This article has been corrected: The correct author information is given below:Satdarshan P. Monga1475-1490. https://doi.org/10.18632/oncotarget.26668Original article: Oncotarget. 2019; 10:1475–1490.


Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14752. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( The Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC‐IUBMB) classifies enzymes into families, using a four number code, on the basis of the reactions they catalyse. There are six main families:EC 1.‐.‐.‐ Oxidoreductases;EC 2.‐.‐.‐ Transferases;EC 3.‐.‐.‐ Hydrolases;EC 4.‐.‐.‐ Lyases;EC 5.‐.‐.‐ Isomerases;EC 6.‐.‐.‐ Ligases.http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24016212?dopt=AbstractPlus], which is not to say that they are of modest importance.Although there are many more enzymes than receptors in biology, and many drugs that target prokaryotic enzymes are effective medicines, overall the number of enzyme drug targets is relatively small .A number of organophosphorus compounds inhibit acetylcholinesterase and cholinesterase irreversibly, including pesticides such as chlorpyrifos‐oxon, and nerve agents such as tabun, soman and sarin. AChE is unusual in its exceptionally high turnover rate which has been calculated at 740 000/min/molecule , which is insensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5179 [http://www.ncbi.nlm.nih.gov/pubmed/20147294?dopt=AbstractPlus]. Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:228 (http://www.uniprot.org/uniprot/Q9BUB4) deaminates transfer RNA; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:225 ; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:226  andhttps://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:227  act on double‐stranded RNA. Particular polymorphisms of the ADA gene result in loss‐of‐function and severe combined immunodeficiency syndrome. Adenosine deaminase is able to complex with dipeptidyl peptidase IV  to form a cell‐surface activity [http://www.ncbi.nlm.nih.gov/pubmed/8101391?dopt=AbstractPlus].An extracellular adenosine deaminase activity, termed ADA2 or adenosine deaminase growth factor  Adenosinergic signaling in epilepsy. et al. (2015) Moonlighting adenosine deaminase: a target protein for drug development. Med Res Rev35: 85–125 https://www.ncbi.nlm.nih.gov/pubmed/24933472?dopt=AbstractPlusCortés A Nat Rev Mol Cell Biol17: 83–96 https://www.ncbi.nlm.nih.gov/pubmed/26648264?dopt=AbstractPlusNishikura K. (2016) A‐to‐I editing of coding and non‐coding RNAs by ADARs. Neuroscience338: 1–18 https://www.ncbi.nlm.nih.gov/pubmed/26500181?dopt=AbstractPlusSawynok J. (2016) Adenosine receptor targets for pain. et al. (2015) Role of S‐adenosylhomocysteine in cardiovascular disease and its potential epi‐genetic mechanism. Int. J. Biochem. Cell Biol. 67: 158–66 https://www.ncbi.nlm.nih.gov/pubmed/26117455?dopt=AbstractPlusXiao Y http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5276 as co‐substrate and co‐factor, respectively. In humans, as well as in other mammals, there are two distinct L‐Tryptophan hydroxylase 2 genes. In humans, these genes are located on chromosomes 11 and 12 and encode two different homologous enzymes, TPH1 and TPH2.The amino acid hydroxylases (monooxygenases), EC.1.14.16.‐, are iron‐containing enzymes which utilise molecular oxygen and et al. (2015) Serotonergic gene variation in substance use pharmacotherapy: a systematic review. Pharmacogenomics16: 1307–14 https://www.ncbi.nlm.nih.gov/pubmed/26265436?dopt=AbstractPlusBauer IE et al. (2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys508: 1–12 https://www.ncbi.nlm.nih.gov/pubmed/21176768?dopt=AbstractPlusDaubner SC et al. (2013) Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life65: 341–9 https://www.ncbi.nlm.nih.gov/pubmed/23457044?dopt=AbstractPlusFlydal MI et al. (2013) Mechanisms of tryptophan and tyrosine hydroxylase. IUBMB Life65: 350–7 https://www.ncbi.nlm.nih.gov/pubmed/23441081?dopt=AbstractPlusRoberts KM et al. (2014) Complex molecular regulation of tyrosine hydroxylase. J Neural Transm121: 1451–81 https://www.ncbi.nlm.nih.gov/pubmed/24866693?dopt=AbstractPlusTekin I et al. (2017) Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease. Expert Opin Ther Targets21: 167–180 https://www.ncbi.nlm.nih.gov/pubmed/27973928?dopt=AbstractPlusWalen K http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 is a basic amino acid with a guanidino sidechain. As an amino acid, metabolism of L‐arginine to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725, catalysed by arginase, forms the last step of the urea production cycle. L‐Ornithine may be utilised as a precursor of polyamines (see http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240) or recycled via http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5324 to L‐arginine. L‐Arginine http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240#Decarboxylases to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4127, although the prominence of this pathway in human tissues is uncertain. L‐Arginine may be used as a precursor for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5325 formation in the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4496 synthesis pathway under the influence of arginine:glycine amidinotransferase with L‐ornithine as a byproduct. Nitric oxide synthase uses L‐arginine to generate nitric oxide, with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 also as a byproduct. L‐Arginine in proteins may be subject to post‐translational modification through methylation, catalysed by protein arginine methyltransferases. Subsequent proteolysis can liberate asymmetric http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229 (ADMA), which is an endogenous inhibitor of nitric oxide synthase activities. ADMA is hydrolysed by dimethylarginine dimethylhydrolase activities to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5177.N‐methyltransferases  encompass histone arginine N‐methyltransferases  and myelin basic protein N‐methyltransferases . They are dimeric or tetrameric enzymes which use http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4786 as a methyl donor, generating http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5265 as a by‐product. They generate both mono‐methylated and di‐methylated products; these may be symmetric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5271) or asymmetric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.Protein arginine http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254.Information on members of this family may be found in the http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.5.3.1) are manganese‐containing isoforms, which appear to show differential distribution, where the ARG1 isoform predominates in the liver and erythrocytes, while ARG2 is associated more with the kidney.Arginase  are cytoplasmic enzymes which hydrolyse http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229 to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5177 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722.Dimethylarginine dimethylaminohydrolases  are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen‐dependent consumption of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 with the resultant by‐product, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post‐translation mechanisms regulating enzyme activity. The nomenclature suggested by NC‐IUPHAR of NOS I, II and III [http://www.ncbi.nlm.nih.gov/pubmed/9228663?dopt=AbstractPlus] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C‐terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4‐dependent reduction of heme bound oxygen for insertion into the substrate, L‐arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351  with great avidity and is essentially calcium‐independent and constitutively active. Efficient stimulus‐dependent coupling of nNOS and eNOS is achieved via subcellular targeting through respective N‐terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5213 and related modified arginine analogues are inhibitors of all three isoforms, with IC50 values in the micromolar range.Nitric oxide synthases  Nitric Oxide Signaling in T Cell‐Mediated Immunity et al. (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov14: 623–41 https://www.ncbi.nlm.nih.gov/pubmed/26265312?dopt=AbstractPlusLundberg JO et al. (2016) Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene575: 584–99 https://www.ncbi.nlm.nih.gov/pubmed/26428312?dopt=AbstractPlusOliveira‐Paula GH BrJPharmacol176: 177–188 https://www.ncbi.nlm.nih.gov/pubmed/30402946Stuehr DJ and Haque MM (2019) Nitric oxide synthase enzymology in the 20 years after the Nobel Prize. Br J Pharmacol176: 147–154 https://www.ncbi.nlm.nih.gov/pubmed/30357812Wallace JL (2019) Nitric oxide in the gastrointestinal tract: opportunities for drug development. et al. (2016) Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers. J Diabetes Res2016: 1982096 https://www.ncbi.nlm.nih.gov/pubmed/26770984?dopt=AbstractPlusLai L et al. (1997) International Union of Pharmacology Nomenclature in Nitric Oxide Re‐search. Pharmacol. Rev. 49: 137–42 https://www.ncbi.nlm.nih.gov/pubmed/9228663?dopt=AbstractPlusMoncada S et al. (2015) The crucial role of l‐arginine in macrophage activation: What you need to know about it. Life Sci. 137: 44–8 https://www.ncbi.nlm.nih.gov/pubmed/26188591?dopt=AbstractPlusPekarova M et al. (2017) Arginase Inhibitors: A Rational Approach Over One Century. Med Res Rev37: 475–513 https://www.ncbi.nlm.nih.gov/pubmed/27862081?dopt=AbstractPlusPudlo M et al. (2016) Benefits of L‐Arginine on Cardiovascular System. Mini Rev Med Chem16: 94–103 https://www.ncbi.nlm.nih.gov/pubmed/26471966?dopt=AbstractPlusSudar‐Milovanovic E Carbonic anhydrases facilitate the interconversion of water and carbon dioxide with bicarbonate ions and protons (EC 4.2.1.1), with over a dozen gene products identified in man. The enzymes function in acid‐base balance and the movement of carbon dioxide and water. They are targetted for therapeutic gain by particular antiglaucoma agents and diuretics.Bioorg Med Chem21: 1570–70 https://www.ncbi.nlm.nih.gov/pubmed/22607884Imtaiyaz Hassan M, Shajee B, Waheed A, Ahmad F and Sly WS. (2013) Structure, function and applications of carbonic anhydrase isozymes. Expert Opin Drug Discov12: 61–88 https://www.ncbi.nlm.nih.gov/pubmed/27783541Supuran CT (2017) Advances in structure‐based drug discovery of carbonic anhydrase inhibitors. Future Med Chem10: 561–573 https://www.ncbi.nlm.nih.gov/pubmed/29478330Supuran CT (2018) Carbonic anhydrase activators. 3‐ or CO2 into target molecules. Two groups of carboxylase activities, some of which are bidirectional, can be defined on the basis of the cofactor requirement, making use of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 (EC 6.4.1.‐) or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5286 (EC 4.1.1.‐).The carboxylases allow the production of new carbon‐carbon bonds by introducing HCOhttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2478 are able to activate ACC1/ACC2 activity allosterically. PCC is able to function in forward and reverse modes as a ligase (carboxylase) or lyase (decarboxylase) activity, respectively. Loss‐of‐function mutations in GGCX are associated with clotting disorders.Dicarboxylic acids including 2 and the indicated products from acidic substrates, requiring http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5249 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809 as a co‐factor.The decarboxylases generate COet al. (2010) Structural biology of S‐adenosylmethionine decarboxylase. Amino Acids38: 451–60 . Complexes involving SPT3 appeared more broad in substrate selectivity, with incorporation of myristoylCoA prominent for SPT1/SPT3/ssSPTa complexes, while SP1/SPT3/ssSPTb complexes had similar activity with C16, C18 and C20 acylCoAs [http://www.ncbi.nlm.nih.gov/pubmed/19416851?dopt=AbstractPlus].The functional enzyme is a heterodimer of SPT1 (LCB1) with either SPT2 (LCB2) or SPT3 (LCB2B); the small subunits of SPT (ssSPTa or ssSPTb) bind to the heterodimer to enhance enzymatic activity. The complexes of SPT1/SPT2/ssSPTa and SPT1/SPT2/ssSPTb were most active with palmitoylCoA as substrate, with the latter complex also showing some activity with stearoylCoA .DEGS1 activity is inhibited by a number of natural products, including Following translocation from the ER to the Golgi under the influence of the ceramide transfer protein, sphingomyelin synthases allow the formation of sphingomyelin by the transfer of phosphocholine from the phospholipid phosphatidylcholine. Sphingomyelin synthase‐related protein 1 is structurally related but lacks sphingomyelin synthase activity.Also known as sphingomyelinase.http://www.ncbi.nlm.nih.gov/pubmed/8808629?dopt=AbstractPlus] and polycomb protein EED [http://www.ncbi.nlm.nih.gov/pubmed/20080539?dopt=AbstractPlus] allow coupling between TNF receptors and neutral sphingomyelinase phosphodiesterases.Protein FAN . In normal cells, tissues and organs, precise co‐ordination of these proteins ensures expression of only those genes required to specify phenotype or which are required at specific times, for specific functions. Chromatin modifications allow DNA modifications not coded by the DNA sequence to be passed on through the genome and underlies heritable phenomena such as X chromosome inactivation, aging, heterochromatin formation, reprogramming, and gene silencing (epigenetic control).Chromatin modifying enzymes, and other chromatin‐modifying proteins, fall into three broad categories: http://www.ncbi.nlm.nih.gov/pubmed/17320507?dopt=AbstractPlus].To date at least eight distinct types of modifications are found on histones. These include small covalent modifications such as acetylation, methylation, and phosphorylation, the attachment of larger modifiers such as ubiquitination or sumoylation, and ADP ribosylation, proline isomerization and deimination. Chromatin modifications and the functions they regulate in cells are reviewed by Kouzarides (2007) , where awide variety of cellular and protein abberations are known to perturb chromatin structure, gene transcription and ultimately cellular pathways . Due to the reversible nature of epigenetic modifications, chromatin regulators are very tractable targets for drug discovery and the development of novel therapeutics. Indeed, small molecule inhibitors of writers  and erasers  are already being used in the clinic. The search for the next generation of compounds with improved specificity against chromatin‐associated proteins is an area of intense basic and clinical research [http://www.ncbi.nlm.nih.gov/pubmed/25974248?dopt=AbstractPlus]. Current progress in this field is reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].Dysregulated epigenetic control can be associated with human diseases such as cancer .Classes I, II and IV use Znhttp://www.ncbi.nlm.nih.gov/pubmed/19608861?dopt=AbstractPlus] such as microtubules [http://www.ncbi.nlm.nih.gov/pubmed/12024216?dopt=AbstractPlus], the hsp90 chaperone [http://www.ncbi.nlm.nih.gov/pubmed/15916966?dopt=AbstractPlus] and the tumour suppressor p53 [http://www.ncbi.nlm.nih.gov/pubmed/11099047?dopt=AbstractPlus].HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins , making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [http://www.ncbi.nlm.nih.gov/pubmed/24382387?dopt=AbstractPlus]. Several small molecule HDAC inhibitors are already approved for clinical use: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7006, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6852, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7489, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7009 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8305. HDACs and HDAC inhibitors currently in development as potential anti‐cancer therapeutics are reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].Dysregulated HDACactivity has been identified in cancer cells and tumour tissues . Four families of membranous adenylyl cyclase are distinguishable: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351 ‐stimulated , Ca2+‐ and Gβγ‐inhibitable , Gβγ‐stimulated and Ca2+‐insensitive , and forskolin‐insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH‐insensitive) sensor [http://www.ncbi.nlm.nih.gov/pubmed/10915626?dopt=AbstractPlus].Adenylyl cyclase, http://www.ncbi.nlm.nih.gov/pubmed/24006339?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24008337?dopt=AbstractPlus]. AC3 shows only modest in vitro activation by Ca2+/CaM.Many of the activators and inhibitors listed are only somewhat selective or have not been tested against all AC isoforms . Once activated, Epacs induce an enhanced activity of the monomeric G proteins, Rap1 and Rap2 by facilitating binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1742 in place of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2410, leading to activation of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244 [http://www.ncbi.nlm.nih.gov/pubmed/11715024?dopt=AbstractPlus].Epacs are members of a family of guanine nucleotide exchange factors  The role of Epac in the heart. Cell. Mol. Life Sci. 74: 591‐606 https://www.ncbi.nlm.nih.gov/pubmed/27549789?dopt=AbstractPlusFujita T Physiol Rev98: 919‐1053 https://www.ncbi.nlm.nih.gov/pubmed/29537337Robichaux WG and Cheng X. (2018) Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. et al. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg. Med. Chem. Lett. 27: 1633‐1639 https://www.ncbi.nlm.nih.gov/pubmed/28283242?dopt=AbstractPlusWang P http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.4.17, catalyse the hydrolysis of a 3’,5’‐cyclic nucleotide . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=388 is a nonselective inhibitor with an IC50 value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2’,3’‐cyclic nucleotide 3’‐phosphodiesterase (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.3’,5’‐Cyclic nucleotide phosphodiesterases , PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane‐bound homodimer. PDE3A and PDE3B are membrane‐bound.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 specific. The potency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5292 at other members of the PDE4 family has not been reported. PDE4B‐D long forms are inhibited by extracellular signal‐regulated kinase (ERK)‐mediated phosphorylation . PDE4A‐D splice variants can be membrane‐bound or cytosolic [http://www.ncbi.nlm.nih.gov/pubmed/12444918?dopt=AbstractPlus]. PDE4 isoforms may be labelled with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5313.PDE4 isoforms are essentially http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 specific and is activated by the a‐subunit of transducin (Gat) and inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4743, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2919 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4807 with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness.PDE6 is a membrane‐bound tetramer composed of two catalytic chains (PDE6A or PDE6C and PDE6B), an inhibitory chain (PDE6G or PDE6H) and the PDE6D chain. The enzyme is essentially Cell. Signal. 28: 713‐8 https://www.ncbi.nlm.nih.gov/pubmed/26498857?dopt=AbstractPlusKlussmann E. (2016) Protein‐protein interactions of PDE4 family members ‐ Functions, interactions and therapeutic value. et al. (2018) Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure. Br. J. Pharmacol. 175: 223‐231 https://www.ncbi.nlm.nih.gov/pubmed/28213937?dopt=AbstractPlusKorkmaz‐Icöz S et al. (2018) Phosphodiesterase‐4 Inhibitors for the Treatment of Inflammatory Diseases. Front Pharmacol9: 1048 https://www.ncbi.nlm.nih.gov/pubmed/30386231Li H Life Sci230: 150‐161 https://www.ncbi.nlm.nih.gov/pubmed/31125564Mehta A and Patel BM. (2019) Therapeutic opportunities in colon cancer: Focus on phosphodiesterase inhibitors. et al. (2019) Experimental and investigational phosphodiesterase inhibitors in development for asthma. Expert Opin Investig Drugs28: 261‐266 https://www.ncbi.nlm.nih.gov/pubmed/30678501Ntontsi P J Cereb Blood Flow Metab38: 189‐203 https://www.ncbi.nlm.nih.gov/pubmed/29256324Pauls MM. (2018) The effect of phosphodiesterase‐5 inhibitors on cerebral blood flow in humans: A systematic review. et al. (2018) Inhibitors of phosphodiesterase as cancer therapeutics. Eur J Med Chem150: 742‐756 https://www.ncbi.nlm.nih.gov/pubmed/29574203Peng T et al. (2018) Fragment‐Based Drug Discovery of Phosphodiesterase Inhibitors. J Med Chem61: 1415–1424 https://www.ncbi.nlm.nih.gov/pubmed/28800229Svensson F et al. (2018) Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal49: 105‐115 https://www.ncbi.nlm.nih.gov/pubmed/29902522Wahlang B et al. (2018) Phosphodiesterase 10 Inhibitors ‐ Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery. Curr Med Chem25: 3455‐3481 https://www.ncbi.nlm.nih.gov/pubmed/29521210Zagorska A The cytochrome P450 enzyme family (CYP450), E.C. 1.14.‐.‐, were originally defined by their strong absorbance at 450 nm due to the reduced carbon monoxide‐complexed haem component of the cytochromes. They are an extensive family of haemcontaining monooxygenases with a huge range of both endogenous and exogenous substrates. These include sterols, fat‐soluble vitamins, pesticides and carcinogens as well as drugs. The substrates of some orphan CYP are not known. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologuemay not catalyse the metabolism of the same substrates. Although the majority of CYP450 enzyme activities are concentrated in the liver, the extrahepatic enzyme activities also contribute to patho/physiological processes. Genetic variation of CYP450 isoforms is widespread and likely underlies a significant proportion of the individual variation to drug administration.et al. (2016) Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev68: 168‐241 https://www.ncbi.nlm.nih.gov/pubmed/26721703?dopt=AbstractPlusBackman JT et al. (2017) Cytochrome P450 eicosanoids in cerebrovascular function and disease. Pharmacol Ther179: 31‐46 https://www.ncbi.nlm.nih.gov/pubmed/28527918?dopt=AbstractPlusDavis CM et al. (2016) Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure‐Function Perspective. J Med Chem. 59: 5131‐48 https://www.ncbi.nlm.nih.gov/pubmed/26689671?dopt=AbstractPlusGhosh D et al. (2015) Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol. 147: 24‐30 https://www.ncbi.nlm.nih.gov/pubmed/25448748?dopt=AbstractPlusGo RE et al. (2016) Recent Structural Insights into Cytochrome P450 Function. Trends Pharmacol Sci37: 625‐640 https://www.ncbi.nlm.nih.gov/pubmed/27267697?dopt=AbstractPlusGuengerich FP Pharmacol Ther192: 1‐19 https://www.ncbi.nlm.nih.gov/pubmed/29964123?dopt=AbstractPlusImig JD. (2018) Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics. et al. (2017) Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism. Drug Discov Today22: 366‐376 https://www.ncbi.nlm.nih.gov/pubmed/27693711?dopt=AbstractPlusIsvoran A et al. (2017) Cytochrome P450‐derived eicosanoids and heart function. Pharmacol Ther179: 47–83 https://www.ncbi.nlm.nih.gov/pubmed/28551025?dopt=AbstractPlusJamieson KL et al. (2018) Spectroscopic studies of the cytochrome P450 reaction mechanisms. Biochim Biophys Acta1866: 178‐204 https://www.ncbi.nlm.nih.gov/pubmed/28668640?dopt=AbstractPlusMak PJ et al. (2016) Cholesterol 24‐hydroxylase: Brain cholesterol metabolism and beyond. Biochim Biophys Acta1861: 1911‐1920 https://www.ncbi.nlm.nih.gov/pubmed/27663182?dopt=AbstractPlusMoutinho M et al. (2018) Keeping the spotlight on cytochrome P450. Biochim Biophys Acta1866: 80‐87 https://www.ncbi.nlm.nih.gov/pubmed/28599858?dopt=AbstractPlusShalan H DNA topoisomerases regulate the supercoiling of nuclear DNA to influence the capacity for replication or transcription. The enzymatic function of this series of enzymes involves cutting the DNA to allow unwinding, followed by re‐attachment to reseal the backbone. Members of the family are targetted in anti‐cancer chemotherapy.et al. (2017) Topoisomerases: Resistance versus Sensitivity, How Far We Can Go? Med Res Rev37: 404‐438 https://www.ncbi.nlm.nih.gov/pubmed/27687257?dopt=AbstractPlusBansal S et al. (2017) Type I DNA Topoisomerases. J. Med. Chem. 60: 2169‐2192 https://www.ncbi.nlm.nih.gov/pubmed/28072526?dopt=AbstractPlusCapranico G et al. (2017) DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov. Today22: 510‐518 https://www.ncbi.nlm.nih.gov/pubmed/27856347?dopt=AbstractPlusNagaraja V et al. (2016) Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat. Rev. Mol. Cell Biol. 17: 703‐721 https://www.ncbi.nlm.nih.gov/pubmed/27649880?dopt=AbstractPlusPommier Y et al. (2016) The dynamic interplay between DNA topoisomerases and DNA topology. Biophys Rev8: 101‐111 https://www.ncbi.nlm.nih.gov/pubmed/28510219?dopt=AbstractPlusSeol Y http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729 (2‐AG), and N‐acylethanolamines, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 . The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re‐uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [http://www.ncbi.nlm.nih.gov/pubmed/29531087?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2535 (https://www.uniprot.org/uniprot/Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [http://www.ncbi.nlm.nih.gov/pubmed/28584105?dopt=AbstractPlus]. For the generation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 synthesis have been described, the best characterized of which involves N‐acylphosphatidylethanolamine‐phospholipase D . A transacylation enzyme which forms N‐acylphosphatidylethanolamines has been identified as a cytosolic enzyme, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24791 (http://www.uniprot.org/uniprot/Q3MJ16) [http://www.ncbi.nlm.nih.gov/pubmed/27399000?dopt=AbstractPlus]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities .The principle endocannabinoids are 2‐acylglycerol esters, such as N‐acylethanolamine biosynthesis other than through NAPE‐PLD activity have been identified [http://www.ncbi.nlm.nih.gov/pubmed/23394527?dopt=AbstractPlus].Routes for http://www.ncbi.nlm.nih.gov/pubmed/22969151?dopt=AbstractPlus], but may also regulate lysophosphatidylserine levels [http://www.ncbi.nlm.nih.gov/pubmed/25580854?dopt=AbstractPlus]. Loss‐of‐function mutations in ABHD12 are associated with a disorder known as PHARC  [http://www.ncbi.nlm.nih.gov/pubmed/20797687?dopt=AbstractPlus].ABHD12 is a 398‐aa protein, with serine hydrolase activity. It has a molecular weight of 45 kDa. A single TM is predicted at 75‐95, with an extracellular catalytic domain. ABHD12 is a monoacylglycerol hydrolase [http://www.ncbi.nlm.nih.gov/pubmed/17015445?dopt=AbstractPlus] and a limited range of inhibitors have been assessed at this enzyme activity. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729 has been reported to be hydrolysed by multiple enzyme activities from neural preparations [http://www.ncbi.nlm.nih.gov/pubmed/29751000?dopt=AbstractPlus], including https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21398 (http://www.uniprot.org/uniprot/Q9BV23) [http://www.ncbi.nlm.nih.gov/pubmed/26989199?dopt=AbstractPlus] and carboxylesterase 1 . https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21398 (http://www.uniprot.org/uniprot/Q9BV23) has also been described as a triacylglycerol lipase and ester hydrolase [http://www.ncbi.nlm.nih.gov/pubmed/27247428?dopt=AbstractPlus], while https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15868 (http://www.uniprot.org/uniprot/Q8N2K0) is also able to hydrolyse lysophosphatidylserine [http://www.ncbi.nlm.nih.gov/pubmed/2397193?dopt=AbstractPlus]. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15868 (http://www.uniprot.org/uniprot/Q8N2K0) has been described to be inhibited selectively by pentacyclic triterpenoids, such as oleanolic acid [http://www.ncbi.nlm.nih.gov/pubmed/24879289?dopt=AbstractPlus].Many of the compounds described as inhibitors are irreversible and so potency estimates will vary with incubation time. FAAH2 is not found in rodents .http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 as substrate, these products are hydroperoxyeicosatetraenoic acids (HPETEs). In humans there are five lipoxygenases, the 5S‐(arachidonate : oxygen 5‐oxidoreductase), 12R‐, 12S‐(arachidonate : oxygen 12‐oxidoreductase), and two distinct 15S‐(arachidonate : oxygen 15‐oxidoreductase) LOXs that oxygenate arachidonic acid in different positions along the carbon chain and form the corresponding 5S‐, 12S‐, 12R‐, or 15S‐hydroperoxides, respectively.The lipoxygenases (LOXs) are a structurally related family of non‐heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. For http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=1.13.11.40, arachidonate:oxygen 8‐oxidoreductase) may be the mouse orthologue of 15‐LOX‐2 [http://www.ncbi.nlm.nih.gov/pubmed/12432921?dopt=AbstractPlus]. Some general LOX inhibitors are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4265 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5180. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5297 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5155 are used as 5‐lipoxygenase inhibitors, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5144 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5162 are 12‐lipoxygenase inhibitors. The specificity of these inhibitors has not been rigorously assessed with all LOX forms: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5144, along with other flavonoids, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5182 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5215, also inhibits 15‐LOX‐1 [http://www.ncbi.nlm.nih.gov/pubmed/12628491?dopt=AbstractPlus].An 8‐LOX(4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214), produced by 5‐LOX activity, and lipoxins may be subject to further oxidative metabolism; ω‐hydroxylation is mediated by http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242#show_object_1344 and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242#show_object_1345, while ß‐oxidation in mitochondria and peroxisomes proceeds in a manner dependent on coenzyme A conjugation. Conjugation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214 at the 6 position with reduced glutathione to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3354 occurs under the influence of leukotriene C4 synthase, with the subsequent formation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3352, all three of which are agonists at http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 formation is catalysed by γ‐glutamyltransferase, and subsequently dipeptidase 2 removes the terminal http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3352. Leukotriene A4 hydrolase converts the 5,6‐epoxide LTA4 to the 5‐hydroxylated LTB4, an agonist for http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214 is also acted upon by 12S‐LOX to produce the trihydroxyeicosatetraenoic acids lipoxins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1034 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5216. Treatment with a LTA4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA4 levels, in addition to reducing http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2487, in lung lavage fluid [http://www.ncbi.nlm.nih.gov/pubmed/20110560?dopt=AbstractPlus]. LTA4 hydrolase is also involved in biosynthesis of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=134. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4139 has been reported to increase endogenous formation of 18S‐hydroxyeicosapentaenoate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5105) compared with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3400, a resolvin precursor. Both enantiomers may be metabolised by human recombinant 5‐LOX; recombinant LTA4 hydrolase converted chiral 5S(6)‐epoxide‐containing intermediates to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3333 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5106 [http://www.ncbi.nlm.nih.gov/pubmed/21206090?dopt=AbstractPlus].Leukotriene Ahttp://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000001675), which also includes aminopeptidase B  and aminopeptidase B‐like 1 . Dipeptidase 1 and 2 are members of a family of membrane dipeptidases, which also includes  for which http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 appears not to be a substrate.LTA4H is a member of a family of arginyl aminopeptidases  The double‐edged role of 12/15‐lipoxygenase during inflammation and immunity. Biochim. Biophys. Acta1862: 371–381 https://www.ncbi.nlm.nih.gov/pubmed/27480217?dopt=AbstractPlusAckermann JA et al. (2017) The Cardiovascular Pharmacology of Nonsteroidal Anti‐Inflammatory Drugs. Trends Pharmacol. Sci. 38: 733–748 https://www.ncbi.nlm.nih.gov/pubmed/28651847?dopt=AbstractPlusGrosser T J Clin Invest128: 2680–2690 https://www.ncbi.nlm.nih.gov/pubmed/30108195Haeggstrom JZ. (2018) Leukotriene biosynthetic enzymes as therapeutic targets. et al. (2019) Beyond leukotriene formation‐The noncanonical functions of 5‐lipoxygenase. Prostaglandins Other Lipid Mediat142: 24–32 https://www.ncbi.nlm.nih.gov/pubmed/30930090Hafner AK Br J Pharmacol176: 1038–1050 https://www.ncbi.nlm.nih.gov/pubmed/29468666Mitchell JA and Kirkby NS. (2019) Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. et al. (2015) Perspective of microsomal prostaglandin E2 synthase‐1 as drug target in inflammation‐related disorders. Biochem. Pharmacol. 98: 1–15 https://www.ncbi.nlm.nih.gov/pubmed/26123522?dopt=AbstractPlusKoeberle A et al. (2015) Mammalian lipoxygenases and their biological relevance. Biochim. Biophys. Acta1851: 308–30 https://www.ncbi.nlm.nih.gov/pubmed/25316652?dopt=AbstractPlusKuhn H et al. (2015) Cyclooxygenase inhibitors: From pharmacology to clinical read‐outs. Biochim. Biophys. Acta1851: 422–32 https://www.ncbi.nlm.nih.gov/pubmed/25263946?dopt=AbstractPlusPatrignani P et al. (2015) 5‐Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim. Biophys. Acta1851: 331–9 https://www.ncbi.nlm.nih.gov/pubmed/25152163?dopt=AbstractPlusRådmark O et al. (2017) Role of prostacyclin synthase in carcinogenesis. Prostaglandins Other Lipid Mediat. 133: 49–52 https://www.ncbi.nlm.nih.gov/pubmed/28506876?dopt=AbstractPlusSasaki Y et al. (2017) Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog. Lipid Res. 66: 50–68 https://www.ncbi.nlm.nih.gov/pubmed/28392405?dopt=AbstractPlusSeo MJ et al. (2016) COX‐1 Inhibitors: Beyond Structure Toward Therapy. Med Res Rev36: 641–71 https://www.ncbi.nlm.nih.gov/pubmed/27111555?dopt=AbstractPlusVitale P http://www.ncbi.nlm.nih.gov/pubmed/8126575?dopt=AbstractPlus] where GABA is principally accumulated in vesicles through the action of the vesicular inhibitory amino acid transporter http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=219. The role of γ‐aminobutyraldehyde dehydrogenase (ALDH9A1) in neurotransmitter GABA synthesis is less clear. Following release from neurons, GABA may interact with either GABAA or GABAB receptors and may be accumulated in neurones and glia through the action of members of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=144. Successive metabolism through GABA transaminase and succinate semialdehyde dehydrogenase generates succinic acid, which may be further metabolized in the mitochondria in the tricarboxylic acid cycle.The inhibitory neurotransmitter γ‐aminobutyrate  is generated in neurones by glutamic acid decarboxylase. GAD1 and GAD2 are differentially expressed during development, whereGAD2 is thought to subserve a trophic role in early life and is distributed throughout the cytoplasm. GAD1 is expressed in later life and is more associated with nerve terminals , although this mechanism of action has been questioned [http://www.ncbi.nlm.nih.gov/pubmed/15302681?dopt=AbstractPlus]. The aminosteroid http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5283 has been described as an inhibitor of phosphoinositide‐specific PLC [http://www.ncbi.nlm.nih.gov/pubmed/2338654?dopt=AbstractPlus], although its selectivity among the isoforms is untested and it has been reported to occupy the H1 histamine receptor [http://www.ncbi.nlm.nih.gov/pubmed/11138848?dopt=AbstractPlus].Phosphoinositide‐specific phospholipase C , catalyses the hydrolysis of https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9063, http://www.uniprot.org/uniprot/Q15111; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9064, http://www.uniprot.org/uniprot/Q9UPR0 and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29185, http://www.uniprot.org/uniprot/Q4KWH8) form a family with PLCδ and PLCζ1 isoforms, but appear to lack catalytic activity. PLC‐δ2 has been cloned from bovine sources [http://www.ncbi.nlm.nih.gov/pubmed/1848183?dopt=AbstractPlus].A series of PLC‐like proteins  Phosphoinositide‐specific phospholipase C in health and disease. J. Lipid Res.56: 1853–60 https://www.ncbi.nlm.nih.gov/pubmed/25821234?dopt=AbstractPlusCocco L et al. (2016) Topological organisation of the phosphatidylinositol 4,5‐bisphosphatephospholipase C resynthesis cycle: PITPs bridge the ER‐PM gap. Biochem. J. 473: 4289–4310 https://www.ncbi.nlm.nih.gov/pubmed/27888240?dopt=AbstractPlusCockcroft S Life Sci. 137: 116–24 https://www.ncbi.nlm.nih.gov/pubmed/26239437?dopt=AbstractPlusLitosch I. (2015) Regulating G protein activity by lipase‐independent functions of phospholipase C. et al. (2017) Regulation and physiological functions of mammalian phospholipase C. J. Biochem. 161: 315–321 https://www.ncbi.nlm.nih.gov/pubmed/28130414?dopt=AbstractPlusNakamura Y et al. (2016) The sperm phospholipase C‐ζ and Ca2+ signalling at fertilization in mammals. Biochem. Soc. Trans. 44: 267–72 https://www.ncbi.nlm.nih.gov/pubmed/26862214?dopt=AbstractPlusSwann K 2  cleaves the sn‐2 fatty acid of phospholipids, primarily phosphatidylcholine, to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2508 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391. Most commonly‐used inhibitors  are either non‐selective within the family of phospholipase A2 enzymes or have activity against other eicosanoid‐metabolising enzymes.Phospholipase A2‐1B, sPLA2‐2A, sPLA2‐2D, sPLA2‐2E, sPLA2‐2F, sPLA2‐3, sPLA2‐10 and sPLA2‐12AsPLA2‐4A, cPLA2‐4B, cPLA2‐4C, cPLA2‐4D, cPLA2‐4E and cPLA2‐4FcPLA2‐G5, iPLA2‐G6, PLA2‐G7 and PAFAH2 (platelet‐activating factor acetylhydrolase 2)PLA2‐2C suggests a lack of catalytic activity, while PLA2‐12B  appears to be catalytically inactive [http://www.ncbi.nlm.nih.gov/pubmed/14516201?dopt=AbstractPlus]. A further fragment has been identified with sequence similarities to Group II PLA2 members. Otoconin 90 (OC90) shows sequence homology to PLA2‐G10.The sequence of PLA2 has been identified which shows modest selectivity for sPLA2‐1B over sPLA2‐2A, and also binds snake toxin phospholipase A2 [http://www.ncbi.nlm.nih.gov/pubmed/7548076?dopt=AbstractPlus]. The binding protein appears to have clearance function for circulating secretory phospholipase A2, as well as signalling functions, and is a candidate antigen for idiopathic membraneous nephropathy [http://www.ncbi.nlm.nih.gov/pubmed/19571279?dopt=AbstractPlus].A binding protein for secretory phospholipase A2‐G7 and PAFAH2 also express platelet‐activating factor acetylhydrolase activity (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.1.47).PLABiochim Biophys Acta Mol Cell Biol Lipids1864: 772–783 https://www.ncbi.nlm.nih.gov/pubmed/30010011Astudillo AM. (2019) Selectivity of phospholipid hydrolysis by phospholipase A2 enzymes in activated cells leading to polyunsaturated fatty acid mobilization. etal. (2019) Cytosolic phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids1864: 838–845 https://www.ncbi.nlm.nih.gov/pubmed/30905348Kita Y Biochim Biophys Acta Mol Cell Biol Lipids1864: 766–771 https://www.ncbi.nlm.nih.gov/pubmed/30905345Mouchlis VD and Dennis EA. (2019) Phospholipase A2 catalysis and lipid. mediator lipidomics. et al. (2019) Group IID, IIE, IIF and III secreted phospholipase A2s. Biochim Biophys Acta Mol Cell Biol Lipids. 1864: 803–818 https://www.ncbi.nlm.nih.gov/pubmed/30905347Murakami M Biochim Biophys Acta Mol Cell Biol Lipids1864: 819–826 https://www.ncbi.nlm.nih.gov/pubmed/30308324Samuchiwal SK and Balestrieri B. (2019) Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions. Biochim Biophys Acta Mol Cell Biol Lipids. 1864: 932–940 https://www.ncbi.nlm.nih.gov/pubmed/30077006Shayman JA and Tesmer JJG. (2019) Lysosomal phospholipase A2. http://www.ncbi.nlm.nih.gov/pubmed/2186929?dopt=AbstractPlus].Phosphatidylcholine‐specific phospholipase D  catalyses the formation of phosphatidic acid from phosphatidylcholine. In addition, the enzyme can make use of alcohols, such as butanol in a transphosphatidylation reaction . This enzyme activity appears to be enhanced by polyamines in the physiological range [http://www.ncbi.nlm.nih.gov/pubmed/12047899?dopt=AbstractPlus] and fails to transphosphatidylate with alcohols [http://www.ncbi.nlm.nih.gov/pubmed/10428468?dopt=AbstractPlus].A lysophospholipase D activity , PLD4  and PLD5 . PLD3 has been reported to be involved in myogenesis [http://www.ncbi.nlm.nih.gov/pubmed/22428023?dopt=AbstractPlus]. PLD4 is described not to have phospholipase D catalytic activity [http://www.ncbi.nlm.nih.gov/pubmed/21085684?dopt=AbstractPlus], but has been associated with inflammatory disorders . Sequence analysis suggests that PLD5 is catalytically inactive.Three further, less well‐characterised isoforms are PLD3  Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov16: 351‐367 https://www.ncbi.nlm.nih.gov/pubmed/28209987?dopt=AbstractPlusBrown HA Trends Pharmacol. Sci. 36: 137‐44 https://www.ncbi.nlm.nih.gov/pubmed/25661257?dopt=AbstractPlusFrohman MA. (2015) The phospholipase D superfamily as therapeutic targets. et al. (2015) Physiological and pathophysiological roles for phospholipase D. J. Lipid Res. 56: 2229‐37 https://www.ncbi.nlm.nih.gov/pubmed/25926691?dopt=AbstractPlusNelson RK Lipid phosphate phosphatases, divided into phosphatidic acid phosphatases or lipins catalyse the dephosphorylation of phosphatidic acid (and other phosphorylated lipid derivatives) to generate inorganic phosphate and diacylglycerol. PTEN, a phosphatase and tensin homolog  is a phosphatidylinositol 3,4,5‐trisphosphate 3‐phosphatase which acts as a tumour suppressor by reducing cellular levels of PI 3,4,5‐P, thereby toning down activity of PDK1 and PKB. Loss‐of‐function mutations are frequently identified as somatic mutations in cancers.Trends Neurosci40: 83‐91 https://www.ncbi.nlm.nih.gov/pubmed/28081942Knafo S and Esteban JA. (2017) PTEN: Local and Global Modulation of Neuronal Function in Health and Disease. et al. (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol19: 547‐562 https://www.ncbi.nlm.nih.gov/pubmed/29858604Lee YR et al. (2019) PTEN‐opathies: from biological insights to evidence‐based precision medicine. J Clin Invest129: 452‐464 https://www.ncbi.nlm.nih.gov/pubmed/30614812Yehia L Phosphatidylinositol may be phosphorylated at either 3‐ or 4‐ positions on the inositol ring by PI 3‐kinases or PI 4‐kinases, respectively.2). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:795 (http://www.uniprot.org/uniprot/Q13315) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3942 (http://www.uniprot.org/uniprot/P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3Krelated kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium‐binding domain and helical domains, alongside structurally‐conserved catalytic domains. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6004 are widely‐used inhibitors of PI3K activities. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.Phosphatidylinositol 3‐kinases  catalyse the introduction of a phosphate into the 3‐position of phosphatidylinositol (PI), phosphatidylinositol 4‐phosphate (PIP) or phosphatidylinositol 4,5‐bisphosphate (PIPClass I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5‐bisphosphate to generate phosphatidylinositol 3,4,5‐trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110ß and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linkedmore with GPCR signalling.Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3‐phosphate . Three monomeric members exist, PI3KC2α, ß and ß, and include Ras‐binding, Phox homology and two C2domains.class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).The only Phosphatidylinositol 4‐kinasesPhosphatidylinositol 4‐kinases (EC 2.7.1.67) generate phosphatidylinositol 4‐phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.et al. (2017) [http://www.ncbi.nlm.nih.gov/pubmed/28802037?dopt=AbstractPlus].PI3K activation is one of the most important signal transduction pathways used to transmit signals from cell‐surface receptors to regulate intracellular processes . PI3K catalytic (and regulatory) subunits play vital roles in normal cell function and in disease. Progress made in developing PI3K‐targeted agents as potential therapeutics for treating cancer and other diseases is reviewed by Fruman http://www.ncbi.nlm.nih.gov/pubmed/9367159?dopt=AbstractPlus]. This enzyme family is also known as type I PIP(5)Ks.Type I PIP kinases are required for the production of the second messenger phosphatidylinositol 4,5‐bisphosphate P2) by phosphorylating PtdIns(4)P [http://www.ncbi.nlm.nih.gov/pubmed/9367159?dopt=AbstractPlus]. This enzyme family is also known as type II PIP(5)Ks.Type II PIP kinases are essential for the production of the second messenger phosphatidylinositol 4,5‐bisphosphate P2) by phosphorylating PtdIns(5)P ) and induces proteasomal degradation of SK1 [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus]. ABC294640 is in clinical trials for advanced cholangiocarcinoma, advanced hepatocellular carcinoma and refractory/relapsed multiple myeloma .et al. (2016) Sphingosine Kinases: Emerging Structure‐Function Insights. Trends Biochem. Sci. 41: 395‐409 https://www.ncbi.nlm.nih.gov/pubmed/27021309?dopt=AbstractPlusAdams DR et al. (2016) Sphingosine kinase inhibitors: a review of patent literature (2006‐2015). Expert Opin Ther Pat26: 1409‐1416 https://www.ncbi.nlm.nih.gov/pubmed/27539678?dopt=AbstractPlusLynch KR et al. (2016) Recent advances in the development of sphingosine kinase inhibitors. Cell. Signal. 28: 1349‐63 https://www.ncbi.nlm.nih.gov/pubmed/27297359?dopt=AbstractPlusPitman MR et al. (2018) An intrinsic lipid‐binding interface controls sphingosine kinase 1 function. J. Lipid Res. 59: 462‐474 https://www.ncbi.nlm.nih.gov/pubmed/29326159?dopt=AbstractPlusPulkoski‐Gross MJ et al. (2017) Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol. Sci. 38: 581‐591 https://www.ncbi.nlm.nih.gov/pubmed/28606480?dopt=AbstractPlusPyne NJ et al. (2018) Sphingosine Kinases as Druggable Targets. Handb Exp Pharmacolhttps://www.ncbi.nlm.nih.gov/pubmed/29460151?dopt=AbstractPlusPyne S http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 also inhibits type III phosphatidylinositol 4‐kinases and polo‐like kinase [http://www.ncbi.nlm.nih.gov/pubmed/15664519?dopt=AbstractPlus]. PIK93 also inhibits PI 3‐kinases [http://www.ncbi.nlm.nih.gov/pubmed/16647110?dopt=AbstractPlus]. Adenosine activates http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=3.et al. (2018) Phosphoinositide 3‐kinase inhibitors in advanced breast cancer: A systematic review and meta‐analysis. Eur J Cancer91: 38‐46 https://www.ncbi.nlm.nih.gov/pubmed/29331750Raphael J et al. (2019) Upstream regulators of phosphoinositide 3‐kinase and their role in diseases. J Cell Physiol. https://www.ncbi.nlm.nih.gov/pubmed/30710358Wang D et al. (2018) Phosphatidylinositol 3‐Kinase, Growth Disorders, and Cancer. N Engl J Med379: 2052‐2062 https://www.ncbi.nlm.nih.gov/pubmed/30462943Goncalves MD 2 is generated by phosphorylation of PI 4‐phosphate or PI 5‐phosphate by type I PI 4‐phosphate 5‐kinases or type II PI 5‐phosphate 4‐kinases.PIPet al. (2015) Phosphoinositides: Lipids with informative heads and mastermind functions in cell division. Biochim. Biophys. Acta1851: 832‐43 https://www.ncbi.nlm.nih.gov/pubmed/25449648?dopt=AbstractPlusCauvin C J. Lipid Res. 57: 1987‐1994 https://www.ncbi.nlm.nih.gov/pubmed/27623846?dopt=AbstractPlusIrvine RF. (2016) A short history of inositol lipids. et al. (2016) Nuclear Phosphatidylinositol Signaling: Focus on Phosphatidylinositol Phosphate Kinases and Phospholipases C. J. Cell. Physiol. 231: 1645‐55 https://www.ncbi.nlm.nih.gov/pubmed/26626942?dopt=AbstractPlusPoli A http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=1.14.99.3, converts http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4349 into http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5153 and carbonmonoxide, utilizing http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3041 as cofactor.Haem oxygenase ), http://www.ncbi.nlm.nih.gov/pubmed/15246535?dopt=AbstractPlus]. The chemical http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5279 acts as a haem oxygenase inhibitor in rat liver with an IC50 value of 11 nM [http://www.ncbi.nlm.nih.gov/pubmed/6947237?dopt=AbstractPlus].The existence of a third non‐catalytic version of haem oxygenase, HO3, has been proposed, although this has been suggested to be a pseudogene .Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide  Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 169: 922‐32 https://www.ncbi.nlm.nih.gov/pubmed/23488457?dopt=AbstractPlusAsimakopoulou A et al. (2017) International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmacol. Rev. 69: 497‐564 https://www.ncbi.nlm.nih.gov/pubmed/28978633?dopt=AbstractPlusSzabo C http://www.uniprot.org/uniprot/P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone‐sensitive lipase is also a relatively non‐selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2  The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol Rev. 276: 121‐144 https://www.ncbi.nlm.nih.gov/pubmed/28258700Allard B et al. (2018) CD39‐adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal14: 109‐120 https://www.ncbi.nlm.nih.gov/pubmed/29332180Kishore BK et al. (2018) Carboxylesterase 1 genes: systematic review and evaluation of existing genotyping procedures. Drug Metab Pers Ther33: 3‐14 https://www.ncbi.nlm.nih.gov/pubmed/29427553Rasmussen HB et al. (2018) Carboxylesterase Inhibitors: An Update. Curr Med Chem. 25: 1627‐1649 https://www.ncbi.nlm.nih.gov/pubmed/29210644Zou LW myo‐inositol is a component of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244, where the principal second messenger is inositol 1,4,5‐trisphosphate, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222, which acts at intracellular ligand‐gated ion channels, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=123 to elevate intracellular calcium. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 is recycled to inositol by phosphatases or phosphorylated to form other active inositol polyphosphates. Inositol produced from dephosphorylation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 is recycled into membrane phospholipid under the influence of phosphatidyinositol synthase activity (CDP‐diacylglycerol‐inositol 3‐phosphatidyltransferase [http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.8.11]).The sugar alcohol D‐http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.1.127, http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000001260) catalyse the generation of inositol 1,3,4,5‐tetrakisphosphate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5202) from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222. IP3 kinase activity is enhanced in the presence of calcium/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351  [http://www.ncbi.nlm.nih.gov/pubmed/2559811?dopt=AbstractPlus].Inositol 1,4,5‐trisphosphate 3‐kinases  generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5119, 4‐phosphatases  generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5099 and 5‐phosphatases (http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.36 or http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.56) generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5098.Members of this family exhibit phosphatase activity towards IPhttp://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=281.Information on members of this family may be found in the In vitro analysis suggested http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5202 were poor substrates for SKIP, synaptojanin 1 and synaptojanin 2, but suggested that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2387 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2353 were more efficiently hydrolysed [http://www.ncbi.nlm.nih.gov/pubmed/15474001?dopt=AbstractPlus].http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.3.25, IMPase, myo‐inositol‐1(or 4)‐phosphate phosphohydrolase) is a magnesium‐dependent homodimer which hydrolyses myoinositol monophosphate to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 and phosphate. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5195 may be a physiological phosphate acceptor. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5212 is a nonselective un‐competitive inhibitor more potent at IMPase 1  than IMPase 2 . IMPase activity may be inhibited competitively by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5208 , although the enzyme selectivity is not yet established.Inositol monophosphatase  A tale of two inositol trisphosphates. et al. (2016) Phosphate, inositol and polyphosphates. Biochem. Soc. Trans. 44: 253‐9 https://www.ncbi.nlm.nih.gov/pubmed/26862212?dopt=AbstractPlusLivermore TM et al. (2017) Probes for manipulating and monitoring IP_3. Cell Calcium64: 57‐64 https://www.ncbi.nlm.nih.gov/pubmed/27887748?dopt=AbstractPlusMiyamoto A et al. (2017) Inositol‐1,4,5‐trisphosphate 3‐kinase‐A (ITPKA) is frequently over‐expressed and functions as an oncogene in several tumor types. Biochem. Pharmacol. 137: 1‐9 https://www.ncbi.nlm.nih.gov/pubmed/28377279?dopt=AbstractPlusWindhorst S http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.11.1) use the co‐substrate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 to phosphorylate serine and/or threonine residues on target proteins. Analysis of the human genome suggests the presence of 518 protein kinases in man (divided into 15 subfamilies), with over 100 protein kinase‐like pseudogenes [http://www.ncbi.nlm.nih.gov/pubmed/12471243?dopt=AbstractPlus]. It is beyond the scope of the Concise Guide to list all these protein kinase activities, but full listings are available on the ’Detailed page’ provided for each enzyme.Protein kinases , which in turn may be activated by Gα12/13 subunits [http://www.ncbi.nlm.nih.gov/pubmed/9641915?dopt=AbstractPlus].Rho kinase  is activated by members of the Rho small G protein family, which are activated by GTP exchange factors, such as et al. (2016) Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J. Med. Chem. 59: 2269‐300 https://www.ncbi.nlm.nih.gov/pubmed/26486225?dopt=AbstractPlusFeng Y et al. (2015) Developing novel methods to search for substrates of protein kinases such as Rho‐kinase. Biochim. Biophys. Acta1854: 1663‐6 https://www.ncbi.nlm.nih.gov/pubmed/25770685?dopt=AbstractPlusNishioka T et al. (2016) RhoA/Rho‐Kinase in the Cardiovascular System. Circ. Res. 118: 352‐66 https://www.ncbi.nlm.nih.gov/pubmed/26838319?dopt=AbstractPlusShimokawa H http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2341).Protein kinase C is the target for the tumour‐promoting phorbol esters, such as tetradecanoyl‐β‐phorbol acetate  Dynamics and Membrane Interactions of Protein Kinase C. et al. (2017) Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor. Trends Pharmacol. Sci. 38: 438‐447 https://www.ncbi.nlm.nih.gov/pubmed/28283201?dopt=AbstractPlusNewton AC et al. (2016) Protein Kinase C δ: a Gatekeeper of Immune Homeostasis. J. Clin. Immunol. 36: 631‐40 https://www.ncbi.nlm.nih.gov/pubmed/27541826?dopt=AbstractPlusSalzer E et al. (2016) The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17: 104‐12 https://www.ncbi.nlm.nih.gov/pubmed/26551880?dopt=AbstractPlusHukelmann JL et al. (2017) mTOR Signaling in Growth, Metabolism, and Disease. Cell169: 361‐371 https://www.ncbi.nlm.nih.gov/pubmed/28388417?dopt=AbstractPlusSaxton RA http://www.ncbi.nlm.nih.gov/pubmed/24879308?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22512864?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25561469?dopt=AbstractPlus].Five of the cyclin‐dependent kinases  are involved in the phosphorylation of serine residues in the C‐terminal domain of RNA polymerase II, the enzyme that is responsible for the transcription of protein‐coding genes into mRNA in eukaryotes. Phosphorylation of RNA polymerase II at Ser5 is essential for transcriptional initiation, and phosphorylation of Ser 2 contributes to transcriptional elongation and termination. All five of the C‐terminal domain kinases can phosphorylate Ser5, but only CDK9, CDK12, and CDK13 can phosphorylate at Ser2 [http://www.ncbi.nlm.nih.gov/pubmed/26115571?dopt=AbstractPlus], with detailed content covering CDK4 and CDK6 inhibitors that are under clinical evaluation. Data produced by Jorda et al. (2018) highlights the caution that must be used when deploying commercially available CDK inhibitors as pharmacological probes [http://www.ncbi.nlm.nih.gov/pubmed/30234987?dopt=AbstractPlus], as most of them are more promiscuous in their selectivity than indicated. To make their findings easily accessible the Jorda data is hosted on the http://rustreg.upol.cz/CDKiDB/.The development of CDK inhibitors as anticancer drugs is reviewed in .Since it is beyond the scope of the Guide to list all peptidase and proteinase activities, this summary focuses on selected enzymes of significant pharmacological interest that have ligands  directed against them. For those interested in detailed background we recommend the MEROPS database  (with whhttp://www.ncbi.nlm.nih.gov/pubmed/2881207?dopt=AbstractPlus] in the generation of amyloid beta (Aβ) . Given that the accumulation and aggregation of Aβ in the brain is pivotal in the development of Alzheimer's disease (AD), inhibition of PS activity is one mechanism being investigated as a therapeutic option for AD [http://www.ncbi.nlm.nih.gov/pubmed/11378516?dopt=AbstractPlus]. Several small molecule inhibitors of PS‐1 have been investigated, with some reaching early clinical trials, but none have been formally approved. Dewji et al. (2015) have reported that small peptide fragments of human PS‐1 can significantly inhibit Aβ production  both in vitro and when infused in to the brains of APP transgenic mice [http://www.ncbi.nlm.nih.gov/pubmed/25923432?dopt=AbstractPlus]. The most active small peptides in this report were http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8344 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8345, from the amino‐terminal domain of PS‐1.Presenilin (PS)‐1 or ‐2 act as the catalytic component/ essential co‐factor of the γ‐secretase complex responsible for the final carboxy‐terminal cleavage of amyloid precursor protein (APP) ) on functional and structural bases into gelatinases, collagenases, stromyelinases and matrilysins, as well as membrane type‐MMP (MT‐MMP).Matrix metalloproteinases (MMP) are calcium‐ and zinc‐dependent proteinases regulating the extracellular matrix and are often divided  proteins are endogenous inhibitors acting to chelate MMP proteins: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5309 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5310 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5311 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5312 ADAM  metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=739.Information on members of this family may be found in the http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000235812;r=14:70712470‐70714518), AC136428.3‐2 (ENSG00000185520) and ADAMDEC1 .Additional ADAM family members include AC123767.2 , AL160191.3 , AC139425.3‐1 (ENSG00000225577), and AC126339.6‐1 (ENSG00000225734).http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6878 has been used for imaging purposes.Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N‐acetaspartylglutamate to form N‐acetylaspartate and L‐glutamate. In the gut, the enzyme assists in the assimilation of folate by hydrolysing dietary poly‐gamma‐glutamylfolate. The enzyme is highly expressed in the prostate, and its expression is up‐regulated in cancerous tissue. A tagged version of the antibody http://www.ncbi.nlm.nih.gov/pubmed/16142822?dopt=AbstractPlus]. This catalytic core enables the degradation of peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the cleavage site. The β5 subunit is the principal target of the approved drug proteasome inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6391.The T1 macropain beta subunits form the catalytic proteinase core of the 20S proteasome complex . Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry. Several monoclonal antibodies including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6744, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7343, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7730, RG‐7652 and LY3015014 are under development. One RNAi therapeutic, code named ALN‐PCS02, is also in development .One member of this family has garnered intense interest as a clinical drug target. As liver PCSK9 acts to maintain cholesterol homeostasis, it has become a target of intense interest for clinical drug development. Inhibition of PCSK9 can lower low‐density cholesterol (LDL‐C) by clearing LDLR‐bound LDL particles, thereby lowering circulating cholesterol levels. It is hypothesised that this action may improve outcomes in patients with atherosclerotic cardiovascular disease ) and induces proteasomal degradation of SK1 [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus]. ABC294640 is in clinical trials for advanced cholangiocarcinoma, advanced hepatocellular carcinoma and refractory/relapsed multiple myeloma .et al. (2016) Sphingosine Kinases: Emerging Structure‐Function Insights. Trends Biochem. Sci. 41: 395‐409 https://www.ncbi.nlm.nih.gov/pubmed/27021309?dopt=AbstractPlusAdams DR et al. (2016) Sphingosine kinase inhibitors: a review of patent literature (2006‐2015). Expert Opin Ther Pat26: 1409‐1416 https://www.ncbi.nlm.nih.gov/pubmed/27539678?dopt=AbstractPlusLynch KR et al. (2016) Recent advances in the development of sphingosine kinase inhibitors. Cell. Signal. 28: 1349‐63 https://www.ncbi.nlm.nih.gov/pubmed/27297359?dopt=AbstractPlusPitman MR et al. (2018) An intrinsic lipid‐binding interface controls sphingosine kinase 1 function. J. Lipid Res. 59: 462‐474 https://www.ncbi.nlm.nih.gov/pubmed/29326159?dopt=AbstractPlusPulkoski‐Gross MJ et al. (2017) Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol. Sci. 38: 581‐591 https://www.ncbi.nlm.nih.gov/pubmed/28606480?dopt=AbstractPlusPyne NJ et al. (2018) Sphingosine Kinases as Druggable Targets. Handb Exp Pharmacolhttps://www.ncbi.nlm.nih.gov/pubmed/29460151?dopt=AbstractPlusPyne S http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=911. The phenotype of Sgpp1(‐/‐) mice differ with genetic background. Sgpp2(‐/‐) mice are also available. No specific SGPP inhibitors available [http://www.ncbi.nlm.nih.gov/pubmed/22052905?dopt=AbstractPlus].SGPP1 and SGPP2 are non‐redundant endoplasmic reticulum enzymes that dephosphorylate intracellular et al. (2013) Sphingosine‐1‐phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis. J. Biol. Chem. 288: 18381‐91 https://www.ncbi.nlm.nih.gov/pubmed/23637227?dopt=AbstractPlusAllende ML et al. (2016) Sphingosine‐1‐phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J. 30: 2945‐58 https://www.ncbi.nlm.nih.gov/pubmed/27130484?dopt=AbstractPlusHuang WC et al. (2011) Sphingosine‐1‐phosphate phosphohydrolase‐1 regulates ER stress‐induced autophagy. Cell Death Differ. 18: 350‐61 https://www.ncbi.nlm.nih.gov/pubmed/20798685?dopt=AbstractPlusLépine S et al. (2000) Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine‐1‐ phosphate and induces cell death. Proc. Natl. Acad. Sci. U.S.A. 97: 7859‐64 https://www.ncbi.nlm.nih.gov/pubmed/10859351?dopt=AbstractPlusMandala SM et al. (2016) Sphingosine‐1‐phosphate Phosphatase 2 Regulates Pancreatic Islet β‐Cell Endoplasmic Reticulum Stress and Proliferation. J. Biol. Chem. 291: 12029‐38 https://www.ncbi.nlm.nih.gov/pubmed/27059959?dopt=AbstractPlusTaguchi Y http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6626 (2‐Acetyl‐5‐tetrahydroxybutyl imidazole) inhibits the enzyme activity in intact cell preparations [http://www.ncbi.nlm.nih.gov/pubmed/16151014?dopt=AbstractPlus]. Recessive mutations in the S1P lyase (SGPL1) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS) [http://www.ncbi.nlm.nih.gov/pubmed/30274713?dopt=AbstractPlus]. A Phase 2 clinical trial of LX3305 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9851) for rheumatoid arthritis has been completed .et al. (2018) A novel mutation in sphingosine‐1‐phosphate lyase causing congenital brain malformation. Brain Dev. 40: 480‐483 https://www.ncbi.nlm.nih.gov/pubmed/29501407?dopt=AbstractPlusBamborschke D et al. (2019) Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. Adv Biol Regul71: 128‐140 https://www.ncbi.nlm.nih.gov/pubmed/30274713Choi YJ et al. (2017) Mutations in sphingosine‐1‐phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J. Clin. Invest. 127: 912‐928 https://www.ncbi.nlm.nih.gov/pubmed/28165339?dopt=AbstractPlusLovric S et al. (2017) Sphingosine‐1‐phosphate lyase mutations cause primary adrenal insufficiency and steroid‐resistant nephrotic syndrome. J. Clin. Invest. 127: 942‐953 https://www.ncbi.nlm.nih.gov/pubmed/28165343?dopt=AbstractPlusPrasad R http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635, respectively, are synthesized in the thyroid gland by sequential metabolism of tyrosine residues in the glycosylated homodimeric protein thyroglobulin  under the influence of the haem‐containing protein iodide peroxidase. Iodide peroxidase/TPO is a haem‐containing enzyme, from the same structural family as eosinophil peroxidase , lactoperoxidase  and myeloperoxidase . Circulating thyroid hormone is bound to thyroxine‐binding globulin .The thyroid hormones triiodothyronine and thyroxine, usually abbreviated as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635  to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634  or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2636 . DIO1 is also able to deiodinate RT3 to form 3,3′‐diidothyronine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6648). Iodotyrosine deiodinase is a 1TM homodimeric enzyme.These are 1 TM selenoproteins that remove an iodine from et al. (2015) Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor‐mediated impact on vertebrate development. Biochim. Biophys. Acta1849: 130‐41 https://www.ncbi.nlm.nih.gov/pubmed/24844179?dopt=AbstractPlusDarras VM et al. (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol11: 642‐652 https://www.ncbi.nlm.nih.gov/pubmed/26416219?dopt=AbstractPlusGereben B et al. (2017) Novel thyroid hormone analogues, enzyme inhibitors andmimetics, and their action. Mol. Cell. Endocrinol. 458: 91‐104 https://www.ncbi.nlm.nih.gov/pubmed/28408161?dopt=AbstractPlusMondal S et al. (2015) New insights into the structure and mechanism of iodothyronine deiodinases. J. Mol. Endocrinol. 55: R37‐52 https://www.ncbi.nlm.nih.gov/pubmed/26390881?dopt=AbstractPlusSchweizer U et al. (2017) Thyroid hormone metabolism in innate immune cells. J. Endocrinol. 232: R67‐R81 https://www.ncbi.nlm.nih.gov/pubmed/27852725?dopt=AbstractPlusvan der Spek AH et al. (2015) Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway. J. Med. Chem. 58: 8762‐82 https://www.ncbi.nlm.nih.gov/pubmed/26207924?dopt=AbstractPlusDounay AB et al. (2017) The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology112: 297‐306 https://www.ncbi.nlm.nih.gov/pubmed/27245499?dopt=AbstractPlusErhardt S et al. (2017) L‐Tryptophan‐kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences. Neuropharmacology112: 264‐274 https://www.ncbi.nlm.nih.gov/pubmed/26767951?dopt=AbstractPlusFujigaki H et al. (2016) Kynurenine‐3‐monooxygenase: a review of structure, mechanism, and inhibitors. Drug Discov. Today21: 315‐24 https://www.ncbi.nlm.nih.gov/pubmed/26589832?dopt=AbstractPlusSmith JR et al. (2017) Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell. Mol. Life Sci. 74: 2899‐2916 https://www.ncbi.nlm.nih.gov/pubmed/28314892?dopt=AbstractPlusSong P http://www.ncbi.nlm.nih.gov/pubmed/8621375?dopt=AbstractPlus]. Protein farnesyltransferase catalyses the post‐translational formation of a thioether linkage between the C‐1 of an isoprenyl group and a cysteine residue fourth from the C‐terminus of a protein  [http://www.ncbi.nlm.nih.gov/pubmed/7756316?dopt=AbstractPlus]. Farnesyltransferase is a dimer, composed of an alpha and beta subunit and requires Mg2+ and Zn2+ ions as cofactors. The active site is located between the subunits. Prenylation creates a hydrophobic domain on protein tails which acts as a membrane anchor.Farnesyltransferase is a member of the prenyltransferases family which also includes geranylgeranyltransferase types I (EC 2.5.1.59) and II (EC 2.5.1.60) .Classes I, II and IV use Znhttp://www.ncbi.nlm.nih.gov/pubmed/19608861?dopt=AbstractPlus] such as microtubules [http://www.ncbi.nlm.nih.gov/pubmed/12024216?dopt=AbstractPlus], the hsp90 chaperone [http://www.ncbi.nlm.nih.gov/pubmed/15916966?dopt=AbstractPlus] and the tumour suppressor p53 [http://www.ncbi.nlm.nih.gov/pubmed/11099047?dopt=AbstractPlus].HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins , making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [http://www.ncbi.nlm.nih.gov/pubmed/24382387?dopt=AbstractPlus]. Several small molecule HDAC inhibitors are already approved for clinical use: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7006, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6852, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7489, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7009 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8305. HDACs and HDAC inhibitors currently in development as potential anti‐cancer therapeutics are reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].Dysregulated HDACactivity has been identified in cancer cells and tumour tissues . Overexpression and/or increased PADI activity is observed in several diseases, including rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer [http://www.ncbi.nlm.nih.gov/pubmed/23175390?dopt=AbstractPlus]. Pharmacological PADI inhibition reverses protein‐hypercitrullination and disease in mouse models of multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/23118341?dopt=AbstractPlus].In humans, the peptidyl arginine deiminases  PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin. Ther. Targets21: 433‐447 https://www.ncbi.nlm.nih.gov/pubmed/28281906?dopt=AbstractPlusKoushik S et al. (2016) Peptidyl Arginine Deiminases and Neurodegenerative Diseases. Curr. Med. Chem. 23: 104‐14 https://www.ncbi.nlm.nih.gov/pubmed/26577926?dopt=AbstractPlusTu R Neurochem. Int. 67: 23‐31 https://www.ncbi.nlm.nih.gov/pubmed/24508404?dopt=AbstractPlusWhiteley CG. (2014) Arginine metabolising enzymes as targets against Alzheimers’ disease. small G‐proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G‐protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G‐proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best‐known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.The RAS proteins  are small membrane‐localised G protein‐likemolecules of 21 kd. They act as an on/off switch linking receptor and non‐receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.http://www.ncbi.nlm.nih.gov/pubmed/7900159?dopt=AbstractPlus], which leads to increased cell proliferation and decreased apoptosis [http://www.ncbi.nlm.nih.gov/pubmed/17721087?dopt=AbstractPlus]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [http://www.ncbi.nlm.nih.gov/pubmed/22004085?dopt=AbstractPlus].The RAS proto‐oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP‐hydrolysing ability of the proteins causing constitutive activation [http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=897.Information on members of this family may be found in the et al. (2017) Deciphering the RAS/ERK pathway in vivo. Biochem. Soc. Trans. 45: 27‐36 https://www.ncbi.nlm.nih.gov/pubmed/28202657?dopt=AbstractPlusDorard C et al. (2017) The RAS‐Effector Interaction as a Drug Target. Cancer Res. 77: 221‐226 https://www.ncbi.nlm.nih.gov/pubmed/28062402?dopt=AbstractPlusKeeton AB et al. (2016) Ras Conformational Ensembles, Allostery, and Signaling. Chem. Rev. 116: 6607‐65 https://www.ncbi.nlm.nih.gov/pubmed/26815308?dopt=AbstractPlusLu S et al. (2016) Direct small‐molecule inhibitors of KRAS: from structural insights to mechanism‐based design. Nat Rev Drug Discov15: 771‐785 https://www.ncbi.nlm.nih.gov/pubmed/27469033?dopt=AbstractPlusOstrem JM et al. (2017) Drugging RAS: Know the enemy. Science355: 1158‐1163 https://www.ncbi.nlm.nih.gov/pubmed/28302824?dopt=AbstractPlusPapke B et al. (2016) Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti‐Ras drugs. Pharmacol. Ther. 162: 35‐57 https://www.ncbi.nlm.nih.gov/pubmed/27016467?dopt=AbstractPlusQuah SY et al. (2017) RAS Proteins and Their Regulators in Human Disease. Cell170: 17‐33 https://www.ncbi.nlm.nih.gov/pubmed/28666118?dopt=AbstractPlusSimanshu DK http://www.genenames.org/cgi‐bin/genefamilies/set/388, http://www.genenames.org/cgi‐bin/genefamilies/set/388 ).The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface ( see http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=938.Information on members of this family may be found in the


NORDLAND study. PLoS ONE 14(6): e0218521. https://doi.org/10.1371/journal.pone.0218521The third author’s name is incorrect. The correct name is: Knut-Tore Lappegard. The correct citation is: Catalan-Matamoros D, Lopez-Villegas A, Tore-Lappegard K, Lopez-Liria R (2019) Patients' experiences of remote communication after pacemaker implant: The


This article has been corrected: The correct author affiliation information is given below:1,2Hong Zhao84102-84111. https://doi.org/10.18632/oncotarget.21106Original article: Oncotarget. 2017; 8:


This article has been corrected: The authors recently became aware that the antibody used for 5545-5561. https://doi.org/10.18632/oncotarget.23798 Original article: Oncotarget. 2018; 9:5545–5561.


This article has been corrected: The correct author name is given below:Sepideh Saadatmand24335-24346. https://doi.org/10.18632/oncotarget.25262Original article: Oncotarget. 2018; 9:


Correction to: Mol Med 22:224–232, 2016DOI 10.2119/molmed.2016.00003Following publication of the original article (Sonkar et al.


This article has been corrected: The corrected author name is given below:Christina Gavegnano94040-94053. https://doi.org/10.18632/oncotarget.21541Original article: Oncotarget. 2017; 8:


Correction to: BMC Health Services Research (2018) 18:575https://doi.org/10.1186/s12913-018-3368-3Following publication of the original article , the autTable Table Incorrect values:1.088(0.621–1.906)Single vs. Non-Users:1.067(0.721–1.581)Multiple vs. Single:Correct values:1.061(0.721–1.563)Single vs. Non-Users:1.047(0.815–1.345)Multiple vs. Single:


There are errors in the Author Contributions. The correct contributions are: Conceptualization: HZ RWM FGG. Data curation: HZ RG KM FGG. Formal analysis: HZ RG MW FGG. Funding acquisition: HZ YPZ. Investigation: HZ MW FGG. Methodology: HZ MW FGG. Project administration: HZ YPZ. Resources: HZ FGG. Software: HZ FGG. Supervision: HZ RWM YPZ FGG. Validation: HZ RWM JCA RG PRMF GGM ABQ NLO MW YPZ FGG. Visualization: HZ JCA RG PRMF KM GGM ABQ NLO MW YPZ FGG. Writing–original draft: HZ JCA RG PRMF GGM ABQ MW FGG. Writing–review & editing: HZ RWM JCA RG PRMF KM GGM ABQ NLO MW YPZ FGG.


This article has been corrected: The correct author name is given below:Takuro Uchida25075-25088. https://doi.org/10.18632/oncotarget.25308Original article: Oncotarget. 2018; 9:


There is an error in the Correction published on July 5, 2019. The third author’s name is incorrect in the citation. The publisher apologizes for this error.NORDLAND study. PLoS ONE 14(6): e0218521. https://doi.org/10.1371/journal.pone.0218521.The correct citation is: Catalan-Matamoros D, Lopez-Villegas A, Lappegard KT, Lopez-Liria R (2019) Patients' experiences of remote communication after pacemaker implant: The


Correction to: BMC Microbiology (2018) 18:191.https://doi.org/10.1186/s12866-018-1329-yFollowing publication of the original article , we haveftp://ftp.ncbi.nih.gov/genomes/genbank/fungi/Stemphylium_lycopersici/latest_assembly_versions/GCA_001191545.1_ASM119154v1/GCA_001191545.1_ASM119154v1_protein.faa.gz) is:The correct citation for the data presented in section “Materials and Methods - Sequence data and preparation” .


This article has been corrected: The corrected author name is given below:Ruiqi Chenhttps://doi.org/10.18632/oncotarget.19386Original article: Oncotarget. 2017; 8:84863-84876.


This article has been corrected: The correct Author name is given below:Stephen D. Robinsonhttps://doi.org/10.18632/oncotarget.23378Original article: Oncotarget. 2018; 9:3815-3829.


VOLUME 107107(3) July, page 302http://dx.doi.org/10.5195/jmla.2019.712.Martin ER. Social justice and the medical librarian. J Med Libr Assoc. 2019 Jul;107(3):291–303. DOI: Page 302: The quote by Martin Luther King Jr. should be:—Injustice anywhere is a threat to justice everywhere. Martin Luther King [41]


This article has been corrected: During production, the author name for this article was given incorrectly. The proper author name is shown below.N. Andres Parrahttps://doi.org/10.18632/oncotarget.26437Original article: Oncotarget. 2018; 9:37125-37136.