a) a tRNA binding site;
• (b) a binding site to an N-methyl amino acid substrate; and
• (c) a catalytically active site having activity to catalyze a reaction in which an acyl group is transferred from the N-methyl amino acid substrate to 3′ end of a tRNA,
wherein the modified ARSs are characterized in that they can correctly recognize tRNAs and N-methyl amino acids in a translation reaction mixture, acylates the tRNAs, and further reuse tRNAs released after the transacylation reaction to repeat acylation reactions again.
Moreover, the modified ARSs according to the present invention may comprise, in addition to (a), (b), and (c) as described above, (d) an editing site where a tRNA acylated with any undesired amino acid is hydrolyzed.
Synthesis of Acylated tRNAs Using the Modified ARSs According to the Present Invention
The modified ARSs according to the present invention can be used to synthesize tRNAs acylated with desired N-methyl amino acid substrates.
A method for producing acylated tRNAs using the modified ARSs according to the present invention, comprising the following steps:
• (a) providing one or more modified ARSs according to the present invention;
• (b) providing tRNAs;
• (c) providing N-methyl amino acids; and
• (d) contacting the modified ARSs with the tRNAs and N-methyl amino acids to acylate the tRNAs.
In addition to the steps as described above, the method may further comprise the step of (e) collecting the reaction product comprising the acylated tRNAs. The acylated tRNAs require no purification in the collecting step, and the reaction mixture can be collected and used directly. By not separating or purifying the produced aminoacyl-tRNAs from the ARSs, deacylation can be prevented.
This method uses N-methyl amino acids as substrates. Particularly preferable N-methyl amino acids include N-methylphenylalanine, N-methylvaline, N-methylthreonine, N-methyltryptophan, N-methylleucine, and/or N-methylserine. A substrate of an ARS (an amino acid corresponding to the ARS) is appropriately selected as N-methyl amino acid used as a substrate.
In a method for producing an acylated tRNA using a modified ARS according to the present invention, a tRNA that can be used is a tRNA corresponding to an ARS of a corresponding natural amino acid. The term “corresponding natural amino acid” refers to an amino acid that is not N-methylated relative to an N-methyl amino acid. For example, for N-methylphenylalanine, the corresponding amino acid is phenylalanine, and the corresponding tRNA is a tRNA recognizing the codon UUU or UUC (having the anticodon corresponding to the codon). For N-methylvaline, the corresponding amino acid is valine, and the corresponding tRNA is a tRNA recognizing the codon GUU, GUC, GUA, or GUG (having the anticodon corresponding to the codon). For N-methylserine, the corresponding amino acid is serine, and the corresponding tRNA is a tRNA recognizing the codon UCU, UCC, UCA, UCG, AGU, or AGC (having the anticodon corresponding to the codon). For N-methylthreonine, the corresponding amino acid is threonine, and the corresponding tRNA is a tRNA recognizing the codon ACU, ACC, ACA, or ACG (having the anticodon corresponding to the codon). For N-methyltryptophan, the corresponding amino acid is tryptophan, and the corresponding tRNA is a tRNA recognizing the codon UGG (having the anticodon corresponding to the codon). For N-methylleucine, the corresponding amino acid is leucine, and the corresponding tRNA is a tRNA recognizing the codon UUA, UUG, CUU, CUC, CUA, or CUG (having the anticodon corresponding to the codon). Similarly, for other N-methyl amino acids, tRNAs recognizing codons corresponding to the corresponding amino acid (having the anticodons corresponding to the codons) can be used.
When a tRNA is acylated by a modified ARS in a solution, a pellet obtained by ethanol precipitation of the reaction solution may be dissolved in a suitable buffer (such as 1 mM potassium acetate, pH 5) and added to a translation system. Typical reaction conditions include, for example, a reaction performed at 37° C. for 5 minutes to 1 hour in 0.1 M reaction buffer (pH 7.5) containing a final concentration of 0.5 μM to 40 μM of a tRNA, 0.1 μM to 10 μM of a modified ARS according to the present invention, 0.1 mM to 10 mM of an N-methyl amino acid, 0.1 mM to 10 mM ATP, and 0.1 mM to 10 mM MgCl2.
Furthermore, for an aminoacylation reaction, a tRNA can be refolded by, for example, heating 1 to 50 μM tRNA, 10 to 200 (e.g., 50 to 200) mM HEPES-K (pH 7.0 to 8.0 (e.g., 7.6)), 1 to 100 (e.g., 10) mM KCl solution at 95° C. for 2 minutes and then left at room temperature for 5 minutes or more. This tRNA solution can be added to an acylation buffer (a final concentration of 25 to 100 (e.g., 50) mM HEPES-K [pH 7.0 to 8.0 (e.g., 7.6)], 1 to 10 (e.g., 2) mM ATP, 10 to 100 (e.g., 100) mM potassium acetate, 1 to 20 (e.g., 10) mM magnesium acetate, 0.1 to 10 (e.g., 1) mM DTT, 0.1 mg/mL Bovine Serum Albumin) to a final concentration of 1 to 40 (e.g., 10) μM, mixed with a modified ARS (a final concentration of 0.1 to 10 (e.g., 0.5) μM) and an N-methyl amino acid (a final concentration of 0.1 to 10 (e.g., 1) mM), and incubated at 37° C. for 5 to 60 (e.g., 10) minutes.
Thus, the acylation reaction using a modified ARS according to the present invention requires no activated amino acids that need substrates and need to be synthesized. The acylation reaction can be performed with commercially available N-methyl amino acids and therefore is convenient. The modified ARSs according to the present invention can be combined with their substrates to form a kit product for obtaining acylated tRNAs. The kit may at least comprise (a) one or more modified ARSs according to the present invention, (b) N-methyl amino acid(s), and (c) tRNA(s), and may further comprise a reaction buffer, a reaction vessel, instructions for use, and the like. In the kit, each of (b) N-methyl amino acid(s) and (c) tRNA(s) acts as a substrate for (a) modified ARSs. In other words, the tRNAs recognize codons corresponding to natural amino acids equivalent to the N-methyl amino acids (the tRNAs have anticodons corresponding to the codons).
Synthesis of N-Methyl Amino Acid-Containing Polypeptides Using the Modified ARSs According to the Present Invention
N-methyl amino acid-bound tRNAs can be used to produce polypeptides with N-methyl amino acids introduced into desired sites. The method comprises translating a nucleic acid encoding a polypeptide of interest in the presence of a modified ARS according to the present invention.
More specifically, for example, a method for producing an N-methyl amino acid-containing polypeptide using a modified ARS(s) according to the present invention comprises (a) providing the modified ARS(s) according to the present invention, (b) establishing a cell-free translation system reconstituted with the modified ARS(s) according to the present invention rather than wild-type ARS(s), (c) providing an mRNA having at a desired site(s) codon(s) corresponding to the anticodon(s) of a tRNA(s) that is the substrate(s) of the modified ARS(s), and (d) adding the mRNA to the cell-free translation system to produce a polypeptide with an N-methyl amino acid(s) introduced into a desired site(s). Matters particularly relevant to the production of polypeptide in (d) will be described below.
N-methyl amino acids preferably used in acylation of tRNAs with N-methyl amino acids using the modified ARSs according to the present invention include N-methylalanine, N-methylleucine, N-methyltryptophan, N-methylphenylalanine, N-methylvaline, N-methylthreonine, and/or N-methylserine, and particularly preferably N-methylphenylalanine, N-methylvaline, N-methylthreonine, N-methyltryptophan, N-methylleucine, and/or N-methylserine.
Specific methods for polypeptide synthesis may be essentially performed according to known methods, for example, performed as described in WO2013100132, and various modifications can be made. Generally, the methods can be performed according to the following description.
A suitable translation system that can be used is a cell-free translation system, typified by PURESYSTEM (Registered trademark) (BioComber, Japan), reconstituted with translation factors. In such a cell-free translation system, components of the translation system can be controlled flexibly. For example, phenylalanine and the ARS corresponding to phenylalanine are removed from the translation system and instead, N-methylphenylalanine and the modified phenylalanine-ARS according to the present invention can be added. This achieves introduction of N-methylphenylalanine into a codon, such as UUU and UUC, encoding phenylalanine in a site-specific manner.
In a cell-free translation system, ribonucleosides preferably used are ATP and GTP at 0.1 mM-10 mM. A buffer preferably used is HEPES-KOH at 5 mM-500 mM and pH 6.5-8.5. Examples of other buffers include, but are not limited to, Tris-HCl, phosphate, and the like. Salts that can be used are acetates such as potassium acetate and ammonium acetate, and glutamates such as potassium glutamate, which are preferably used at 10 mM-1000 mM. A magnesium component preferably used is magnesium acetate at 2 mM-200 mM. Examples of other magnesium components include, but are not limited to, magnesium chloride and the like. Components in an energy-regenerating system preferably used are creatine kinase at 0.4 μg/mL-40 μg/mL and creatine phosphate at 2 mM-200 mM. Other energy-regenerating systems, typified by pyruvate kinase and phosphoenol pyruvate, may also be used. A nucleoside converting enzyme preferably used is myokinase at 0.1 unit/mL-10 unit/mL or nucleoside diphosphate kinase at 0.2 μg/mL-20 μg/mL. A diphosphatase preferably used is inorganic pyrophosphatase at 0.2 unit/mL-20 unit/mL. A polyamine preferably used is spermidine at 0.2 mM-20 mM. Examples of other polyamines include, but are not limited to, spermine and the like. A reducing agent preferably used is dithiothreitol at 0.1 mM-10 mM. Examples of other reducing agents include, but are not limited to, β-mercaptoethanol and the like. A tRNA preferably used is, for example, E. coli MRE600 (RNase-negative)-derived tRNA (Roche) at 0.5 mg/mL-50 mg/mL. Other tRNAs from E. coli may also be used. A formyl donor and an enzyme preferably used to synthesize formylmethionine used in a translational initiation reaction are 10-HCO—H4 folate at 0.1 mM-10 mM and methionyl-tRNA transformylase at 0.05 μM-5 μM. A translation initiation factor preferably used is IF1 at 0.5 μM-50 μM, IF2 at 0.1 μM-50 μM, or IF3 at 0.1 μM-50 μM. A translation elongation factor preferably used is EF-G at 0.1 μM-50 μM, EF-Tu at 1 μM-200 μM, or EF-Ts at 1 μM-200 μM. A translation termination factor preferably used is RF-2, RF3, or RRF at 0.1 μM-10 μM. Ribosome is preferably used at 1 μM-100 μM. There are 20 types of aminoacyl-tRNA synthetases, but only the enzymes corresponding to amino acids included in a peptide to be synthesized may be added. For example, ArgRS, AspRS, LysRS, MetRS, and TyrRS are all preferably used at 0.01 μM-1 μM. Amino acids used as substrates for peptide synthesis are natural 20 amino acids, which compose proteins, and derivatives thereof. Only amino acids included in a peptide to be synthesized are preferably used at 0.25 mM-10 mM. An mRNA as a template for peptide synthesis is preferably used at 0.1 μM-10 μM. When an mRNA is transcribed from a template DNA in a cell-free translation system, commercially available enzymes such as T7 RNA polymerase, T3 RNA polymerase, and SP6 RNA polymerase can be used, and the enzymes suitable for a promoter sequence in the template DNA may be appropriately selected and are preferably used at 1 μg/mL-100 μg/mL. In this case, nucleosides CTP and UTP, which are substrates, are preferably used at 0.1 mM-10 mM. A solution containing mixed these components can be left, for example, at 37° C. for 1 hour to achieve translational synthesis of peptides. Temperature and reaction time are not limited to those.
The modified ARSs according to the present invention can also be used in combination with other techniques for introducing non-natural amino acids, such as the pdCpA method or the Flexizyme method. For example, polypeptides containing both N-methylglycine and N-methylphenylalanine can be synthesized when the aminoacyl-tRNA to which N-methylglycine is attached by the pdCpA method is added to a translation system at the same time as addition of N-methylphenylalanine and the modified phenylalanine ARS.
Alternatively, polypeptides containing N-methyl amino acids can be expressed in cells by inserting the modified ARSs according to the present invention into an expression vector or genome, expressing the modified ARSs in cells, and using N-methyl amino acids added to a medium as substrates.
tRNAs that can be used include a tRNA for a natural amino acid corresponding to an N-methyl amino acid. The tRNAs may be tRNAs that contain modified bases and are purified from a living body, or tRNAs that do not contain modified bases and are produced using an in vitro transcription reaction. Mutant tRNAs, which have a mutation in a portion of tRNA other than the portion recognized by an ARS, can also be used as substrates.
EXAMPLES
The content of the present invention as mentioned above will be described in more detail in the Examples below, but the Examples are illustrative and are not intended to limit the scope of the present invention. Various variations and modifications that can be made by those skilled in the art based on the description in the specification and claims are also included in the present invention.
All prior art literatures cited here are incorporated herein by reference.
Example 1: N-Methylphenylalanine-Accepting ARS
Preparation of Plasmids for Wild-Type and Mutant PheRSs
Using a plasmid (pQE-32(2) 2_wtPheRS) comprising the ORF sequence of wild-type PheRS α subunit gene of E. coli (SEQ ID NOs: 27, 28) as starting material, mutant PheRS plasmids (having His-tag (6×His) at the N-terminus) listed in Table 1 were constructed by introducing site-directed mutations using PCR. Specifically, 2 μL of 10 ng/μL template, 10 μL of 2×KOD Fx buffer (TOYOBO, KFX-101), 0.6 μL of 10 μM forward primer, 0.6 μL of 10 μM reverse primer, 4 μL of 2 mM dNTP, 0.4 μL of KOD FX (TOYOBO, KFX-101), and 2.4 μL of H2O were mixed together. Thereafter, the resulting reaction solution was heated at 94° C. for 2 minutes and then subjected to 10 cycles, each consisting of heating at 98° C. for 10 seconds and heating at 68° C. for 7 minutes, to amplify the mutant gene. The combinations of the template plasmid, forward primer, and reverse primer used are listed in Table 2. Each sequence of primers “F.F02” through “F.F05” corresponds to SEQ ID NOs: 30-33 in ascending order, and each sequence of primers “R.F02” through “R.F05” corresponds to SEQ ID NOs: 34-37 in ascending order. 0.5 μL of 10 U/μL DpnI was then added to the PCR reaction solution and further incubated at 37° C. for 1.5 hours to digest the template DNA, and the resulting mutant DNA was purified. E. coli XL-1 Blue strain (STRATAGENE, 200236) was then co-transformed with the resulting mutant gene DNA and pREP4 (Invitrogen, V004-50) encoding the lacI gene. The transformants were seeded onto agar containing ampicillin and kanamycin. The plasmids of interest were purified from the resulting clones. The mutations were confirmed to be introduced into the plasmids.
TABLE 1 position position Name 169 171 PheRS01(wt) Q S PheRS02 Q A PheRS03 Q G PheRS04 A S PheRS05 G S
TABLE 2 Name Template 5′ primer 3′ primer PheRS02 PheRS01(wt) F. F02 R. F02 PheRS03 PheRS01(wt) F. F03 R. F03 PheRS04 PheRS01(wt) F. F04 R. F04 PheRS05 PheRS01(wt) F. F05 R. F05
Small Scale Expression of Wild-Type and Mutant PheRSs
Next, a plasmid comprising a resulting mutant gene and the gene encoding PheRS β subunit was introduced into E. coli, and a heterodimer comprising the mutant protein was expressed. First, E. coli BL21 strain transformed with the mutant plasmid and pREP4 (Invitrogen, V004-50) was cultured at 37° C. in 4 mL of LB medium containing kanamycin, ampicillin, and 0.5% glucose. Subsequently, when the OD value at 600 nm reached 0.4 to 0.8, IPTG was added to a final concentration of 0.5 mM. After further culturing at 37° C. for 4 hours, the bacterial pellets were collected using a centrifuge.
Small Scale Purification of Wild-Type and Mutant PheRSs
Next, the resulting bacterial pellets were disrupted, and the mutant protein of interest was purified from the supernatant. Specifically, the bacterial pellets as described above were suspended in 600 μL of CHAPS solution (0.5% CHAPS (DOJINDO: 349-04722), 50% TBS (TaKaRa, T903)) and mixed with 6 μL of 30 U/μl rLysozyme (Novagen, 71110-3), and 2 μL of 2.5 U/μL benzonase nuclease (Novagen, 70746-3) followed by incubation at room temperature for 30 minutes. Imidazole was then added to a final concentration of 15 mM, and an insoluble fraction was separated by centrifugation. Then, the mutant protein was purified from the resulting supernatant using QIAGEN Ni-NTA spin column kit (Qiagen, 31314) according to the product manual. Finally, excess imidazole was removed using a desalting column, PD miniTrap G-25 (GE Healthcare, 28-9180-07) according to the product manual.
Large Scale Purification of Wild-Type and Mutant PheRSs
The mutant protein confirmed to have activity was prepared in large scale. Specifically, E. coli BL21 strain transformed with a plasmid comprising the mutant α subunit gene and wild-type β subunit gene and pREP4 (Invitrogen, V004-50) was cultured at 37° C. in 3 L of LB medium containing kanamycin, ampicillin, and 0.5% glucose. Then, when the OD value at 600 nm reached 0.4, IPTG was added to a final concentration of 0.5 mM. After further culturing at 37° C. for 4 hours, the bacterial pellets were collected with a centrifuge. The bacterial pellets as described above were suspended in 1 L of CHAPS solution (0.5% CHAPS (DOJINDO: 349-04722) and 50% TBS (TaKaRa, T903)), mixed with 10 JAL of 30 KU/μl rLysozyme (Novagen, 71110-3), and stirred at room temperature for 10 minutes. Next, 2 mL of 1 M MgCl2 and 320 μL of Benzonase Nuclease (Novagen, 70746-3) were added and stirred at room temperature for 20 minutes. Imidazole was then added to a final concentration of 20 mM, and an insoluble fraction was separated by centrifugation. Subsequently, the mutant protein was purified from the resulting supernatant using a column filled with 15 mL of Ni Sepharose High Performance (GE Healthcare) and AKTA10S (GE Healthcare) with an imidazole concentration gradient (initial concentration 20 mM, final concentration 500 mM). Finally, dialysis was performed three times (2 hours×2, overnight×1) using a dialysis cassette (MWCO 10,000, Slide-A-Lyzer G2 Dialysis Cassettes 70 mL, Thermo Scientific Pierce) and 3 L of stock solution (50 mM Hepes-KOH, 100 mM KCl, 10 mM MgCl2, 1 mM DTT pH 7.6) to obtain the mutant protein.
Aminoacylation Reaction with N-Methylphenylalanine Using Wild-Type and Mutant PheRSs
Synthesis of E. coli tRNAPhe by In Vitro Transcription Reaction
E. coli tRNA (R-tRNAPhe (SEQ ID NO: 39)) was synthesized from a template DNA (D-tRNAPhe (SEQ ID NO: 38)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) in the presence of 7.5 mM GMP, and purified using RNeasy Mini kit (Qiagen).
D-tRNAPhe tRNAPhe DNA sequence: (SEQ ID NO: 38) GGCGTAATACGACTCACTATAGCCCGGATAGCTCAGTCGGTAGAGCAGGG GATTGAAAATCCCCGTGTCCTTGGTTCGATTCCGAGTCCGGGCACCA R-tRNAPhe tRNAPhe RNA sequence: (SEQ ID NO: 39) GCCCGGAUAGCUCAGUCGGUAGAGCAGGGGAUUGAAAAUCCCCGUGUCCU UGGUUCGAUUCCGAGUCCGGGCACCA
Aminoacylation Reaction
For the aminoacylation reaction, the solution containing 40 μM transcribed tRNAPhe, 10 mM HEPES-K (pH 7.6), and 10 mM KCl solution was heated at 95° C. for 2 minutes and then left at room temperature for 5 minutes or more to refold the tRNA. This tRNA solution was added to a final concentration of 10 μM to an acylation buffer (in final concentrations of 50 mM HEPES-K [pH 7.6], 2 mM ATP, 100 mM potassium acetate, 10 mM magnesium acetate, 1 mM DTI, 2 mM spermidine, 0.1 mg/mL Bovine Serum Albumin), mixed with wild-type or mutant PheRS (final concentration 0.5 μM) and phenylalanine (final concentration 0.25 mM, Watanabe Chemical Industries, Ltd., G00029) or N-methylphenylalanine (final concentration 1 mM, Watanabe Chemical Industries, Ltd., J00040), and incubated at 37° C. for 10 minutes. Four volumes of a loading buffer (90 mM sodium acetate [pH 5.2], 10 mM EDTA, 95% (w/w) formamide, 0.001% (w/v) xylene cyanol) was added to the reaction solution and analyzed with acidic PAGE (12% (w/v) polyacrylamide gel, pH 5.2) containing 6 M urea, and aminoacylation activity was detected by separating unreacted tRNA and aminoacylated tRNA. RNA was stained with SYBR Gold (Life Technologies) and detected with LAS4000 (GE Healthcare).
The activity for the aminoacylation reaction was assessed, and mutants 04 and 05 had increased activity for aminoacylation with N-methyl-phenylalanine compared to the wildtype (FIG. 1). The base sequence of mutant 04 is set forth in SEQ ID NO: 12, and the amino acid sequence of mutant 04 is set forth in SEQ ID NO: 1. The base sequence of mutant 05 is set forth in SEQ ID NO: 13, and the amino acid sequence of mutant 05 is set forth in SEQ ID NO: 2.
Translational Introduction of N-Methylphenylalanine Using Wild-Type and Mutant PheRSs
Synthesis of Template DNA-F by In Vitro Transcription Reaction
A template mRNA for translation (R-F (SEQ ID NO: 41)) was synthesized from a template DNA (D-F (SEQ ID NO: 40)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-F DNA sequence: (SEQ ID NO: 40) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTTTCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-F RNA sequence: (SEQ ID NO: 41) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUUUCCGUGACUACAAGGAC GACGACGACAAGUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methylphenylalanine, a desired polypeptide containing N-methylphenylalanine was ribosomally synthesized by adding an N-methyl amino acid and PheRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant PheRS and phenylalanine or N-methylphenylalanine were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 0.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 44 μM EF-Ts, 1.2 μM ribosome, 0.03 μM ArgRS, 0.13 μM AspRS, 0.11 μM LysRS, 0.03 μM MetRS, 0.02 μM TyrRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM arginine, aspartic acid, lysine, methionine, and tyrosine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Electrophoresis
A peptide expression experiment was performed by using aspartic acid labeled with a radioisotope for detecting peptides into which N-methylphenylalanine is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-F (SEQ ID NO: 41)), arginine, lysine, methionine, and tyrosine (each final concentration 250 μM), and 14C-aspartic acid (final concentration 37 μM, Moravek Biochemicals, MC139) added to the cell-free translation system as described above was prepared. Wild-type PheRS or the mutant PheRS 05 (final concentration 0.1 μM) and phenylalanine (final concentration 250 μM) or N-methylphenylalanine (final concentration 1 mM or 250 μM) were added to the solution and incubated at 37° C. for 60 minutes. An equal volume of 2× sample buffer (TEFCO, cat No. 06-323) was added to the resulting translation reaction solution and heated at 95° C. for 3 minutes followed by electrophoresis (16% Peptide-PAGE mini, TEFCO, TB-162). After electrophoresis, the gel was dried using Clear Dry Quick Dry Starter KIT (TEFCO, 03-278), exposed to an imaging plate (GE Healthcare, 28-9564-75) for about 16 hours, detected using a Bioanalyzer System (Typhoon FLA 7000, GE Healthcare), and analyzed with ImageQuantTL (GE Healthcare).
Almost no bands of peptides that were ribosomally synthesized were observed in the presence of 0.1 μM wild-type PheRS when 0.25 mM or 1 mM N-methylphenylalanine was added (FIG. 2). Meanwhile, peptide bands were observed in the presence of 0.1 μM mutant PheRS 05 even when 0.25 mM N-methylphenylalanine was added. The results can provide confirmation that the mutant PheRS 05 had increased aminoacylation activity with N-methylphenylalanine and that peptides containing N-methylphenylalanine were ribosomally synthesized at a high yield.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methylphenylalanine is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-F (SEQ ID NO: 41)) and amino acids, arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. PheRS (final concentration 0.1 μM) and phenylalanine (final concentration 250 μM) or N-methylphenylalanine (final concentration 1 mM or 250 μM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. α-Cyano-4-hydroxycinnamic acid was used as a matrix for translation products.
When a translation experiment was performed as a control experiment in the presence of 0.1 μM wild-type PheRS (SEQ ID NO: 28) or mutant PheRS 05 (SEQ ID NO: 2) with 250 μM phenylalanine added, the peak of the peptide into which phenylalanine was introduced (Calculated [M+H]+=1631.7) was detected in both experiments using wild-type PheRS and the mutant PheRS 05 (FIG. 3(a), (d)).
Translational synthesis was then performed by using wild-type PheRS and adding 0.25 mM N-methylphenylalanine, and the peaks of the peptide containing N-methylphenylalanine (Calculated [M+H]+=1645.7) and the peptide containing phenylalanine were observed (FIG. 3 (b)). This phenomenon is thought to be due to wild-type PheRS recognizing phenylalanine contaminated in N-methylphenylalanine, the subsequent occurrence of the aminoacylation reaction, and proceeding of translational synthesis. Furthermore, the peak intensity of the peptide containing N-methylphenylalanine was increased under the condition of 1 mM N-methylphenylalanine (FIG. 3(c)). The ratio of peak intensities at each amino acid concentration was calculated (the calculating formula: the ratio of peak intensity=the peak intensity of the peptide containing N-methylphenylalanine/the peak intensity of the peptide containing phenylalanine) to be 0.8 at 0.25 mM and 2.6 at 1 mM.
Next, a translational synthesis was performed by using the mutant PheRS 05 and adding 0.25 mM or 1 mM N-methylphenylalanine, and the peak of the peptide containing N-methylphenylalanine was strongly detected, and the ratio of peak intensity of the peptide containing N-methylphenylalanine to the peak intensity of the peptide containing phenylalanine was 12.4 at 0.25 mM and 16.0 at 1 mM (FIG. 3 (e), (f)). These results confirmed that the mutant PheRS 05 had increased aminoacylation activity with N-methylphenylalanine compared to wild-type PheRS, and consequently, translational synthesis of the peptide containing N-methylphenylalanine was promoted.
Peptide sequence P-F1 (SEQ ID NO: 42) formylMetArgPheArgAspTyrLysAspAspAspAspLys Peptide sequence P-MeF1 (SEQ ID NO: 42) formylMetArg[MePhe]ArgAspTyrLysAspAspAspAspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1631.7 (the peptide corresponding to the sequence P-F1)
Calc. m/z: [H+M]+=1645.7 (the peptide corresponding to the sequence P-MeF1)
Comparison with the pdCpA Method
Incorporation efficiency of N-methylphenylalanine using an ARS according to the present invention was compared with that in the pdCpA method. Translation was performed using a sequence containing one, two consecutive, or three consecutive phenylalanines in a cell-free translation system, and the synthesized peptide band was detected by electrophoresis. The amount of the peptide synthesized using a mutant PheRS according to the present invention (PhrRS05 (SEQ ID NO: 2)) was compared with the amount of the peptide synthesized using the pdCpA method. It is confirmed that the amount of the peptide synthesized using the mutant PheRS according to the present invention was detected more than the amount of the peptide synthesized using the pdCpA method in all translations and that translational efficiency obtained by using the mutant PheRS was also higher than that obtained by using the pdCpA method. Particularly, it is revealed that the amount of the peptide produced by translating sequences containing two consecutive and three consecutive N-methylphenylalanines using the mutant PheRS according to the present invention (PhrRS05) was 4 to 8 times higher than the amount of the peptide produced using the pdCpA method.
Example 2: N-Methylvaline-Accepting ARS
Preparation of Plasmids for Wild-Type and Mutant ValRSs
The mutant ValRS plasmids (having His-tag (6×His) at the N-terminus) listed in Table 3 were constructed by introducing site-directed mutations using PCR into the plasmid (PQE-32(2) 2_wtVALRS) comprising the ORF sequence of wild-type ValRS gene of E. coli (SEQ ID NOs: 23, 24), which was used as starting material. Specifically, 2 μL of 10 ng/μL template, 10 μL of 2×KOD Fx buffer (TOYOBO, KFX-101), 0.6 μL of 10 μM forward primer, 0.6 μL of 10 μM reverse primer, 4 μL of 2 mM dNTP, 0.4 μL of KOD FX (TOYOBO, KFX-101), and 2.4 μL of H2O were mixed together. Then, the resulting reaction solution was heated at 94° C. for 2 minutes and then subjected to 10 cycles, each consisting of heating at 98° C. for 10 seconds and heating at 68° C. for 7 minutes, to amplify the mutant gene. The combinations of the template plasmid, forward primer, and reverse primer used are listed in Table 4. Each sequence of primers “F.V2” through “F.V19”, “F.V46” through “F.V48”, and “F.V13-01” through “F.V13-16” corresponds to SEQ ID NOs: 43-79 in ascending order. Each sequence of primers “R.V2” through “R.V19”, “R.V46” through R.V48”, and “R.V13-01” through “R.V13-16” corresponds to SEQ ID NOs: 80-116 in ascending order. 0.5 μL of 10 U/μL DpnI was then added to the PCR reaction solution and further incubated at 37° C. for 1.5 hours to digest the template DNA, and the resulting mutant DNA was purified. E. coli XL-1 Blue strain (STRATAGENE, 200236) was then co-transformed with the resulting mutant gene DNA and pREP4 (Invitrogen, V004-50) encoding the lacI gene. The transformants were seeded onto agar containing ampicillin and kanamycin. The plasmids of interest were purified from the resulting clones. The mutations were confirmed to be introduced into the plasmids.
For plasmid construction requiring multistep mutation introduction, the procedure as described above was repeated to obtain plasmids into which mutations of interest were introduced. The combinations of the primers and template for such plasmid construction are listed in Table 4.
TABLE 3 position position position position position position Name 80 43 41 Name 43 45 85 ValRS001 (wt) D N P ValRS13-01 G T Y ValRS002 A ValRS13-02 G T W ValRS003 G ValRS13-03 G T S ValRS004 A P ValRS13-04 G T M ValRS005 A ValRS13-05 G T K ValRS006 G ValRS13-06 G T N ValRS007 S P ValRS13-07 G T V ValRS008 A ValRS13-08 G T L ValRS009 G ValRS13-09 G Y A ValRS010 V P ValRS13-10 G W A ValRS011 A ValRS13-11 G S A ValRS012 G ValRS13-12 G M A ValRS013 G P ValRS13-13 G K A ValRS014 A ValRS13-14 G N A ValRS015 G ValRS13-15 G V A ValRS016 D P ValRS13-16 G L A ValRS017 A ValRS018 G ValRS019 A N P ValRS020 A ValRS021 G ValRS022 A P ValRS023 A ValRS024 G ValRS025 S P ValRS026 A ValRS027 G ValRS028 V P ValRS029 A ValRS030 G ValRS031 G P ValRS032 A ValRS033 G ValRS034 D P ValRS035 A ValRS036 G ValRS037 S D P ValRS038 A ValRS039 G ValRS040 V D P ValRS041 A ValRS042 G ValRS043 G D P ValRS044 A ValRS045 G ValRS046 S N P ValRS047 V N P ValRS048 G N P
TABLE 4 forward reverse forward reverse primer primer Template primer primer Template ValRS001 ValRS13-01 F. V13-01 R. V13-01 ValRS13 ValRS002 F. V2 R. V2 wild type ValRS13-02 F. V13-02 R. V13-02 ValRS13 ValRS003 F. V3 R. V3 wild type ValRS13-03 F. V13-03 R. V13-03 ValRS13 ValRS004 F. V4 R. V4 wild type ValRS13-04 F. V13-04 R. V13-04 ValRS13 ValRS005 F. V5 R. V5 wild type ValRS13-05 F. V13-05 R. V13-05 ValRS13 ValRS006 F. V6 R. V6 wild type ValRS13-06 F. V13-06 R. V13-06 ValRS13 ValRS007 F. V7 R. V7 wild type ValRS13-07 F. V13-07 R. V13-07 ValRS13 ValRS008 F. V8 R. V8 wild type ValRS13-08 F. V13-08 R. V13-08 ValRS13 ValRS009 F. V9 R. V9 wild type ValRS13-09 F. V13-09 R. V13-09 ValRS13 ValRS010 F. V10 R. V10 wild type ValRS13-10 F. V13-10 R. V13-10 ValRS13 ValRS011 F. V11 R. V11 wild type ValRS13-11 F. V13-11 R. V13-11 ValRS13 ValRS012 F. V12 R. V12 wild type ValRS13-12 F. V13-12 R. V13-12 ValRS13 ValRS013 F. V13 R. V13 wild type ValRS13-13 F. V13-13 R. V13-13 ValRS13 ValRS014 F. V14 R. V14 wild type ValRS13-14 F. V13-14 R. V13-14 ValRS13 ValRS015 F. V15 R. V15 wild type ValRS13-15 F. V13-15 R. V13-15 ValRS13 ValRS016 F. V16 R. V16 wild type ValRS13-16 F. V13-16 R. V13-16 ValRS13 ValRS017 F. V17 R. V17 wild type ValRS018 F. V18 R. V18 wild type ValRS019 F. V19 R. V19 wild type ValRS020 F. V2 R. V2 ValRS019 ValRS021 F. V3 R. V3 ValRS019 ValRS022 F. V4 R. V4 ValRS019 ValRS023 F. V5 R. V5 ValRS019 ValRS024 F. V6 R. V6 ValRS019 ValRS025 F. V7 R. V7 ValRS019 ValRS026 F. V8 R. V8 ValRS019 ValRS027 F. V9 R. V9 ValRS019 ValRS028 F. V10 R. V10 ValRS019 ValRS029 F. V11 R. V11 ValRS019 ValRS030 F. V12 R. V12 ValRS019 ValRS031 F. V13 R. V13 ValRS019 ValRS032 F. V14 R. V14 ValRS019 ValRS033 F. V15 R. V15 ValRS019 ValRS034 F. V16 R. V16 ValRS019 ValRS035 F. V17 R. V17 ValRS019 ValRS036 F. V18 R. V18 ValRS019 ValRS037 F. V16 R. V16 ValRS046 ValRS038 F. V17 R. V17 ValRS046 ValRS039 F. V18 R. V18 ValRS046 ValRS040 F. V16 R. V16 ValRS047 ValRS041 F. V17 R. V17 ValRS047 ValRS042 F. V18 R. V18 ValRS047 ValRS043 F. V16 R. V16 ValRS048 ValRS044 F. V17 R. V17 ValRS048 ValRS045 F. V18 R. V18 ValRS048 ValRS046 F. V46 R. V46 wt ValRS047 F. V47 R. V47 wt ValRS048 F. V48 R. V48 wt
Small Scale Expression of Wild-Type and Mutant ValRSs
Next, a resulting mutant plasmid was introduced into E. coli, and the mutant protein was expressed. First, E. coli BL21 strain transformed with the mutant plasmid and pREP4 (Invitrogen, V004-50) was cultured at 37° C. in 4 mL of LB medium containing kanamycin and ampicillin. Then, when the OD value at 600 nm reached 0.4 to 0.8, IPTG was added to a final concentration of 0.5 mM. After further culturing at 37° C. for 4 hours, the bacterial pellets were collected using a centrifuge.
Small Scale Purification of Wild-Type and Mutant ValRSs
Next, the resulting bacterial pellets were disrupted, and the mutant protein of interest was purified from the supernatant. Specifically, the bacterial pellets as described above were suspended in 600 μL of CHAPS solution (0.5% CHAPS (DOJINDO: 349-04722), 50% TBS (TaKaRa, T903)) and mixed with 6 μL of 30 U/μl rLysozyme (Novagen, 71110-3) followed by incubation at room temperature for 10 minutes. The reaction was further mixed with 2 μL of 2.5 U/μL benzonase nuclease (Novagen, 70746-3) followed by incubation at room temperature for 20 minutes, and an insoluble fraction was separated by centrifugation. The mutant protein was then purified from the resulting supernatant using QIAGEN Ni-NTA spin column kit (Qiagen. 31314) according to the product manual. Finally, excess imidazole was removed using a desalting column, PD miniTrap G-25 (GE Healthcare, 28-9180-07) according to the product manual.
Aminoacylation Reaction with N-Methylvaline Using Wild-Type and Mutant ValRSs
Synthesis of E. coli tRNAVal by In Vitro Transcription Reaction
E. coli tRNA (R-tRNAVal2A (SEQ ID NO: 118)) was synthesized from a template DNA (D-tRNAVal2A (SEQ ID NO: 117)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) in the presence of 7.5 mM GMP, and purified using RNeasy Mini kit (Qiagen).
D-tRNAVal2A tRNAVal2A DNA sequence: (SEQ ID NO: 117) GGCGTAATACGACTCACTATAGCGTCCGTAGCTCAGTTGGTTAGAGCACC ACCTTGACATGGTGGGGGTCGGTGGTTCGAGTCCACTCGGACGCACCA R-tRNAVal2A tRNAVal2A RNA sequence: (SEQ ID NO: 118) GCGUCCGUAGCUCAGUUGGUUAGAGCACCACCUUGACAUGGUGGGGGUCG GUGGUUCGAGUCCACUCGGACGCACCA
Aminoacylation Reaction
For the aminoacylation reaction, the solution containing 40 μM transcribed tRNA, 10 mM HEPES-K (pH 7.6), and 10 mM KCl solution was heated at 95° C. for 2 minutes and then left at room temperature for 5 minutes or more to refold the tRNA. This tRNA solution was added to a final concentration of 10 μM to an acylation buffer (in final concentrations of 50 mM HEPES-K [pH 7.6], 2 mM ATP, 100 mM potassium acetate, 10 mM magnesium acetate, 1 mM DTT, 2 mM spermidine, 0.1 mg/mL Bovine Serum Albumin), mixed with wild-type or mutant ValRS (final concentration 0.2 μM-1 μM) and N-methylvaline (final concentration 5 mM), and incubated at 37° C. for 10 minutes. Four volumes of a loading buffer (90 mM sodium acetate [pH 5.2], 10 mM EDTA, 95% (w/w) formamide, 0.001% (w/v) xylene cyanol) were added to the reaction solution and analyzed with acidic PAGE containing 6 M urea, and aminoacylation activity was detected by separating unreacted tRNA and aminoacyl-tRNA. RNA was stained with SYBR Gold (Life Technologies) and detected with LAS4000 (GE Healthcare) (FIG. 4).
As a result, tRNA acylated with N-methylvaline was observed when mutant 13 was used. It was demonstrated that mutant 13 had increased activity for aminoacylation with N-methylvaline compared to wild-type ValRS (FIG. 4, lane 2 vs 10).
Translational Introduction of N-Methylvaline Using Wild-Type and Mutant ValRSs
Template mRNAs for translation (R-V, R-V2, and R-V3 (SEQ ID NOs: 120, 122, and 124, respectively)) were synthesized from template DNAs (D-V, D-V2, and D-V3 (SEQ ID NOs: 119, 121, and 123, respectively)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-V DNA sequence: (SEQ ID NO: 119) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTGTCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-V RNA sequence: (SEQ ID NO: 120) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUGUCCGUGACUACAAGGAC GACGACGACAAGUAAGCUUCG D-V2 DNA sequence: (SEQ ID NO: 121) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTGTCGTCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-V2 RNA sequence: (SEQ ID NO: 122) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUGUCGUCCGUGACUACAAG GACGACGACGACAAGUAAGCUUCG D-V3 DNA sequence: (SEQ ID NO: 123) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTGTCGTCGTCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-V3 RNA sequence: (SEQ ID NO: 124) GGGUUAACUUUAACAAGGAGAAAAACAUGCGCGUGUCGUCGUCUGACUAC AAGGACGACGACGACAAGUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methylvaline, a desired polypeptide containing N-methylvaline was ribosomally synthesized by adding an N-methylvaline and a mutant ValRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant ValRS and N-methylvaline were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 1.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 0.1 mM 10-HCO—H4 folate, 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 84 μM EF-Ts, 1.2 μM ribosome, 0.03 μM ArgRS, 0.13 μM AspRS, 0.11 μM LysRS, 0.03 μM MetRS, 0.02 μM TyrRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM arginine, aspartic acid, lysine, methionine, and tyrosine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methylvaline is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-V (SEQ ID NO: 120)) and arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. ValRS (final concentration 0.1 μM-1 μM) and N-methylvaline (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. Translation products were identified with MALDI-TOF MS spectrometry using α-cyano-4-hydroxycinnamic acid as a matrix.
As a result of the translation using wild-type ValRS (SEQ ID NO: 24), a peak corresponding to the peptide sequence P-V1 introduced with valine contaminated in the cell-free translation system ((FIG. 5(a), Peak V1, m/z: [H+M]+=1583.6) was observed as main product. Similar experiments were performed using different mutant ValRSs. When ValRS04 (SEQ ID NO: 3) or ValRS13 (SEQ ID NO: 4) was used, a peak corresponding to the peptide sequence P-MeV1 with N-methylvaline introduced ((FIG. 5(b), Peak MeV1, m/z: [H+M]+=1597.5, FIG. 5(c), Peak MeV2, m/z: [H+M]+=1597.5) was observed as main product. This demonstrated, also from a view point of translation reaction that ValRS04 and ValRS13 have increased activity to N-methylvaline compared to wild-type ValRS. Although peaks corresponding to the peptide P-V1 introduced with valine contaminated in the translation system (FIG. 5(b) Peak V2, (c) Peak V3) were also observed at the same time, the intensity of the peak in using ValRS13 was weaker than that in using ValRS04. Therefore, it was suggested that ValRS13 has a higher activity to N-methylvaline (FIG. 5(b), (c)).
Peptide sequence P-V1 (SEQ ID NO: 125) formylMetArgValArgAspTyrLysAspAspAspAspLys Peptide sequence P-MeV1 (SEQ ID NO: 125) formylMetArg[MeVal]ArgAspTyrLysAspAspAspAspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1583.7 (the peptide corresponding to the sequence P-V1)
Calc. m/z: [H+M]+=1597.7 (the peptide corresponding to the sequence P-MeV1)
Production of Mutant ValRS13-11 Having Further Increased Aminoacylation Activity to N-Methylvaline
Improvement in activity to N-methylvaline was aimed by further introducing mutations into ValRS13 as described above. Plasmids into which the mutations of interest are introduced were prepared as mentioned above, expressed in E. coli, and purified to prepare mutant ValRSs (Table 3). As a result of screening by performing aminoacylation reaction and translational synthesis, ValRS13-11 (SEQ ID NO: 5) exhibited higher activity to N-methylvaline compared to ValRS13.
When aminoacylation reactions with N-methylvaline using wild-type ValRS, ValRS13, and ValRS13-11 were investigated, it was observed that the amount of aminoacyl-tRNA synthesized using ValRS13-11 was more than that synthesized using ValRS13 (FIG. 6, lane 8 vs lane 9 and lane 12 vs lane 13). Particularly, the amounts of aminoacyl-tRNA synthesized using ValRS13 and ValRS13-11 with N-methylvaline at the low concentration of 1.25 mM were greatly different, demonstrating that ValRS13-11 had a high activity.
Next, mass spectroscopy was performed using MALDI-TOF MS for confirming translational synthesis of peptides having N-methylvaline using ValRS13 and ValRS13-11. Specifically, a solution containing 1 μM template mRNA (R-V (SEQ ID NO: 120)) and arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. ValRS (final concentration 4 μM) and N-methylvaline (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. Template mRNAs encoding peptide sequences containing two consecutive or three consecutive N-methylvalines (R-V2 (SEQ ID NO: 122), R-V3 (SEQ ID NO: 124)) were used to perform similar experiments. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS.
The intended synthesis of the peptide sequence P-MeV1 containing N-methylvaline using ValRS13 and ValRS13-11 was confirmed when the template mRNA containing one N-methylvaline (R-V (SEQ ID NO: 120)) was used (FIG. 7(a) Peak MeV1, (b) Peak MeV2). A peak corresponding to the peptide sequence P-V1 introduced with valine contaminated in the cell-free translation system was observed weakly (FIG. 7(a) Peak V1, (b) Peak V2).
Next, it was confirmed that the peptide sequence P-MeV2 containing two N-methylvaline residues was synthesized as main product by both the mutant ValRSs when a template mRNA containing two consecutive N-methylvalines (R-V2 (SEQ ID NO: 122)) was used (FIG. 7(c) Peak MeV3, (d) Peak MeV5). Meanwhile, the peptide sequence P-MeV4 containing one N-methylvaline residue and one valine residue (FIG. 7(c) Peak MeV4, (d) Peak MeV6) was observed, but the peak intensity was suppressed when using ValRS13-11 compared to ValRS13.
Finally, template mRNA containing three consecutive N-methylvalines (R-V3 (SEQ ID NO: 124)) was used to perform translation experiments. When ValRS13 was added, the synthesis of the target peptide sequence P-MeV3 containing three N-methylvaline residues was observed (FIG. 7(e), Peak MeV7), but the peptide sequence P-MeV5 comprising two N-methylvaline residues and one valine residue was produced as main product (FIG. 7(e), Peak MeV8). The peptide sequence P-MeV6 comprising one N-methylvaline residue and two valine residues was also observed (FIG. 7(e), Peak MeV9). Meanwhile, when ValRS13-11 was added, it was observed that the target peptide sequence P-MeV3 containing three N-methylvaline residues was ribosomally synthesized as main product (FIG. 7(f), Peak MeV10). The peptide sequences P-MeV5 and P-MeV6 containing valine were also observed, but the peak intensity of these peptide sequences was suppressed compared to that obtained when using ValRS13 (FIG. 7(f), Peak MeV11 and MeV12). These results indicate that ValRS13-11 has increased aminoacylation activity to N-methylvaline compared to ValRS13, leading to the increase of the ribosomally synthesized amount of the target peptide containing N-methylvaline.
Peptide sequence P-MeV2 (SEQ ID NO: 126) formylMetArg[MeVal][MeVal]ArgAspTyrLysAsp AspAspAspLys Peptide sequence P-MeV4 (SEQ ID NO: 126) formylMetArg[MeVal]ValArgAspTyrLysAspAspAspAsp Lys or formylMetArgVal[MeVal]ArgAspTyrLysAspAspAspAsp Lys Peptide sequence P-MeV3 (SEQ ID NO: 127) formylMetArg[MeVal][MeVal][MeVal]ArgAspTyrLysAsp AspAspAspLys Peptide sequence P-MeV5 (SEQ ID NO: 127) formylMetArg[MeVal][MeVal]ValArgAspTyrLysAsp AspAspAspLys or formylMetArg[MeVal]Val[MeVal]ArgAspTyrLysAsp AspAspAspLys or formylMetArgVal[MeVal][MeVal]ArgAspTyrLysAsp AspAspAspLys Peptide sequence P-MeV6 (SEQ ID NO: 127) formylMetArg[MeVal]ValValArgAspTyrLysAspAspAsp AspLys or formylMetArgVal[MeVal]ValArgAspTyrLysAspAspAsp AspLys or formylMetArgValVal[MeVal]ArgAspTyrLysAspAspAsp AspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1710.8 (the peptide corresponding to the sequence P-MeV2)
Calc. m/z: [H+M]+=1696.8 (the peptide corresponding to the sequence P-MeV4)
Calc. m/z: [H+M]+=1823.9 (the peptide corresponding to the sequence P-MeV3)
Calc. m/z: [H+M]+=1809.9 (the peptide corresponding to the sequence P-MeV5)
Calc. m/z: [H+M]+=1795.9 (the peptide corresponding to the sequence P-MeV6)
Example 3: Development of N-Methylserine-Accenting ARS
Preparation of Plasmids for Wild-Type and Mutant SerRSs
The mutant SerRS plasmids (having His-tag (6×His) at the N-terminus) listed in Table 5 were constructed by introducing site-directed mutations using PCR into a plasmid comprising the ORF sequence (SEQ ID NOs: 25, 26) of wild-type SerRS gene of E. coli (PQE-32(2) 2_wtSERRS), which was used as starting material. Specifically, 2.5 μL of 10 ng/μL template, 12.5 μL of 2×KOD Fx buffer (TOYOBO, KFX-101), 0.75 μL of 10 μM forward primer, 0.75 μL of 10 μM reverse primer, 5 JAL of 2 mM dNTP, 0.5 μL of KOD FX (TOYOBO, KFX-101), and 3 μL of H2O were mixed together. Next, the resulting reaction solution was heated at 94° C. for 2 minutes and then subjected to 10 cycles, each consisting of heating at 98° C. for 10 seconds and heating at 68° C. for 7 minutes, to amplify the mutant gene. The combinations of the template plasmid, forward primer, and reverse primer used are listed in Table 6. Each sequence of primers “F.S2” through “F.S8”, “F.S15” through “F.S23”, and “F.S33” through “F.S38” corresponds to SEQ ID NOs: 128-149 in ascending order. Each sequence of primers “R.S2” through “R.S8”, “R.S15” through “R.S23”, and “R.S33” through “R.S38” corresponds to SEQ ID NOs: 150-171 in ascending order. 0.5 μL of 10 U/μL DpnI was then added to the PCR reaction solution and further incubated at 37° C. for 1.5 hours to digest the template DNA, and the resulting mutant DNA was purified. E. coli XL-1 Blue strain (STRATAGENE, 200236) was then co-transformed with the resulting mutant gene DNA and pREP4 (Invitrogen, V004-50) encoding the lacI gene. The transformants were seeded onto agar containing ampicillin and kanamycin. The plasmids of interest were purified from the resulting clones. The mutations were confirmed to be introduced into the plasmids.
For plasmid construction requiring multistep mutation introduction, the procedure as described above was repeated to obtain plasmids into which mutations of interest were introduced. The combinations of the primers and template for such plasmid construction are listed in Table 6.
TABLE 5 Name position 237 position 239 position 389 SerRS01(WT) T E N SerRS02 A E N SerRS03 S SerRS04 G SerRS05 T A N SerRS06 V SerRS07 S SerRS08 T E A SerRS09 A E A SerRS10 S SerRS11 G SerRS12 T A SerRS13 V SerRS14 S SerRS15 A A N SerRS16 V SerRS17 S SerRS18 S A SerRS19 V SerRS20 S SerRS21 G A SerRS22 V SerRS23 S SerRS24 A A A SerRS25 V SerRS26 S SerRS27 S A SerRS28 V SerRS29 S SerRS30 G A SerRS31 V SerRS32 S SerRS33 E291A SerRS34 K289A SerRS35 T G N SerRS36 T D N SerRS37 S G N SerRS38 S D N
TABLE 6 forward revers primer primer Template SerRS001 SerRS002 F. S2 R. S2 wt SerRS003 F. S3 R. S3 wt SerRS004 F. S4 R. S4 wt SerRS005 F. S5 R. S5 wt SerRS006 F. S6 R. S6 wt SerRS007 F. S7 R. S7 wt SerRS008 F. S8 R. S8 wt SerRS009 F. S2 R. S2 SerRS008 SerRS010 F. S3 R. S3 SerRS008 SerRS011 F. S4 R. S4 SerRS008 SerRS012 F. S5 R. S5 SerRS008 SerRS013 F. S6 R. S6 SerRS008 SerRS014 F. S7 R. S7 SerRS008 SerRS015 F. S15 R. S15 wt SerRS016 F. S16 R. S16 wt SerRS017 F. S17 R. S17 wt SerRS018 F. S18 R. S18 wt SerRS019 F. S19 R. S19 wt SerRS020 F. S20 R. S20 wt SerRS021 F. S21 R. S21 wt SerRS022 F. S22 R. S22 wt SerRS023 F. S23 R. S23 wt SerRS024 F. S15 R. S15 SerRS008 SerRS025 F. S16 R. S16 SerRS008 SerRS026 F. S17 R. S17 SerRS008 SerRS027 F. S18 R. S18 SerRS008 SerRS028 F. S19 R. S19 SerRS008 SerRS029 F. S20 R. S20 SerRS008 SerRS030 F. S21 R. S21 SerRS008 SerRS031 F. S22 R. S22 SerRS008 SerRS032 F. S23 R. S23 SerRS008 SerRS033 F. S33 R. S33 wt SerRS034 F. S34 R. S34 wt SerRS035 F. S35 R. S35 wt SerRS036 F. S36 R. S36 wt SerRS037 F. S37 R. S37 wt SerRS038 F. S38 R. S38 wt
Small Scale Expression of Wild-Type and Mutant SerRSs
Next, the resulting mutant plasmid was introduced into E. coli to express the mutant protein. First, E. coli BL21 strain transformed with the mutant plasmid and pREP4 (Invitrogen, V004-50) was cultured at 37° C. in 4 mL of LB medium containing kanamycin and ampicillin. Then, when the OD value at 600 nm reached 0.4 to 0.8, IPTG was added to a final concentration of 0.5 mM. After further culturing at 37° C. for 4 hours, the bacterial pellets were collected with a centrifuge.
Small Scale Purification of Wild-Type and Mutant SerRSs
Next, the resulting bacterial pellets were disrupted, and the mutant protein of interest was purified from the supernatant. Specifically, the bacterial pellets as described above were suspended in 600 μL of CHAPS solution (0.5% CHAPS (DOJINDO: 349-04722), 50% TBS (TaKaRa, T903)) and mixed with 6 μL of 30 U/μl rLysozyme (Novagen, 71110-3) followed by incubation at room temperature for 10 minutes. The reaction was further mixed with 2 μL of 2.5 U/μL benzonase nuclease (Novagen, 70746-3) followed by incubation at room temperature for 20 minutes, and an insoluble fraction was separated by centrifugation. Then, the mutant protein was purified from the resulting supernatant using QIAGEN Ni-NTA spin column kit (Qiagen, 31314) according to the product manual. Finally, excess imidazole was removed using a desalting column, PD miniTrap G-25 (GE Healthcare, 28-9180-07) according to the product manual.
Aminoacylation Reaction with N-Methylserine Using Wild-Type and Mutant SerRSs
Synthesis of E. coli tRNASer by In Vitro Transcription Reaction
E. coli tRNA (R-tRNASer3 (SEQ ID NO: 173)) was synthesized from a template DNA (D-tRNASer3 (SEQ ID NO: 172)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) in the presence of 7.5 mM GMP, and purified using RNeasy Mini kit (Qiagen).
D-tRNASer3 tRNASer3 DNA sequence: (SEQ ID NO: 172) GGCGTAATACGACTCACTATAGGTGAGGTGGCCGAGAGGCTGAAGGCGCT CCCCTGCTAAGGGAGTATGCGGTCAAAAGCTGCATCCGGGGTTCGAATCC CCGCCTCACCGCCA R-tRNASer3 tRNASer3 RNA sequence: (SEQ ID NO: 173) GGUGAGGUGGCCGAGAGGCUGAAGGCGCUCCCCUGCUAAGGGAGUAUGCG GUCAAAAGCUGCAUCCGGGGUUCGAAUCCCCGCCUCACCGCCA
Aminoacylation Reaction
For the aminoacylation reaction, the solution containing 40 μM transcribed tRNA, 10 mM HEPES-K (pH 7.6), and 10 mM KCl solution was heated at 95° C. for 2 minutes and then left at room temperature for 5 minutes or more to refold the tRNA. This tRNA solution was added to a final concentration of 10 μM to an acylation buffer (final concentration 50 mM HEPES-K [pH 7.6], 2 mM ATP, 100 mM potassium acetate, 10 mM magnesium acetate, 1 mM DTT, 2 mM spermidine, 0.1 mg/mL Bovine Serum Albumin), mixed with wild-type or mutant SerRS (final concentration 0.1 μM-2 μM) and N-methylserine (final concentration 1 mM), and incubated at 37° C. for 10 minutes. Four volumes of a loading buffer (90 mM sodium acetate [pH 5.2], 10 mM EDTA, 95% (w/w) formamide, 0.001% (w/v) xylene cyanol) were added to the reaction solution and analyzed with acidic PAGE containing 6 M urea, and aminoacylation activity was detected by separating unreacted tRNA and aminoacyl-tRNA. RNA was stained with SYBR Gold (Life Technologies) and detected with LAS4000 (GE Healthcare) (FIG. 8).
As a result, tRNA acylated with N-methylserine was observed when the mutants 03 (SEQ ID NO: 6), 35 (SEQ ID NO: 8), and 37 (SEQ ID NO: 9) were used. It is suggested that these mutants had increased activity for aminoacylation with N-methylserine compared to wild-type SerRS (FIG. 8, lanes 3, 25, 27).
Translational Introduction of N-Methylserine Using Wild-Type and Mutant SerRSs
Template mRNA (R-S(SEQ ID NO: 175)) was synthesized from a template DNA (D-S (SEQ ID NO: 174)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-S (CT21) DNA sequence: (SEQ ID NO: 174) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTTCCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-S RNA sequence: (SEQ ID NO: 175) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUUCCCGUGACUACAAGGAC GACGACGACAAGUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methylserine, a desired polypeptide containing N-methylserine was ribosomally synthesized by adding N-methylserine and SerRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant SerRS and N-methylserine were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 1.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 0.1 mM 10-HCO—H4 folate, 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 84 μM EF-Ts, 1.2 μM ribosome, 0.03 μM ArgRS, 0.13 μM AspRS, 0.11 μM LysRS, 0.03 μM MetRS, 0.02 μM TyrRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM arginine, aspartic acid, lysine, methionine, and tyrosine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methylserine is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-S(SEQ ID NO: 175)) and arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. SerRS (final concentration 0.1-2 μM) and N-methylserine (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. Translation products were identified with MALDI-TOF MS spectrometry using α-cyano-4-hydroxycinnamic acid as a matrix.
As a result of the translation using wild-type SerRS (SEQ ID NO: 25)), a peak corresponding to the target peptide peak P-CT21MeSer containing N-methylserine (FIG. 9(a), Peak MeS1 m/z: [H+M]+=1585.6) was observed, but the peak corresponding to Ser-containing peptide P-CT21Ser probably derived from Ser contaminated in the translation system in trace amounts (FIG. 9(a), Peak S1 m/z: [H+M]+=1571.6) was observed as main product (FIG. 9(a)). On the other hand, when similar experiments were performed using the modified SerRS with mutations introduced (Ser03 (SEQ ID NO: 6), 05 (SEQ ID NO: 7)), the peak corresponding to P-CT21Ser (FIG. 9(b) Peak S2, (c) Peak S3) was observed similarly but as a side product, and it was revealed that the main product was P-CT21MeSer (FIG. 9(b) Peak MeS2, (c) Peak MeS3). Particularly, when SerRS35 and 37 were used, it was demonstrated that the peak corresponding to P-CT21Ser was not observed and CT21MeSer was synthesized with high purity (FIG. 9(d) Peak MeS4, (e) Peak MeS5). Consequently, these modified SerRSs were demonstrated to have increased activity to MeSer compared to wild-type SerRS.
Peptide sequence P-CT21Ser (SEQ ID NO: 176) formylMetArgSerArgAspTyrLysAspAspAspAspLys Peptide sequence P-CT21MeSer (SEQ ID NO: 176) formylMetArg[MeSer]ArgAspTyrLysAspAspAspAspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1571.7 (the peptide corresponding to the sequence P-CT21Ser)
Calc. m/z: [H+M]+=1585.7 (the peptide corresponding to the sequence P-CT21MeSer)
Example 4: Development of N-Methylthreonine-Accepting ARS
Preparation of Wild-Type and Mutant ThrRS Proteins
Expression vectors having a polyhistidine sequence at the N-terminus and comprising mutations listed in Table 7 were constructed. Subsequently, an expression strain was transformed with the vectors, and the mutant proteins of interest were purified with a nickel column from supernatants obtained by disrupting cells.
TABLE 7 Position Position Position Position Position Position Name 332 334 385 462 484 511 ThrRS01(wt) M C H Y Q H ThrRS02 A C H Y Q H ThrRS03 G C H Y Q H ThrRS04 M A H Y Q H ThrRS05 M G H Y Q H ThrRS06 M C A Y Q H ThrRS07 M C H A Q H ThrRS08 M C H L Q H ThrRS09 M C H V Q H ThrRS10 M C H F Q H ThrRS11 M C H Y A H ThrRS12 M C H Y N H ThrRS13 M C H Y Q A ThrRS14 M C H Y Q G
Translational Introduction of N-Methylthreonine Using Wild-Type and Mutant ThrRSs
A template mRNA (R-T (SEQ ID NO: 178)) was synthesized from a template DNA (D-T (SEQ ID NO: 177)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-T (3lib15#09) DNA sequence: (SEQ ID NO: 177) GGCGTAATACGACTCACTATAGGGTTAACTTTAAGAAGGAGATATACATA TGAAGGCTGGTCCGGGTTTTATGACTAAGAGTGGTAGTGGTAGTTAAGCT TCG R-T RNA sequence: (SEQ ID NO: 178) GGGUUAACUUUAAGAAGGAGAUAUACAUAUGAAGGCUGGUCCGGGUUUUA UGACUAAGAGUGGUAGUGGUAGUUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methylthreonine, a desired polypeptide containing N-methylthreonine was ribosomally synthesized by adding N-methylthreonine and a mutant ThrRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant ThrRS and N-methylthreonine were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 1.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 0.1 mM 10-HCO—H4 folate, 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 93 μM EF-Ts, 1.2 μM ribosome, 2.73 μM AlaRS, 0.13 μM AspRS, 0.09 μM GlyRS, 0.11 M LysRS, 0.03 μM MetRS, 0.68 M PheRS, 0.16 μM ProRS, 0.25 μM SerRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM glycine, proline, alanine, phenylalanine, lysine, methionine, and serine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methylthreonine is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-T (SEQ ID NO: 178)) and glycine, proline, alanine, phenylalanine, lysine, methionine, and serine (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. ThrRS (final concentration 2 μM) and N-methylthreonine (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. Translation products were identified with MALDI-TOF MS spectrometry using α-cyano-4-hydroxycinnamic acid as a matrix.
As a result of the translation using wild-type ThrRS (SEQ ID NO: 29), a peak corresponding to the peptide peak P-3lib15MeThr of interest containing N-methylthreonine ((FIG. 10(a), Peak MeT1) and a peak corresponding to a potassium salt of the peptide (FIG. 10(a), Peak MeT2) were observed as main products, but at the same time, a peak corresponding to the peptide P-3lib15Thr derived from Thr contaminated in the translation system in trace amounts (FIG. 10(a), PeakT1) and a peak corresponding to a potassium salt of the peptide (FIG. 10(a), PeakT2) were also observed, revealing that the purity of the translation products was adversely affected (FIG. 10(a)). On the other hand, when experiments were performed using the modified ThrRS 03 (SEQ ID NO: 10) and the modified ThrRS 14 (SEQ ID NO: 11) with mutations introduced, the peaks derived from P-CT21MeThr (Peak MeT3-6, FIG. 10) were similarly observed, and the peak corresponding to the peptide sequence P-3lib15Thr was only slightly observed (FIG. 10(b), (c)). In other words, it was demonstrated that the peptide with MeThr introduced was synthesized with higher purity using the modified ThrRSs compared to using wild-type ThrRS, and it was suggested that the modified ThrRS 03 and 14 are ARSs that can introduce MeThr into peptides more efficiently compared to wild-type ThrRS.
Peptide sequence P-3lib15Thr (SEQ ID NO: 179) formylMetLysAlaGlyProGlyPheMetThrLysSerGlySerGly Ser Peptide sequence P-3lib15MeThr (SEQ ID NO: 179) formylMetLysAlaGlyProGlyPheMet[MeThr]LysSerGly SerGlySer
MALDI-TOF MS:
Calc. m/z: [H+M]+=1470.7, [K+M]+=1508.8 (the peptide corresponding to the sequence P-3lib15Thr)
Calc. m/z: [H+M]+=1484.7, [K+M]+=1522.8 (the peptide corresponding to the sequence P-3lib15MeThr)
Example 5: Development of N-Methyltryptophan-Accepting ARS
Preparation of Wild-Type and Mutant TrpRS Proteins
Expression vectors having a polyhistidine sequence at the N-terminus and containing mutations listed in Table 8 were constructed. Then, an expression strain was transformed with the vectors, and the mutant proteins of interest were purified with a nickel column from supernatants obtained by disrupting cells.
TABLE 8 Position Position Position Position Name 128 132 150 153 ThrRS01 (wt) Y M Q H ThrRS02 Y M Q A ThrRS03 Y M A H ThrRS04 Y M A A ThrRS05 Y A Q H ThrRS06 Y A Q A ThrRS07 Y A A H ThrRS08 Y A A A ThrRS09 A M Q H ThrRS10 Y M S H ThrRS11 Y M G H ThrRS12 Y M Q G ThrRS13 Y M G A ThrRS14 Y M A G ThrRS15 Y M G G ThrRS16 Y G A A ThrRS17 Y I A A ThrRS18 Y V A A ThrRS19 Y Q A A ThrRS20 Y L A A
Translational Introduction of N-Methyltryptophan Using Wild-Type and Mutant TrpRSs
A template mRNA(R-W (SEQ ID NO: 197)) was synthesized from a template DNA (D-W (SEQ ID NO: 196)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-W (CT29) DNA sequence: (SEQ ID NO: 196) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTTGGCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-W RNA sequence: (SEQ ID NO: 197) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUUGGCGUGACUACAAGGAC GACGACGACAAGUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methyltryptophan, a desired polypeptide containing N-methyltryptophan was ribosomally synthesized by adding N-methyltryptophan and a mutant TrpRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant TrpRS and N-methyltryptophan were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 1.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 0.1 mM 10-HCO—H4 folate, 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 84 μM EF-Ts, 1.2 μM ribosome, 0.03 μM ArgRS, 0.13 μM AspRS, 0.11 μM LysRS, 0.03 μM MetRS, 0.02 μM TyrRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM arginine, aspartic acid, lysine, methionine, and tyrosine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methyltryptophan is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-W (SEQ ID NO: 197)) and arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. TrpRS (final concentration 5 μM) and N-methyltryptophan (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. Translation products were identified with MALDI-TOF MS spectrometry using α-cyano-4-hydroxycinnamic acid as a matrix.
As a result of the translation using wild-type TrpRS (SEQ ID NO: 188), a peak corresponding to the target peptide peak P-CT29MeTrp containing N-methyltryptophan (FIG. 11(a), Peak MeW1) was observed, but a peak corresponding to peptide P-CT29Trp derived from Trp contaminated in the translation system in trace amounts was observed as main product (FIG. 11(a), PeakW1). On the other hand, when experiments were performed using the modified TrpRS 04 (SEQ ID NO: 184), the modified TrpRS 05 (SEQ ID NO: 185), and the modified TrpRS 18 (SEQ ID NO: 186) with mutations introduced, peaks derived from P-CT29MeTrp (Peak MeW2-4, FIG. 11(b)-(d)) were observed as main product. In other words, it is demonstrated that the peptide introduced with MeTrp was synthesized at a higher purity using modified TrpRSs compared to using wild-type TrpRS, and it was suggested that these modified TrpRSs are ARSs that can introduce MeTrp into peptides more efficiently compared to wild-type TrpRS.
Peptide sequence P-CT29Trp (SEQ ID NO: 198) formylMetArgTrpArgAspTyrLysAspAspAspAspLys Peptide sequence P-CT29MeTrp (SEQ ID NO: 199) formylMetArg[MeTrp]ArgAspTyrLysAspAspAspAspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1670.7 (the peptide corresponding to the sequence P-CT29Trp)
Calc. m/z: [H+M]+=1684.7 (the peptide corresponding to the sequence P-CT29MeTrp)
Example 6: Development of N-Methylleucine-Accepting ARS
Preparation of Wild-Type and Mutant LeuRS Proteins
Expression vectors having a polyhistidine sequence at the N-terminus and containing mutations listed in Table 9 were constructed. Subsequently, an expression strain was transformed with the vectors, and the mutant proteins of interest were purified with a nickel column from supernatants obtained by disrupting cells.
TABLE 9 Position Position Position Name 43 80 252 LeuRS01(wt) Y D T LeuRS02 G D T LeuRS03 A D T LeuRS04 E D T LeuRS06 F D T LeuRS07 Y G T LeuRS08 Y A T LeuRS09 E G T LeuRS10 E A T LeuRS11 D G T LeuRS12 D A T LeuRS13 A G T LeuRS14 G G T LeuRS15 Y D A LeuRS16 A G A LeuRS17 G G A LeuRS18 G D A LeuRS19 Y G A LeuRS21 E G A LeuRS22 E A A LeuRS23 D G A
Translational Introduction of N-Methylleucine Using Wild-Type and Mutant LeuRSs
A template mRNA(R-L (SEQ ID NO: 201)) was synthesized from a template DNA (D-L (SEQ ID NO: 200)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) and purified using RNeasy Mini kit (Qiagen).
D-L (CT23) DNA sequence: (SEQ ID NO: 200) GGCGTAATACGACTCACTATAGGGTTAACTTTAACAAGGAGAAAAACATG CGTCTCCGTGACTACAAGGACGACGACGACAAGTAAGCTTCG R-L RNA sequence: (SEQ ID NO: 201) GGGUUAACUUUAACAAGGAGAAAAACAUGCGUCUCCGUGACUACAAGGAC GACGACGACAAGUAAGCUUCG
Cell-Free Translation System
In order to confirm translational introduction of N-methylleucine, a desired polypeptide containing N-methylleucine was ribosomally synthesized by adding N-methylleucine and a mutant LeuRS to a cell-free translation system. The translation system used was PURE system, a reconstituted cell-free protein synthesis system from E. coli. Specifically, wild-type or mutant LeuRS and N-methylleucine were added to a solution containing a basic cell-free translation solution (1 mM GTP, 1 mM ATP, 20 mM creatine phosphate, 50 mM HEPES-KOH pH 7.6, 100 mM potassium acetate, 9 mM magnesium acetate, 2 mM spermidine, 1 mM dithiothreitol, 1.5 mg/ml E. coli MRE600 (RNase negative)-derived tRNA (Roche), 0.1 mM 10-HCO—H4 folate, 4 μg/ml creatine kinase, 3 μg/ml myokinase, 2 unit/ml inorganic pyrophosphatase, 1.1 μg/ml nucleoside diphosphate kinase, 0.6 μM methionyl-tRNA transformylase, 0.26 μM EF-G, 0.24 μM RF2, 0.17 μM RF3, 0.5 μM RRF, 2.7 μM IF1, 0.4 μM IF2, 1.5 μM IF3, 40 μM EF-Tu, 84 μM EF-Ts, 1.2 μM ribosome, 0.03 μM ArgRS, 0.13 μM AspRS, 0.11 μM LysRS, 0.03 μM MetRS, 0.02 μM TyrRS (wherein the proteins prepared by the inventors were essentially prepared as His-tagged proteins)), and 1 μM template mRNA, each 250 μM arginine, aspartic acid, lysine, methionine, and tyrosine, and left at 37° C. for 1 hour to ribosomally synthesize the peptide.
Detection by Mass Spectroscopy
Mass spectroscopy was performed using MALDI-TOF MS for detecting peptides into which N-methylleucine is ribosomally introduced. Specifically, a solution containing 1 μM template mRNA (R-L (SEQ ID NO: 201)) and arginine, lysine, methionine, tyrosine, and aspartic acid (each final concentration 250 μM) added to the cell-free translation system as described above was prepared. LeuRS (final concentration 0.4-2 μM) and N-methylleucine (final concentration 5 mM) were added to the solution and incubated at 37° C. for 60 minutes. The resulting translation reaction products were purified with SPE C-TIP (Nikkyo Technos Co., Ltd) and analyzed with MALDI-TOF MS. Translation products were identified with MALDI-TOF MS spectrometry using α-cyano-4-hydroxycinnamic acid as a matrix.
As a result of the translation using wild-type LeuRS (SEQ ID NO: 189), a peak corresponding to the target peptide peak P-CT23MeLeu containing N-methylleucine was not observed, but the peptide P-CT23Leu derived from Leu contaminated in the translation system in trace amounts (FIG. 12(a), PeakL1) was observed as an almost single product. On the other hand, when experiments were performed using the modified LeuRS 02 (SEQ ID NO: 187) with mutations introduced, the peak derived from P-CT29MeLeu (Peak MeL1, FIG. 12(b)) was observed, and the intensity of the peak was as strong as the intensity of the peak of the peptide P-CT23Leu containing Leu (Peak L2, FIG. 12(b)). In other words, it is demonstrated that the MeLeu-introduced peptide synthesized using the modified LeuRS 02 was more than that using wild-type LeuRS, suggesting that this modified LeuRS is an ARS that can introduce MeLeu into peptides more efficiently compared to wild-type LeuRS.
Peptide sequence P-CT23Leu (SEQ ID NO: 202) formylMetArgLeuArgAspTyrLysAspAspAspAspLys Peptide sequence P-CT23MeLeu (SEQ ID NO: 203) formylMetArg[MeLeu]ArgAspTyrLysAspAspAspAspLys
MALDI-TOF MS:
Calc. m/z: [H+M]+=1597.7 (the peptide corresponding to the sequence P-CT23Leu)
Calc. m/z: [H+M]+=1611.7 (the peptide corresponding to the sequence P-CT23MeLeu)
Example 7: Development of Modified ValRSs Having Increased Selectivity to N-Methylvaline Achieved by Enhancing Valine-Hydrolyzing Ability in the Editing Domain
Preparation of Wild-Type and Mutant ValRS Proteins
Expression vectors for modified ValRSs that have a polyhistidine sequence at the N-terminus and containing mutations (N43G, T45S) in the catalytic domain and mutation T279A(G) in the editing domain, which mutations increase activity to N-methylvaline, were constructed (Table 10). Then, an expression strain was transformed with the vectors, and the mutant proteins of interest were purified using a nickel column from supernatants obtained by disrupting cells.
TABLE 10 Editing Catalytic domain domain Position Position Position Name 43 45 279 ValRS01(wt) N T T ValRS13-11 G S T ValRS66 G S A ValRS67 G S G
Aminoacylation Reaction with Valine and N-Methylvaline Using Mutant ValRSs
Synthesis of E. coli tRNAVal by In Vitro Transcription Reaction
E. coli tRNA (R-tRNAVal1 (SEQ ID NO: 205)) was synthesized from a template DNA (D-tRNAVal1 (SEQ ID NO: 204)) by in vitro transcription reaction using RiboMAX Large Scale RNA production System T7 (Promega, P1300) in the presence of 7.5 mM GMP, and purified using RNeasy Mini kit (Qiagen).
D-tRNAVal1 tRNAVal1 DNA sequence: (SEQ ID NO: 204) GGCGTAATACGACTCACTATAGGGTGATTAGCTCAGCTGGGAGAGCACCT CCCTTACAAGGAGGGGGTCGGCGGTTCGATCCCGTCATCACCCACCA R-tRNAVal1 tRNAVal1 RNA sequence: (SEQ ID NO: 205) GGGUGAUUAGCUCAGCUGGGAGAGCACCUCCCUUACAAGGAGGGGGUCGG CGGUUCGAUCCCGUCAUCACCCACCA
GGGUGAUUAGCUCAGCUGGGAGAGCACCUCCCUUACAAGGAGGGGGUCGGCG GUUCGAUCCCGUCAUCACCCACCA
Aminoacylation Reaction
For the aminoacylation reaction, the solution containing 50 μM transcribed RNA, 10 mM HEPES-K (pH 7.6), and 10 mM KCl solution was heated at 95° C. for 2 minutes and then left at room temperature for 5 minutes or more to refold the tRNA. This tRNA solution was added to a final concentration of 10 μM to an acylation buffer (in final concentrations of 50 mM HEPES-K [pH 7.6], 2 mM ATP, 100 mM potassium acetate, 10 mM magnesium acetate, 1 mM DTT, 2 mM spermidine, 0.1 mg/mL Bovine Serum Albumin), mixed with a mutant ValRS (final concentration 2 μM) and N-methylvaline (final concentration 0.08 mM-5 mM) or valine (final concentration 0.031 mM-0.25 mM), and incubated at 37° C. for 10 minutes. Four volumes of a loading buffer (90 mM sodium acetate [pH 5.2], 10 mM EDTA, 95% (w/w) formamide, 0.1% (w/v) xylene cyanol) were added to the reaction solution and analyzed with acidic PAGE containing 6 M urea, and aminoacylation activity was detected by separating unreacted tRNA and aminoacyl-tRNA. RNA was stained with SYBR Gold (Life Technologies) and detected with LAS4000 (GE Healthcare).
This result proved that the acylation abilities of the mutants 13-11, 66 (SEQ ID NO: 182), and 67 (SEQ ID NO: 183) were not very different at each N-methylvaline concentration when N-methylvaline was used as substrate (FIG. 13, for example, lanes 17-19). On the other hand, it was proved that when valine was used as a substrate, the acylation abilities of mutants 66 and 67 reduced compared to mutants 13-11 (FIG. 14, for example, lanes 17-19). This demonstrated that mutants 66 and 67 having mutations newly introduced into the editing domain are modified ValRSs that have reduced aminoacylation activity to valine and therefore has increased selectivity to N-methylvaline.
INDUSTRIAL APPLICABILITY
The present invention provides modified aminoacyl-tRNA synthetases having increased reactivity with N-methyl amino acids compared to natural aminoacyl-tRNA synthetases (ARSs). The modified aminoacyl-tRNA synthetases according to the present invention can aminoacylate tRNAs with their corresponding N-methyl-substituted amino acids such as N-methyl-phenylalanine, N-methyl-valine, N-methyl-serine, N-methyl-threonine, N-methyl-tryptophan, and N-methyl-leucine more efficiently than natural aminoacyl-tRNA synthetases. The present invention can produce polypeptides containing N-methyl amino acids more efficiently.
Claims
1. A valyl-tRNA synthetase (ValRS) polypeptide modified to enhance aminoacylation reaction with N-methyl-valine, wherein the polypeptide has aminoacyl-tRNA synthetase (ARS) activity, and wherein the modification comprises at least one amino acid substitution at a position(s) corresponding to asparagine at position 43 and/or threonine at position 45 of ValRS from Escherichia coli.
2. The polypeptide according to claim 1, wherein the modification further comprises a substitution at a position corresponding to threonine at position 279 of ValRS from Escherichia coli.
3. The polypeptide according to claim 1, wherein the polypeptide is selected from the group consisting of the following (a) and (b):
(a) a polypeptide comprising amino acids selected from the group consisting of SEQ ID NOs: 3-5, 182, and 183, and
(b) a polypeptide comprising an amino acid sequence having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-5, 182, and 183.
4. A polynucleotide encoding the polypeptide according to claim 1.
5. A vector comprising the polynucleotide according to claim 4.
6. A host cell comprising a polynucleotide encoding a polypeptide according to claim 1.
7. A method for producing the polypeptide according to claim 1, comprising the step of culturing a host cell comprising a polynucleotide encoding the polypeptide according to claim 1.
8. A method for producing a tRNA acylated with N-methyl-valine, comprising the step of contacting N-methyl valine with tRNA in the presence of the polypeptide according to claim 1.
9. A method for producing a polypeptide comprising N-methyl-valine, comprising the step of performing translation in the presence of the polypeptide according to claim 1 and N-methyl-valine.
10. The method according to claim 9, wherein the step of performing translation is carried out in a cell-free translation system.
11. The polypeptide according to claim 1, having (a) glycine or alanine at a position corresponding to asparagine at position 43 and/or (b) serine at a position corresponding to threonine at position 45 of ValRS from Escherichia coli.
12. The polypeptide according to claim 2, having (a) glycine or alanine at a position corresponding to asparagine at position 43 and/or (b) serine at a position corresponding to threonine at position 45 and/or (c) glycine or alanine at a position corresponding to threonine at position 279 of ValRS from Escherichia coli.
13. A host cell comprising a polynucleotide encoding a polypeptide according to claim 2.
14. A method for producing a tRNA acylated with N-methyl-valine, comprising the step of contacting N-methyl-valine with tRNA in the presence of the polypeptide according to claim 2.
15. A method for producing a polypeptide comprising N-methyl-valine, comprising the step of performing translation in the presence of the polypeptide according to claim 2 and the N-methyl-valine.
16. A host cell comprising a polynucleotide encoding a polypeptide according to claim 11.
17. A method for producing a tRNA acylated with N-methyl-valine, comprising the step of contacting N-methyl-valine with tRNA in the presence of the polypeptide according to claim 11.
18. A method for producing a polypeptide comprising N-methyl-valine, comprising the step of performing translation in the presence of the polypeptide according to claim 11 and the N-methyl-valine.
19. A host cell comprising a polynucleotide encoding a polypeptide according to claim 12.
20. A method for producing a tRNA acylated with N-methyl-valine, comprising the step of contacting N-methyl-valine with tRNA in the presence of the polypeptide according to claim 12.
21. A method for producing a polypeptide comprising N-methyl-valine, comprising the step of performing translation in the presence of the polypeptide according to claim 12 and the N-methyl-valine.
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Patent History
Patent number: 10815489
Type: Grant
Filed: Mar 11, 2016
Date of Patent: Oct 27, 2020
Patent Publication Number: 20180127761
Assignee: Chugai Seiyaku Kabushiki Kaisha (Tokyo)
Inventors: Atsushi Ohta (Kanagawa), Yusuke Yamagishi (Kanagawa), Atsushi Matsuo (Shizuoka)
Primary Examiner: Catherine S Hibbert
Application Number: 15/557,532
Classifications
Current U.S. Class: Recombinant Dna Technique Included In Method Of Making A Protein Or Polypeptide (435/69.1)
International Classification: C12N 15/00 (20060101); C12N 15/70 (20060101); C12P 19/34 (20060101); C12N 9/00 (20060101); C12N 5/10 (20060101); C12N 15/09 (20060101); C12P 21/00 (20060101); C12N 9/22 (20060101); C12P 21/02 (20060101); | {
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The Cultivars (morphs)/Genetics Issues Discussions about genetics issues and/or the various cultivars for cornsnakes commercially available.
Testbreeding Buf x Toffee
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Old 08-13-2013, 09:21 AM #1
slangenbroed
Testbreeding Buf x Toffee
First testbreeding between the buf and the toffee gene. ( from me )
Auratumstriped ( Toffee-amel-striped ) x Orange het motley ( Buf-amel het motley )
6 eggs ( Both genes are dominant)
4 Orange colored motleys
2 Orange colored ( one still in the egg )
There are no visual difference in the animals, not in the motleys and not in the other animals.
All 6 are orange colored ( lucky ? )Or is someone Homo ( the parents )The Orange not possible that she is homo, the auratum could be homo becouse he is from auratumstriped x the same.
Old 08-13-2013, 02:20 PM #2
RobbiesCornField
"Or is someone homo" for what? Orange x Auratum would produce all animals expressing the amel gene, because both parents are homo amel. Whether or not they're Orange or Auratum is for you to decide. Pictures would be very helpful, especially to help breach the language barrier.
Old 08-13-2013, 03:28 PM #3
Nanci
Are the babies "just" amel? and toffee and buf were not the same, so the babies are het toffee and buff?
Or are the babies homo amel and homo toffee/buf, which are the same gene?
Old 08-13-2013, 03:29 PM #4
Nanci
I second Robbie's question- is someone homo _what_?
Old 08-14-2013, 03:49 AM #5
BSLMichael
bwahahaha Nanci asked if someone was homo!
ANYWAY! i would love to see pictures
Old 08-14-2013, 06:46 AM #6
slangenbroed
Ok
Buf is a dominant gene discoverd in 2001 in holland its a hypoerythristic gene and made a amel into orange.
Toffee is also a dominant gene discoverd in i beleef 2006-2008 in Germany and looks the same and act the same.
This discoveries are made 200 km from each other, the discossion is, if this gene is the same or not the same.
But there is never made a testbreeding between theese genes, so i get a auratumstriped ( Toffee-amel- striped)male and cross him to a Orange het motley female ( Buf-amel-het motley )Becouse this genes are dominant there must be a hetro and a homosygoot form, but they look the same you can not tell witch one is het ore homo, not until breedings are done.
Example Buf
Bn = Buf B for buf, n for wildtype, when we cross a buf to a buf , the punnet square says.
-----B--------n
B----BB------Bn
n----Bn------nn
BB is the buf in homo form
Bn is the buf in hetero form
nn is wildtype
The BB and the Bn looks the same
The Toffee gene act the same.
Now a made this first testbreeding from Buf-amel x Toffee-amel ( let the motley and stripe away )
One thing we now everything must be amel 100%
I got 6 eggs al 6 are amel that ok ,but also Buf ore Toffee becouse all the offspring is Orange .I can not see any difference between them as a wrote.
What i ment with the homo thing is. If the toffee is homosygoot TT then al the ofspring is Toffee-amel ( auratum )But where is the buf there must be buf in the game.If buf and toffee are the same then all animals look the same ( Orange ).If buf and toffee is not the same , this breeding would produce differentsie thats my opinion
Old 08-19-2013, 07:49 AM #7
NiklasTyreso
Quote:
Originally Posted by slangenbroed View Post
Becouse this genes are dominant there must be a hetro and a homosygoot form, but they look the same you can not tell witch one is het ore homo, not until breedings are done.
Example Buf
Bn = Buf B for buf, n for wildtype, when we cross a buf to a buf , the punnet square says.
-----B--------n
B----BB------Bn
n----Bn------nn
BB is the buf in homo form
Bn is the buf in hetero form
nn is wildtype
The BB and the Bn looks the same
The Toffee gene act the same.
Now a made this first testbreeding from Buf-amel x Toffee-amel ( let the motley and stripe away )
One thing we now everything must be amel 100%
I got 6 eggs al 6 are amel that ok ,but also Buf ore Toffee becouse all the offspring is Orange .I can not see any difference between them as a wrote.
What i ment with the homo thing is. If the toffee is homosygoot TT then al the ofspring is Toffee-amel ( auratum )But where is the buf there must be buf in the game.If buf and toffee are the same then all animals look the same ( Orange ).If buf and toffee is not the same , this breeding would produce differentsie thats my opinion
If all hatchlings look the same orange way then it is likely that buf and toffee are the same gene and that at least one of the parents are homozygote for the dominant gene.
Old 08-22-2013, 11:58 AM #8
slangenbroed
Quote:
Originally Posted by NiklasTyreso View Post
If all hatchlings look the same orange way then it is likely that buf and toffee are the same gene and that at least one of the parents are homozygote for the dominant gene.
They all shed now and i see a little variation just as in a orange only clutch, if a make a pic you can't see the different.Maybee iff they growing up ???? Lets feed them and wait.
Old 08-23-2013, 07:45 AM #9
NiklasTyreso
Quote:
Originally Posted by NiklasTyreso View Post
If all hatchlings look the same orange way then it is likely that buf and toffee are the same gene and that at least one of the parents are homozygote for the dominant gene.
Thinking it over again, what I first wrote might be wrong.
If one parent is homozygote fore a dominant (orange) trait all hachlings should show that trait.
The traits might mask each other, or they might enhange each other. You can not know.
The best testbreeding would be to breed two known heterozygote:
Het dominant Buf amel X Het dominant Toffe amel
Then you would get about 25 % without buf or toffe
50% with buf or toffe
25 % with double trait dominant het buf+ dominant het toffe (extreme orange?)
If you got 75 % orange but 25 % of them look differen orange, then it might be different genes.
If you have two different orange dominant genes and one parent is het dominant and the other is homo for the other dominant gene, then all should be orange but 50% should be double hets for two dominant genes. Then there probably would be that half of the clutch would be different in the orange than the other half.
If you get no clear proportions in the clutch, but just a gradient of natural variation, then buf and toffe is probably just the same gene.
So, calculate proportions for the outcome you should get from what you know of the parents, if they are het or homo for the dominant genes.
Let the proportions guide you.
Old 08-14-2013, 06:50 AM #10
Nanci
(I always forget about it being dominant- sorry!)
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4,805,494,293,074,219,000 | Existing, qualitative notions with respect to the way in which enzyme properties control metabolism are discussed in the light of the control analysis developed by H. Kacser and J. A. Burns ((1973) in: Rate Control of Biological Processes, Davies DD, ed., Cambridge University Press, pp. 63–104) and R. Heinrich and T. A. Rapoport ((1974) Eur. 3. Biochem. 42, 89–95), and recent experimental data. Points at which the existing notions should be adjusted are: (i) Metabolic control is shared by enzymes rather than confined to one rate-limiting enzyme per pathway. (if) Whether an enzyme exercises strong control on a flux cannot be deduced solely from its own properties, nor is it directly related to its distance from equilibrium. With respect to metabolic control, enzymes should be classified into four groups, rather than two (reversible versus irreversible). (iii) The distribution of control among the enzymes depends on the metabolic conditions. (iv) Control structures of metabolic pathways probably differ with the function of that pathway.
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
-7,676,630,044,356,630,000 | atb2 - SPAC1039.02
S. pombe
SSL interaction
Identifiers
Gene Name Gene ID Diseases Drugs GO terms Orthologs
atb2 SPBC800.05c
No diseases in record
No drugs in record
GTP binding
structural constituent of cytoskeleton
GTPase activity
No GO terms in record
SPAC1039.02 SPAC1039.02
No diseases in record
No drugs in record
5'-nucleotidase activity
No GO terms in record
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} | 57 | cf5cd1df0ee2161e1684bdc019357275 |
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