THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 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 (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 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/bph.15542. 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‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The majority of drugs which act on enzymes act as inhibitors; one exception is ingenol mebutate, which is a non-selective protein kinase C activator approved for the topical treatment of actinic keratoses. Kinetic assays allow discrimination of competitive, non-competitive, and un-competitive inhibitors. The majority of inhibitors are competitive (acting at the enzyme's ligand recognition site), non-competitive (acting at a distinct site; potentially interfering with co-factor or co-enzyme binding) or of mixed type. One rare example of an uncompetitive inhibitor is lithium ions, which are effective inhibitors at inositol monophosphatase only in the presence of high substrate concentrations. Some inhibitors are irreversible, including a group known as suicide substrates, which bind to the ligand recognition site and then couple covalently to the enzyme. It is beyond the scope of the Guide to give mechanistic information about the inhibitors described, although generally this information is available from the indicated literature.
Many enzymes require additional entities for functional activity. Some of these are used in the catalytic steps, while others promote a particular conformational change. Co-factors are tightly bound to the enzyme and include metal ions and heme groups. Co-enzymes are typically small molecules which accept or donate functional groups to assist in the enzymatic reaction. Examples include ATP, NAD, NADP and S-adenosylmethionine, as well as a number of vitamins, such as riboflavin (vitamin B1) and thiamine (vitamin B2). Where co-factors/co-enzymes have been identified, the Guide indicates their involvement.     Selective inhibitors pentostatin (pIC 50 10.8) [8], EHNA (pK i 8.8) [8] A134974 (pIC 50 10.2) [464], ABT702 (pIC 50 8.8) [336] αβ-methyleneADP (pIC 50 8.7) [71] 3-deazaadenosine (pIC 50 8.5) [265] Comments -The enzyme exists in two isoforms derived from alternative splicing of a single gene product: a short isoform, ADK-S, located in the cytoplasm is responsible for the regulation of intra-and extracellular levels of adenosine and hence adenosine receptor activation; a long isoform, ADK-L, located in the nucleus contributes to the regulation of DNA methylation [62,735].
Pharmacological inhibition of CD73 is being investigated as a novel cancer immunotherapy strategy [714].

Amino acid hydroxylases
Enzymes → Amino acid hydroxylases Overview: The amino acid hydroxylases (monooxygenases), EC.1.14.16.-, are iron-containing enzymes which utilise molecular oxygen and sapropterin 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.

L-Arginine turnover
Enzymes → L-Arginine turnover Overview: L-arginine is a basic amino acid with a guanidino sidechain. As an amino acid, metabolism of L-arginine to form L-ornithine, catalysed by arginase, forms the last step of the urea production cycle. L-Ornithine may be utilised as a precursor of polyamines (see Carboxylases and Decarboxylases) or recycled via L-argininosuccinic acid to L-arginine. L-Arginine may itself be decarboxylated to form agmatine, although the prominence of this pathway in human tissues is uncertain. L-Arginine may be used as a precursor for guanidoacetic acid formation in the creatine 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 L-citrulline 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 N G ,N G -dimethyl-L-arginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase activities. ADMA is hydrolysed by dimethylarginine dimethylhydrolase activities to generate L-citrulline and dimethylamine. tetrameric enzymes which use S-adenosyl methionine as a methyl donor, generating S-adenosylhomocysteine as a by-product. They generate both mono-methylated and di-methylated products; these may be symmetric (SDMA) or asymmetric (N G ,N G -dimethyl-L-arginine) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.

Further reading on L-Arginine turnover
Information on members of this family may be found in the online database.

Arginase
Enzymes → L-Arginine turnover → Arginase Overview: Arginase (EC 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.
Information on members of this family may be found in the online database.

Nitric oxide synthases
Enzymes → L-Arginine turnover → Nitric oxide synthases Overview: Nitric oxide synthases (NOS, E.C. 1.14.13.39) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of L-arginine with the resultant by-product, L-citrulline. 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 [483] 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 Ca 2+ /calmodulin (CALM1 CALM2 CALM3, P62158) 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. L-NAME and related modified arginine analogues are inhibitors of all three isoforms, with IC 50 values in the micromolar range. Comments L-aspartic acid is a less rapidly metabolised substrate of mouse brain glutamic acid decarboxylase generating β-alanine [743]. Autoantibodies against GAD1 and GAD2 are elevated in type 1 diabetes mellitus and neurological disorders (see Further reading).

Further reading on Nitric oxide synthases
L-aspartic acid is a less rapidly metabolised substrate of mouse brain glutamic acid decarboxylase generating β-alanine [743]. Autoantibodies against GAD1 and GAD2 are elevated in type 1 diabetes mellitus and neurological disorders (see Further reading).

Catecholamine turnover
Enzymes → Catecholamine turnover Overview: Catecholamines are defined by the presence of two adjacent hydroxyls on a benzene ring with a sidechain containing an amine. The predominant catacholamines in mammalian biology are the neurotransmitter/hormones dopamine, (-)-noradrenaline (norepinephrine) and (-)-adrenaline (epinephrine). These hormone/transmitters are synthesized by sequential metabolism from L-phenylalanine via L-tyrosine. Hydroxylation of L-tyrosine generates levodopa, which is decarboxylated to form dopamine. Hydroxylation of the ethylamine sidechain generates (-)-noradrenaline (norepinephrine), which can be methylated to form (-)-adrenaline (epinephrine). In particular neuronal and adrenal chromaffin cells, the catecholamines dopamine, (-)-noradrenaline and (-)-adrenaline are accumulated into vesicles under the influence of the vesicular monoamine transporters (VMAT1/SLC18A1 and VMAT2/SLC18A2). After release into the synapse or the bloodstream, catecholamines are accumulated through the action cell-surface transporters, primarily the dopamine (DAT/SLC6A3) and norepinephrine transporter (NET/SLC6A2). The primary routes of metabolism of these catecholamines are oxidation via monoamine oxidase activities of methylation via catechol O-methyltransferase. Comments PAH is an iron bound homodimer or -tetramer from the same structural family as tyrosine 3-monooxygenase and the tryptophan hydroxylases. Deficiency or loss-of-function of PAH is associated with phenylketonuria Tyrosine may also be metabolized in the liver by tyrosine transaminase to generate 4-hydroxyphenylpyruvic acid, which can be further metabolized to homogentisic acid.

Further reading on Catecholamine turnover
TAT is a homodimer, where loss-of-function mutations are associated with type II tyrosinemia.
TH is a homotetramer, which is inhibited by dopamine and other catecholamines in a physiological negative feedback pathway [139].
DBH is a homotetramer.
A protein structurally-related to DBH (MOXD1, Q6UVY6) has been described and for which a function has yet to be identified [93].

Ceramide turnover
Enzymes → Ceramide turnover Overview: Ceramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates 3-ketosphinganine, which is reduced to dihydrosphingosine (dihydrosphingosine). N-Acylation allows the formation of dihydroceramides, which are subsequently reduced to form ceramides. Once synthesized, ceramides are trafficked from the ER to the Golgi bound to the ceramide transfer protein, CERT (COL4A3BP, Q9Y5P4). Ceramide can be metabolized via multiple routes, ensuring tight regulation of its cellular levels. Addition of phosphocholine generates sphingomyelin while carbohydrate is added to form glucosyl-or galactosylceramides. Ceramidase re-forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates.

Ceramide synthase
Enzymes → Ceramide turnover → Ceramide synthase Overview: This family of enzymes, also known as sphingosine N-acyltransferase, is located in the ER facing the cytosol with an as-yet undefined topology and stoichiometry. Ceramide synthase in vitro is sensitive to inhibition by the fungal derived toxin, fumonisin B1.

Sphingomyelin synthase
Enzymes → Ceramide turnover → Sphingomyelin synthase Overview: 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. Comments Glycoceramides are an extended family of sphingolipids, differing in the content and organization of the sugar moieties, as well as the acyl sidechains.

Acid ceramidase
Enzymes → Ceramide turnover → Acid ceramidase Overview: The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.

Neutral ceramidases
Enzymes → Ceramide turnover → Neutral ceramidases Overview: The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.

Comments
The enzyme is associated with the plasma membrane [670].

-
Comments: ASAH2B appears to be an enzymatically inactive protein, which may result from gene duplication and truncation.

Alkaline ceramidases
Enzymes → Ceramide turnover → Alkaline ceramidases Overview: The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.

Chromatin modifying enzymes
Enzymes → Chromatin modifying enzymes Overview: Chromatin modifying enzymes, and other chromatin-modifying proteins, fall into three broad categories: writers, readers and erasers. The function of these proteins is to dynamically maintain cell identity and regulate processes such as differentiation, development, proliferation and genome integrity via recognition of specific 'marks' (covalent post-translational modifications) on histone proteins and DNA [378]. 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).
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) [378].
Writer proteins include the histone methyltransferases, histone acetyltransferases, some kinases and ubiquitin ligases.
Readers include proteins which contain methyl-lysine-recognition motifs such as bromodomains, chromodomains, tudor domains, PHD zinc fingers, PWWP domains and MBT domains.
Dysregulated epigenetic control can be associated with human diseases such as cancer [185], where a wide variety of cellular and protein abberations are known to perturb chromatin structure, gene transcription and ultimately cellular pathways [41,626]. 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 (e.g. azacitidine and decitabine target the DNA methyltransferases DNMT1 and DNMT3 for the treatment of myelodysplastic syndromes [228,730]) and erasers (e.g. the HDAC inhibitors vorinostat, romidepsin and belinostat for the treatment of T-cell lymphomas [203,361]) 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 [76]. Current progress in this field is reviewed by Simó-Riudalbas and Esteller (2015) [627].  Overview: Histone deacetylases act as erasers of epigenetic acetylation marks on lysine residues in histones. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression.
The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues: Class I contains HDACs 1, 2, 3 and 8 Class IIa contains HDACs 4, 5, 7 and 9 Class IIb contains HDACs 6 and 10 Class III contains the sirtuins (SIRT1-7) Class IV contains only HDAC11.
Classes I, II and IV use Zn + as a co-factor, whereas catalysis by Class III enzymes requires NAD + as a co-factor, and members of this subfamily have ADP-ribosylase activity in addition to protein deacetylase function [600].
Dysregulated HDAC activity has been identified in cancer cells and tumour tissues [413,586], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [732]. Several small molecule HDAC inhibitors are already approved for clinical use: romidepsin, belinostat, vorinostat, panobinostat, belinostat, valproic acid and tucidinostat. HDACs and HDAC inhibitors currently in development as potential anti-cancer therapeutics are reviewed by Simó-Riudalbas and Esteller (2015) [627].

Cyclic nucleotide turnover/signalling
Enzymes → Cyclic nucleotide turnover/signalling Overview: Cyclic nucleotides are second messengers generated by cyclase enzymes from precursor triphosphates and hydrolysed by phosphodiesterases. The cellular actions of these cyclic nucleotides are mediated through activation of protein kinases (cAMP-and cGMP-dependent protein kinases), ion channels (cyclic nucleotide-gated, CNG, and hyperpolarization and cyclic nucleotide-gated, HCN) and guanine nucleotide exchange factors (GEFs, Epac).
For details of the enzymes involved in cGMP synthesis see the Receptor Guanylyl Cyclase (RGC) family, in the Catalytic receptors section.
PDE4 isoforms are essentially cyclic AMP specific. The potency of YM976 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 [305,306]. PDE4A-D splice variants can be membrane-bound or cytosolic [311]. PDE4 isoforms may be labelled with 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 cyclic GMP specific and is activated by the α-subunit of transducin (Gα t ) and inhibited by sildenafil, zaprinast and dipyridamole with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness.

Cytochrome P450
Enzymes → Cytochrome P450 Overview: The cytochrome P450 enzyme superfamily (CYP), E.C. 1.14.-.-, are haem-containing monooxygenases with a vast range of both endogenous and exogenous substrates. These include sterols, fatty acids, eicosanoids, fat-soluble vitamins, hormones, pesticides and carcinogens as well as drugs. Listed below are the human enzymes, their relationship with rodent CYP enzyme activities is obscure in that the species orthologue may not metabolise the same substrates. Some of the CYP enzymes located in the liver are particularly important for drug metabolism, both hepatic and extrahepatic CYP enzymes also contribute to patho/physiological processes. Genetic variation of CYP isoforms is widespread and likely underlies a proportion of individual variation in drug disposition. The superfamily has the root symbol CYP, followed by a number to indicate the family, a capital letter for the subfamily with a numeral for the individual enzyme. Some CYP are able to metabolise multiple substrates, others are oligo-or mono-specific.

CYP1 family
Enzymes → Cytochrome P450 → CYP1 family Overview: CYP1 enzymes catalyse the generation of highly mutagenic compounds via activation of procarcinogens (such as polycyclic aromatic hydrocarbons and aromatic amines) that are present in combustion products. They can also deactivate many anticancer agents [463]. Comments CYP1A1 is an extra-hepatic enzyme. It shows a preference for linear planar aromatic molecules [645].
CYP1A2 is constitutively expressed in liver. It shows a preference for triangular planar aromatic molecules [645].
Mainly expressed in extra-hepatic tissues such as breast, prostate and uterus. Can metabolise 17β-estradiol into a mutagen [172], as well as leukotrienes and eicosanoids [160]. Gene variants have been associated with primary congenitial glaucoma [699].
Comments: Targeting these enzymes for inhibition is a possible cancer prevention strategy and possible therapeutic target due to over-expression of the CYP1 family in many cancers. Overview: CYP1, 2 and 3 family enzymes are involved in the biotransformation of xenobiotics, including clinically used drugs. Polymorphisms, particularly in the CYP2 family, impact upon an individual's response to drugs [772], including the risk of adverse drug reactions, drug efficacy and dose requirement.
Hydroxylates albendazole [748]. Expressed in cardiomyocytes [639]. Overview: Compared to the other CYP2 family enzymes, this subset have physiological rather than drug metabolising enzyme activities.
Appears to have cancer specific expression [528]. Potential drug target in colorectal cancer [113].

CYP3 family
Enzymes → Cytochrome P450 → CYP3 family Overview: CYP1, 2 and 3 family enzymes are involved in the biotransformation of xenobiotics, including clinically used drugs. CYP3A4 is the major enzyme involved in drug metabolism by the liver.

CYP4 family
Enzymes → Cytochrome P450 → CYP4 family Overview: CYP4 family enzymes catalyse the ω-oxidation of endogenous fatty acids and eicosanoids [176]. They have been proposed as molecular targets for the treatment of fatty acid-linked orphan diseases.
Converts 4-ipomeanol into a toxicant, and is also important in oxidation of endobiotic fatty acids and fatty alcohols [682].

DNA topoisomerases
Enzymes → DNA topoisomerases Overview: 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.  [271]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [105]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD,

Further reading on DNA topoisomerases
[628]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [513]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [17,205,638].  Comments NAPE-PLD activity appears to be enhanced by polyamines in the physiological range [420], but fails to transphosphatidylate with alcohols [542] unlike phosphatidylcholine-specific phospholipase D.
Microdeletion in a FAAH pseudogene that is expressed in dorsal root ganglia and brain (FAAH-OUT), and a functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity, have been identified in a patient with high anandamide concentrations and pain insensitivity, a discovery that points to a new mechanistic target for developing FAAH-based analgesic therapeutics [267].
The FAAH2 gene is found in many primate genomes, marsupials, and other distantly related vertebrates, but not a variety of lower placental mammals, including mouse and rat [727]. Comments ---ABHD6 has also been shown to accept diacylglycerol as a substrate, thereby producing 2-acylglycerols [697]. WWL70 has been suggested to have activity at oxidative metabolic pathways independent of ABHD6 [668].

Eicosanoid turnover
Enzymes → Eicosanoid turnover Overview: Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and its metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.

Leukotriene and lipoxin metabolism
Enzymes → Eicosanoid turnover → Leukotriene and lipoxin metabolism Overview: Leukotriene A 4 (LTA 4 ), produced by 5-LOX activity, and lipoxins may be subject to further oxidative metabolism; ω-hydroxylation is mediated by CYP4F2 and CYP4F3, while β-oxidation in mitochondria and peroxisomes proceeds in a manner dependent on coenzyme A conjugation. Conjugation of LTA 4 at the 6 position with reduced glutathione to generate LTC 4 occurs under the influence of leukotriene C 4 synthase, with the subsequent formation of LTD 4 and LTE 4 , all three of which are agonists at CysLT receptors. LTD 4 formation is catalysed by γ-glutamyltransferase, and subsequently dipeptidase 2 removes the terminal glycine from LTD 4 to generate LTE 4 . Leukotriene A 4 hydrolase converts the 5,6-epoxide LTA 4 to the 5-hydroxylated LTB 4 , an agonist for BLT receptors. LTA 4 is also acted upon by 12S-LOX to produce the trihydroxyeicosatetraenoic acids lipoxins LXA 4 and LXB 4 . Treatment with a LTA 4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA 4 levels, in addition to reducing LTB 4 , in lung lavage fluid [568]. LTA 4 hydrolase is also involved in biosynthesis of resolvin Es. Aspirin has been reported to increase endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a resolvin precursor. Both enantiomers may be metabolised by human recombinant 5-LOX; recombinant LTA 4 hydrolase converted chiral 5S(6)-epoxide-containing intermediates to resolvin E1 and 18S-resolvin E1 [514].

Nomenclature
Leukotriene C4 synthase γ-Glutamyltransferase Comments: LTA4H is a member of a family of arginyl aminopeptidases (ENSFM00250000001675), which also includes aminopeptidase B (RNPEP, 9H4A4) and aminopeptidase B-like 1 (RNPEPL1, Q9HAU8). Dipeptidase 1 and 2 are members of a family of membrane dipeptidases, which also includes (DPEP3, Q9H4B8) for which LTD 4 appears not to be a substrate.

GABA turnover
Enzymes → GABA turnover

Glycerophospholipid turnover
Enzymes → Glycerophospholipid turnover Overview: Phospholipids are the basic barrier components of membranes in eukaryotic cells divided into glycerophospholipids (phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol and its phosphorylated derivatives) and sphingolipids (ceramide phosphorylcholine and ceramide phosphorylethanolamine). Ca 2+ ions are required for catalytic activity of PLC isoforms and have been suggested to be the major physiological form of regulation of PLC-δ activity. PLC has been suggested to be activated non-selectively by the small molecule m3M3FBS [34], although this mechanism of action has been questioned [384]. The aminosteroid U73122 has been described as an inhibitor of phosphoinositide-specific PLC [635], although its selectivity among the isoforms is untested and it has been reported to occupy the H 1 histamine receptor [318].    Comments: The sequence of PLA 2 -2C suggests a lack of catalytic activity, while PLA 2 -12B (GXIIB, GXIII sPLA 2 -like) appears to be catalytically inactive [590]. A further fragment has been identified with sequence similarities to Group II PLA 2 members.
A binding protein for secretory phospholipase A 2 has been identified which shows modest selectivity for sPLA 2 -1B over sPLA 2 -2A, and also binds snake toxin phospholipase A 2 [20].
The binding protein appears to have clearance function for circulating secretory phospholipase A 2 , as well as signalling functions, and is a candidate antigen for idiopathic membraneous nephropathy [44].

Lipid phosphate phosphatases
Enzymes → Glycerophospholipid turnover → Lipid phosphate phosphatases Overview: 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 (BZS, MHAM, MMAC1, PTEN1, TEP1) 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.

Overview:
Phosphatidylinositol may be phosphorylated at either 3-or 4positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively. Phosphatidylinositol 3-kinases Phosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP 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 ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases.

Further reading on Phosphatidylinositol kinases
Goncalves MD et al.

) [707] -Rat
Comments: The existence of a third non-catalytic version of haem oxygenase, HO3, has been proposed, although this has been suggested to be a pseudogene [293]. The chemical tin protoporphyrin IX acts as a haem oxygenase inhibitor in rat liver with an IC 50 value of 11 nM [167].

Hydrogen sulphide synthesis
Enzymes → Hydrogen sulphide synthesis Overview: 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 (H 2 S) and the enzymatic characteristics are described accordingly.
Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H 2 S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H 2 S levels, see Szabo and Papapetropoulos, 2017 [661].

Enzymes → Hydrolases
Overview: 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 (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. Information on members of this family may be found in the online database.

Comments:
In vitro analysis suggested IP 3 and IP 4 were poor substrates for SKIP, synaptojanin 1 and synaptojanin 2, but suggested that PIP 2 and PIP 3 were more efficiently hydrolysed [602].

Nomenclature
Kinases (EC 2.7. x.x) Enzymes → Kinases (EC 2.7. x.x) Overview: Protein kinases (E.C. 2.7.11.-) use the co-substrate ATP 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 [447]. 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.
Most inhibitors of these enzymes have been assessed in cell-free investigations and so may appear to 'lose' potency and selectivity in intact cell assays. In particular, ambient ATP concentrations may be influential in responses to inhibitors, since the majority are directed at the ATP binding site [140].

Nomenclature
Rho associated coiled-coil containing protein kinase 1 Rho associated coiled-coil containing protein kinase 2 Systematic nomenclature ROCK1 ROCK2 Overview: Protein kinase C is the target for the tumour-promoting phorbol esters, such as tetradecanoyl-β-phorbol acetate (TPA, also known as phorbol 12-myristate 13-acetate). Subfamilies of protein kinase C are identified on the basis of sequence similarities, although functional division groups classical protein kinase C isoforms (PKCα, PKCβ, and PKCγ) activated by Ca 2+ and diacylglycerol, novel protein kinase C isoforms (PKCδ, PKCε, PKCη, and PKCθ) activated by diacylglycerol and atypical protein kinase C isoforms (PKCι and PKCζ) are useful.

Nomenclature
protein kinase C beta protein kinase C gamma

FRAP subfamily
Enzymes → Kinases (EC 2.7.x.x) → Atypical → Phosphatidyl inositol 3' kinase-related kinases (PIKK) family → FRAP subfamily Overview: The protein product of the MTOR gene (previously been known as FK506-binding protein 12-rapamycin-associated protein 1; FRAP1) is the only member of this kinase subfamily. mTOR is the key enzymatic component of the TORC1 and TORC2 protein complexes. It can act as a Ser/Thr kinase (in both complexes) or a Tyr kinase (in TORC2). The clinically used drugs temsirolimus and everolimus inhibit mTOR kinase activity.  Cyclin-dependent kinase (CDK) family

Further reading on FRAP subfamily
Enzymes → Kinases (EC 2.7. x.x) → CMGC: Containing CDK, MAPK, GSK3, CLK families → Cyclin-dependent kinase (CDK) family Overview: Five of the cyclin-dependent kinases (CDKs: 7, 8, 9, 12, and 13) 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.

CDK4 subfamily
Enzymes → Kinases (EC 2.7.x.x) → CMGC: Containing CDK, MAPK, GSK3, CLK families → Cyclin-dependent kinase (CDK) family → CDK4 subfamily Overview: CDK4 and CDK6 are Ser/Thr protein kinases that are components of protein complexes that regulate progression through the G1 phase of the cell cycle. These kinases are important integrators of mitogenic and antimitogenic signals, and are oncology drug targets. CDK4/6 inhibitors are in clinical use (e.g. abemaciclib, ribociclib and palbociclib). , 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 cyclin-dependent kinase inhibitor database (CDKiDB).

GSK subfamily
Enzymes → Kinases (EC 2.7. x.x) → CMGC: Containing CDK, MAPK, GSK3, CLK families → Glycogen synthase kinase (GSK) family → GSK subfamily Overview: GSK3A and GSK3B are protein Ser/Thr kinases that are involved in the regulation of glycogen synthesis. GSK3B (GSK-3β) has been associated with the pathogenesis and progression of diseases including obesity, diabetes, cancer and Alzheimer's, and as a result pharmacological inhibition of this enzyme is an attractive therapeutic mechanism.

Further reading on GSK subfamily
Beurel E et al.  Comments Due to its Tau phosphorylating activity, small molecule inhibitors of GSK-3β are being investigated as potential treatments for Alzheimer's disease (AD) [47]. GSK-3β also plays a role in canonical Wnt pathway signalling, the normal activity of which is crucial for the maintenance of normal bone mass. It is hypothesised that small molecule inhibitors of GSK-3β may provide effective therapeutics for the treatment of diseases characterised by low bone mass [451].

Polo-like kinase (PLK) family
Enzymes → Kinases (EC 2.7. x.x) → Other protein kinases → Polo-like kinase (PLK) family Overview: The Polo-like kinases (PLK) are Ser/Thr kinases of the cell cycle that are involved in regulating mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis [40,595]. PLK inhibitors are predicted to offer anti-proliferative potential for application in oncology [607,779].

Abl family
Enzymes → Kinases (EC 2.7.x.x) → TK: Tyrosine kinase → Non-receptor tyrosine kinases (nRTKs) → Abl family Overview: ABL1 is a tyrosine kinase. Deletion of the kinase's inhibitory SH3 domain converts it into an oncogene. A fusion protein caused by a gene translocation, t(9;22), that generates a BCR-ABL fusion is present in many cases of chronic myelogenous leukemia (CML). The clinically approved drug imatinib, was the first kinase inhibitor to target ABL1 activity to treat CML.

Comments -
The JAK2 V617F mutation, which causes constitutive activation, plays an oncogenic role in the pathogenesis of the myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis [79,145]. Small molecule compounds which inhibit aberrant JAK2 activity are being developed as novel anti-cancer pharmaceuticals. --

Src family
Enzymes → Kinases (EC 2.7. x.x) → TK: Tyrosine kinase → Non-receptor tyrosine kinases (nRTKs) → Src family Overview: Activation of Src-family kinases leads to both stimulatory and inhibitory signaling responses, with cell-specific and signaling pathway-specific outcomes and redundancy of kinase function.

Immune system:
In immune cells Src kinases are involved in many signalling pathways, including ITAM-and ITIM-domain-containing receptor signaling, integrin signaling, and responses to chemokines/chemoattractants, cytokines, innate immune stimuli and a large variety of non-immune cell specific stimuli (UV irradiation, heat, osmotic shock etc.). In many cases Src kinases signal to MAP kinase or NF-κB pathways, but they can also modulate other pathways through less well characterized mechanisms.

RAF family
Enzymes → Kinases (EC 2.7.x.x) → TKL: Tyrosine kinase-like → RAF family Overview: The RAF (acronym for rapidly accelerated fibrosarcoma) kinases are a family of related Ser/Thr kinases that are important for normal cellular and physiological processes, but are also associated with oncogenesis [400]. They are components of the Ras-Raf-MAPK signalling pathway.

Enzymes → Lanosterol biosynthesis pathway
Overview: Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of acetoacetyl CoA and the mitochondrial generation of (S)-3-hydroxy-3-methylglutaryl-CoA) are also associated with oxidation of fatty acids.  Comments: TYMS allows the interconversion of dUMP and dTMP, thereby acting as a crucial step in DNA synthesis. PNP allows separation of a nucleoside into the nucleobase and ribose phosphate for nucleotide salvage. XDH generates urate in the purine degradation pathway. Post-translational modifications of XDH convert the enzymatic reaction to a xanthine oxidase, allowing the interconversion of hypoxanthine and xanthine, with the production (or consumption) of reactive oxygen species.

Paraoxonase (PON) family
Enzymes → Paraoxonase (PON) family Overview: Paraoxonases (PON) are calcium-dependent esterases, which may be involved in lipoprotein turnover and the conversion of lactone statin prodrugs, as well as being targets of organophosphates, such as the insecticide paraoxon.   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 (mostly small-molecules) directed against them. For those interested in detailed background we recommend the MEROPS database [570] (with whom we collaborate) as an information resource [571].

Blood coagulation components
Enzymes → Peptidases and proteinases → Blood coagulation components Overview: Coagulation as a process is interpreted as a mechanism for reducing excessive blood loss through the generation of a gel-like clot local to the site of injury. The process involves the activation, adhesion (see Integrins), degranulation and aggregation of platelets, as well as proteins circulating in the plasma. The coagulation cascade involves multiple proteins being converted to more active forms from less active precursors (for example, prothrombin [Factor II] is converted to thrombin

A22: Presenilin
Enzymes → Peptidases and proteinases → AD: Aspartic (A) Peptidases → A22: Presenilin Overview: 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) [352] in the generation of amyloid beta (Aβ) [12,665]. 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 [ -) which derive their name from Cysteine ASPartate-specific proteASES, include at least two families; initiator caspases (caspases 2, 8, 9 and 10), which are able to hydrolyse and activate a second family of effector caspases (caspases 3, 6 and 7), which themselves are able to hydrolyse further cellular proteins to bring about programmed cell death. Caspases are heterotetrameric, being made up of two pairs of subunits, generated by a single gene product, which is proteolysed to form the mature protein. Members of the mammalian inhibitors of apoptosis proteins (IAP) are able to bind the procaspases, thereby preventing maturation to active proteinases.
Information on members of this family may be found in the online database.   ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell-surface or transmembrane proteins to generate soluble and membrane-limited products.
Information on members of this family may be found in the online database.

Comments
Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N-acetaspartylglutamate to form N-acetylaspartate and L-glutamate (L-glutamic acid). 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 capromab has been used for imaging purposes.
Comments: 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 capromab has been used for imaging purposes.

S8: Subtilisin
Enzymes → Peptidases and proteinases → SB: Serine (S) Peptidases → S8: Subtilisin Overview: 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 [427,593,651]. Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry.
Information on members of this family may be found in the online database. Comments PIN1 isomerises phosphorylated serine/threonine-proline bonds. It plays roles in cell cycle control, neuropathologies and the immune system [183].

S9: Prolyl oligopeptidase
-Cyclosporin A (CsA) is the prototypical cyclophilin D (CyPD) inhibitor, but it also inhibits cyclophilin A and the calcineurin pathway, an effect that has long been used for immunosuppression in humans [552].

Poly ADP-ribose polymerases
Enzymes → Poly ADP-ribose polymerases Overview: The Poly ADP-ribose polymerase family is a series of enzymes, where the best characterised members are nuclear proteins which are thought to function by binding to single strand breaks in DNA, allowing the recruitment of repair enzymes by the synthesis of NAD-derived ADP-ribose polymers, which are subsequently degraded by a glycohydrolase (PARG, Q86W56). The most well defined function of the tankyrases (TNKSs) is their regulatory action on Wnt/β-catenin signalling [449].

Prolyl hydroxylases
Enzymes → Prolyl hydroxylases Overview: Hypoxia-inducible factors (HIFs) are rapidly-responding sensors of reductions in local oxygen tensions, prompting changes in gene transcription. Listed here are the 4-prolyl hydroxylase family, members of which have been identified to hydroxylate proline residues in HIF1α (HIF1A; Q16665) leading to an increased degradation through proteasomal hydrolysis. This action requires molecular oxygen and 2-oxoglutarate, and so reduced oxygen tensions prevents HIF1α hydroxylation, allowing its translocation to the nucleus and dimerisation with HIF1β (also known as ARNT; P27540), thereby allowing interaction with the genome as a transcription factor.  Sphingosine 1-phosphate turnover

Further reading on Prolyl hydroxylases
Enzymes → Sphingosine 1-phosphate turnover Overview: S1P (sphingosine 1-phosphate) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC 2.7.1.91). It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC 4.1.2.27). Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery.

Sphingosine kinase
Enzymes → Sphingosine 1-phosphate turnover → Sphingosine kinase Overview: SPHK1 and SPHK2 are encoded by different genes with some redundancy of function; genetic deletion of both Sphk1 and Sphk2, but not either alone, is embryonic lethal in mice. There are splice variants of each isoform (SphK1a-c and SphK2a, b), distinguished by their N-terminal sequences. SPHK1 and SPHK2 differ in tissue distribution, sub-cellular localisation, biochemical properties and regulation. They regulate discrete pools of S1P. Receptor stimulation induces SPHK1 translocation from the cytoplasm to the plasma membrane. SPHK1 translocation is regulated by phosphorylation/dephosphorylation, specific protein:protein interactions and interaction with specific lipids at the plasma membrane. SPHK1 is a dimeric protein, as confirmed by its crystal structure which forms a positive cluster, between protomers, essential for interaction with anionic phospholipids in the plasma membrane. SPHK2 is localised to the ER or associated with mitochondria or shuttles in/out of the nucleus, regulated by phosphorylation. Intracellular targets of nuclear S1P include the catalytic subunit of telomerase (TERT) and regulators of gene expression including histone deacetylases (HDAC 1/2) and peroxisome proliferator-activated receptor gamma (PPARγ). SPHK2 phosphorylates the pro-drug FTY720 (fingolimod, which is used to treat some forms of multiple sclerosis) to a mimic of S1P and that acts as a functional antagonist of S1P 1 receptors. Inhibitors of SPHK1 and SPHK2 have therapeutic potential in many diseases. Isoform-selective inhibitors are becoming available; some early inhibitors have recognised off-target effects.  [6], SLC4101431 (pK i 7.1) [106], compound 27d (pIC 50 6.8) [605], opaganib (pK i 5) [207], ROMe (pK i 4.8) [412] Comments SPHK1 inhibitors induce its proteasomal degradation [432,465]. SPHK1 crystal structures confirm that it is dimeric [5]; there is no crystal structure available for SPHK2.
There is no crystal structure available for SPHK2.

Thyroid hormone turnover
Enzymes → Thyroid hormone turnover

Overview:
The thyroid hormones triiodothyronine and thyroxine, usually abbreviated as triiodothyronine and T 4 , respectively, are synthesized in the thyroid gland by sequential metabolism of tyrosine residues in the glycosylated homodimeric protein thyroglobulin (TG, P01266) 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 (EPX, P11678), lactoperoxidase (LPO, P22079) and myeloperoxidase (MPO, P05164). Circulating thyroid hormone is bound to thyroxine-binding globulin (SERPINA7, P05543).

Small monomeric GTPases
Overview: 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.

RAS subfamily
Enzymes → 3.6.5.2 Small monomeric GTPases → RAS subfamily Overview: The RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules 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.
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 [648], which leads to increased cell proliferation and decreased apoptosis [776]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [38]. Information on members of this family may be found in the online database.

RAB subfamily
Enzymes → 3.6.5.2 Small monomeric GTPases → RAB subfamily Overview: 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 HGNC RAB, 65 genes ).
Information on members of this family may be found in the online database.