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THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes

Stephen PH Alexander, Doriano Fabbro, Eamonn Kelly and 9 more

British Journal of Pharmacology · 2017

Abstract

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands ( www.guidetopharmacology.org ), which provides more detailed views of target and ligand properties. 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.13877/full . Enzymes are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other 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‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Conflict of interest

1The authors state that there are no conflicts of interest to declare.

Overview

2Enzymes are protein catalysts facilitating the conversion of substrates into products. 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:

3EC 1.‐.‐.‐ Oxidoreductases;

4EC 2.‐.‐.‐ Transferases;

5EC 3.‐.‐.‐ Hydrolases;

6EC 4.‐.‐.‐ Lyases;

7EC 5.‐.‐.‐ Isomerases;

8EC 6.‐.‐.‐ Ligases.

9Although 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 [392, 430], which is not to say that they are of modest importance.

10The majority of drugs which act on enzymes act as inhibitors; one exception is metformin, which appears to stimulate activity of AMP‐activated protein kinase, albeit through an imprecisely‐defined mechanism. 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.

11Many 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.

Family structure

12S275 Kinases (EC 2.7.x.x)

13– AGC: Containing PKA, PKG, PKC families

14– DMPK family

15– GEK subfamily

16– Other DMPK family kinases

17S276 Rho kinase

18– G protein‐coupled receptor kinases (GRKs)

19– Beta‐adrenergic receptor kinases (βARKs)

20– Opsin/rhodopsin kinases

21– GRK4 subfamily

22– MAST family

23– NDR family

24– PDK1 family

25– Protein kinase A

26– Akt (Protein kinase B)

27S276 Protein kinase C (PKC)

28S277 Alpha subfamily

29S277 Delta subfamily

30S277 Eta subfamily

31– Iota subfamily

32– Protein kinase G (PKG)

33– Protein kinase N (PKN) family

34– RSK family

35– MSK subfamily

36– p70 subfamily

37– RSK subfamily

38– RSKR subfamily

39– RSKL family

40– SGK family

41– YANK family

42– Atypical

43– ABC1 family

44– ABC1‐A subfamily

45– ABC1‐B subfamily

46– Alpha kinase family

47– ChaK subfamily

48– eEF2K subfamily

49– Other alpha kinase family kinases

50– BCR family

51– Bromodomain kinase (BRDK) family

52– G11 family

53– Phosphatidyl inositol 3' kinase‐related kinases (PIKK) family

54– ATR subfamily

55S278 FRAP subfamily

56– SMG1 subfamily

57– TRRAP subfamily

58– Other PIKK family kinases

59– RIO family

60– RIO1 subfamily

61– RIO2 subfamily

62– RIO3 subfamily

63– PDHK family

64– Pyruvate dehydrogenase kinase (PDHK) family

65– TAF1 family

66– TIF1 family

67– CAMK: Calcium/calmodulin‐dependent protein kinases

68– CAMK1 family

69– CAMK2 family

70– CAMK‐like (CAMKL) family

71– AMPK subfamily

72– BRSK subfamily

73– CHK1 subfamily

74– HUNK subfamily

75– LKB subfamily

76– MARK subfamily

77– MELK subfamily

78– NIM1 subfamily

79– NuaK subfamily

80– PASK subfamily

81– QIK subfamily

82– SNRK subfamily

83– CAMK‐unique family

84– CASK family

85– DCAMKL family

86– Death‐associated kinase (DAPK) family

87– MAPK‐Activated Protein Kinase (MAPKAPK) family

88– MAPKAPK subfamily

89– MKN subfamily

90– Myosin Light Chain Kinase (MLCK) family

91– Phosphorylase kinase (PHK) family

92– PIM family

93– Protein kinase D (PKD) family

94– PSK family

95– RAD53 family

96– Testis specific kinase (TSSK) family

97– Trbl family

98– Trio family

99– CK1: Casein kinase 1

100– Casein kinase 1 (CK1) family

101– Tau tubulin kinase (TTBK) family

102– Vaccina related kinase (VRK) family

103– CMGC: Containing CDK, MAPK, GSK3, CLK families

104– CLK family

105S279 Cyclin‐dependent kinase (CDK) family

106– CCRK subfamily

107– CDK1 subfamily

108S279 CDK4 subfamily

109– CDK5 subfamily

110– CDK7 subfamily

111– CDK8 subfamily

112– CDK9 subfamily

113– CDK10 subfamily

114– CRK7 subfamily

115– PITSLRE subfamily

116– TAIRE subfamily

117– Cyclin‐dependent kinase‐like (CDKL) family

118– Dual‐specificity tyrosine‐(Y)‐phosphorylation regulated kinase (DYRK) family

119– Dyrk1 subfamily

120– Dyrk2 subfamily

121– HIPK subfamily

122– PRP4 subfamily

123– Glycogen synthase kinase (GSK) family

124S279 GSK subfamily

125– Mitogen‐activated protein kinases (MAP kinases)

126– ERK subfamily

127– Erk7 subfamily

128– JNK subfamily

129– p38 subfamily

130– nmo subfamily

131– RCK family

132– SRPK family

133– Other protein kinases

134– CAMKK family

135– Meta subfamily

136– Aurora kinase (Aur) family

137– Bub family

138– Bud32 family

139– Casein kinase 2 (CK2) family

140– CDC7 family

141– Haspin family

142– IKK family

143– IRE family

144– MOS family

145– NAK family

146– NIMA (never in mitosis gene a)

147‐ related kinase (NEK) family

148– NKF1 family

149– NKF2 family

150– NKF4 family

151– NKF5 family

152– NRBP family

153– Numb‐associated kinase (NAK) family

154– Other‐unique family

155S280 Polo‐like kinase (PLK) family

156– PEK family

157– GCN2 subfamily

158– PEK subfamily

159– Other PEK family kinases

160– SgK493 family

161– Slob family

162– TBCK family

163– TOPK family

164– Tousled‐like kinase (TLK) family

165– TTK family

166– Unc‐51‐like kinase (ULK) family

167– VPS15 family

168– WEE family

169– Wnk family

170– Miscellaneous protein kinases

171– actin‐binding proteins ADF family

172– Twinfilin subfamily

173– SCY1 family

174– Hexokinases

175– STE: Homologs of yeast Sterile 7, Sterile 11, Sterile 20 kinases

176S280 STE7 family

177– STE11 family

178– STE20 family

179– FRAY subfamily

180– KHS subfamily

181– MSN subfamily

182– MST subfamily

183– NinaC subfamily

184– PAKA subfamily

185– PAKB subfamily

186– SLK subfamily

187– STLK subfamily

188– TAO subfamily

189– YSK subfamily

190– STE20 family

191– STE‐unique family

192– TK: Tyrosine kinase

193– Non‐receptor tyrosine kinases (nRTKs)

194S281 Abl family

195S281 Ack family

196– Csk family

197– Fak family

198– Fer family

199S281 Janus kinase (JakA) family

200S282 Src family

201– Syk family

202S282 Tec family

203– TKL: Tyrosine kinase‐like

204– Interleukin‐1 receptor‐associated kinase (IRAK) family

205– Leucine‐rich repeat kinase (LRRK) family

206– LIM domain kinase (LISK) family

207– LIMK subfamily

208– TESK subfamily

209– Mixed Lineage Kinase (MLK) family

210– HH498 subfamily

211– ILK subfamily

212– LZK subfamily

213– MLK subfamily

214– TAK1 subfamily

215S283 RAF family

216– Receptor interacting protein kinase (RIPK) family

217– TKL‐unique family

218S284 Peptidases and proteinases

219– AA: Aspartic (A) Peptidases

220S284 A1: Pepsin

221– AD: Aspartic (A) Peptidases

222S284 A22: Presenilin

223– CA: Cysteine (C) Peptidases

224– C1: Papain

225– C2: Calpain

226– C12: Ubiquitin C‐terminal hydrolase

227– C19: Ubiquitin‐specific protease

228– C54: Aut2 peptidase

229– C101: OTULIN peptidase

230– CD: Cysteine (C) Peptidases

231– C13: Legumain

232S284 C14: Caspase

233– CE: Cysteine (C) Peptidases

234– C48: Ulp1 endopeptidase

235– M‐: Metallo (M) Peptidases

236– M79: Prenyl protease 2

237– MA: Metallo (M) Peptidases

238S285 M1: Aminopeptidase N

239S285 M2: Angiotensin‐converting (ACE and ACE2)

240S286 M10: Matrix metallopeptidase

241S286 M12: Astacin/Adamalysin

242– M13: Neprilysin

243– M49: Dipeptidyl‐peptidase III

244– MC: Metallo (M) Peptidases

245– M14: Carboxypeptidase A

246– ME: Metallo (M) Peptidases

247– M16: Pitrilysin

248– MF: Metallo (M) Peptidases

249– M17: Leucyl aminopeptidase

250– MG: Metallo (M) Peptidases

251– M24: Methionyl aminopeptidase

252– MH: Metallo (M) Peptidases

253– M18: Aminopeptidase I

254– M20: Carnosine dipeptidase

255S286 M28: Aminopeptidase Y

256– MJ: Metallo (M) Peptidases

257S287 M19: Membrane dipeptidase

258– MP: Metallo (M) Peptidases

259– M67: PSMD14 peptidase

260– PA: Serine (S) Peptidases

261S287 S1: Chymotrypsin

262– PB: Threonine (T) Peptidases

263– C44: Phosphoribosyl pyrophosphate amidotransferase

264S288 T1: Proteasome

265– T2: Glycosylasparaginase precursor

266– PC: Cysteine (C) Peptidases

267– C26: Gamma‐glutamyl hydrolase

268– SB: Serine (S) Peptidases

269S289 S8: Subtilisin

270– SC: Serine (S) Peptidases

271S289 S9: Prolyl oligopeptidase

272– S10: Carboxypeptidase Y

273– S28: Lysosomal Pro‐Xaa carboxypeptidase

274– S33: Prolyl aminopeptidase

275– AAA ATPases

276S290 Acetylcholine turnover

277S291 Adenosine turnover

278S292 Amino acid hydroxylases

279S293 L‐Arginine turnover

280S294 2.1.1.‐ Protein arginine N‐methyltransferases

281S294 Arginase

282S294 Arginine:glycine amidinotransferase

283S294 Dimethylarginine dimethylaminohydrolases

284S295 Nitric oxide synthases

285S296 Carboxylases and decarboxylases

286S296 Carboxylases

287S298 Decarboxylases

288S299 Catecholamine turnover

289S302 Ceramide turnover

290S302 Serine palmitoyltransferase

291– 3‐ketodihydrosphingosine reductase

292S303 Ceramide synthase

293S304 Sphingolipid Δ4‐desaturase

294S304 Sphingomyelin synthase

295S305 Sphingomyelin phosphodiesterase

296S305 Neutral sphingomyelinase coupling factors

297S305 Ceramide glucosyltransferase

298S306 Acid ceramidase

299S306 Neutral ceramidases

300S307 Alkaline ceramidases

301S307 Ceramide kinase

302S308 Chromatin modifying enzymes

303– Enzymatic bromodomain‐containing proteins

304– Bromodomain kinase (BRDK) family

305– TAF1 family

306– TIF1 family

307– 1.14.11.‐ Histone demethylases

308S309 2.1.1.‐ Protein arginine N‐methyltransferases

309– 2.1.1.43 Histone methyltransferases (HMTs)

310– 2.3.1.48 Histone acetyltransferases (HATs)

311S309 3.5.1.‐ Histone deacetylases (HDACs)

312– 3.6.1.3 ATPases

313S310 Cyclic nucleotide turnover/signalling

314S310 Adenylyl cyclases (ACs)

315S311 Exchange protein activated by cyclic AMP (EPACs)

316S312 Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase

317S313 Phosphodiesterases, 3Š,5Š‐cyclic nucleotide (PDEs)

318S317 Cytochrome P450

319S317 CYP1 family

320S317 CYP2 family

321S318 CYP3 family

322S319 CYP4 family

323S320 CYP5, CYP7 and CYP8 families

324S320 CYP11, CYP17, CYP19, CYP20 and CYP21 families

325S321 CYP24, CYP26 and CYP27 families

326S321 CYP39, CYP46 and CYP51 families

327S323 Endocannabinoid turnover

328S323 N‐Acylethanolamine turnover

329S324 2‐Acylglycerol ester turnover

330S325 Eicosanoid turnover

331S325 Cyclooxygenase

332S326 Prostaglandin synthases

333S327 Lipoxygenases

334S328 Leukotriene and lipoxin metabolism

335S329 GABA turnover

336S330 Glycerophospholipid turnover

337S331 Phosphoinositide‐specific phospholipase C

338S332 Phospholipase A2

339S333 Phosphatidylcholine‐specific phospholipase D

340S334 Lipid phosphate phosphatases

341S335 Phosphatidylinositol kinases

342S336 Phosphatidylinositol phosphate kinases

343S339 Haem oxygenase

344S340 Hydrogen sulphide synthesis

345S341 Hydrolases

346S342 Inositol phosphate turnover

347S342 Inositol 1,4,5‐trisphosphate 3‐kinases

348S343 Inositol polyphosphate phosphatases

349S343 Inositol monophosphatase

350S344 Lanosterol biosynthesis pathway

351– LPA synthesis

352S346 Nucleoside synthesis and metabolism

353S347 Sphingosine 1‐phosphate turnover

354S348 Sphingosine kinase

355S348 Sphingosine 1‐phosphate phosphatase

356S349 Sphingosine 1‐phosphate lyase

357S349 Thyroid hormone turnover

358– 1.‐.‐.‐ Oxidoreductases

359– 1.1.1.42 Isocitrate dehydrogenases

360– 1.4.3.13 Lysyl oxidases

361– 1.13.11.‐ Dioxygenases

362S350 1.14.11.29 2‐oxoglutarate oxygenases

363S351 1.14.13.9 kynurenine 3‐monooxygenase

364– 1.17.4.1 Ribonucleoside‐diphosphate reductases

365– 2.1.1.‐ Methyltransferases

366– 2.1.2.‐ Hydroxymethyl‐, formyl‐ and related transferases

367– 2.3.‐.‐ Acyltransferases

368– 2.4.2.1 Purine‐nucleoside phosphorylase

369S351 2.4.2.30 poly(ADP‐ribose)polymerases

370S352 2.5.1.58 Protein farnesyltransferase

371– 2.6.1.42 Branched‐chain‐amino‐acid transaminase

372– 3.1.‐.‐ Ester bond enzymes

373– 3.1.1.‐ Carboxylic Ester Hydrolases

374– 3.2.1.‐ Glycosidases

375– 3.4.21.46 Complement factor D

376S353 3.5.1.‐ Histone deacetylases (HDACs)

377– 3.5.1.2 Glutaminases

378S353 3.5.3.15 Peptidyl arginine deiminases (PADI)

379– 3.6.5.2 Small monomeric GTPases

380S354 RAS subfamily

381– RAB subfamily

382S355 4.2.1.1 Carbonate dehydratases

383– 5.‐.‐.‐ Isomerases

384– 5.2.‐.‐ Cis‐trans‐isomerases

385S355 5.99.1.2 DNA Topoisomerases

386– 6.3.3.‐ Cyclo‐ligases

Overview

387Protein 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 [335]. 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.

388Most 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 [110].

389Rho kinase (also known as P160ROCK, Rho‐activated kinase) is activated by members of the Rho small G protein family, which are activated by GTP exchange factors, such as ARHGEF1(Q92888, p115‐RhoGEF), which in turn may be activated by Gα 12/13 subunits [282].

Overview

393Protein 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).

394Classical protein kinase C isoforms: PKCα, PKCβ, and PKCγ are activated by Ca2+ and diacylglycerol, and may be inhibited by GF109203X, calphostin C, Gö 6983, chelerythrine and Ro31‐8220.

395Novel protein kinase C isoforms: PKCδ, PKCϵ, PKCη, PKCθ and PKCμ are activated by diacylglycerol and may be inhibited by calphostin C, Gö 6983 and chelerythrine.

396Atypical protein kinase C isoforms:PKCι, PKCζ.

Overview

402The development of CDK inhibitors as anticancer drugs is reviewed in [508], with detailed content covering CDK4 and CDK6 inhibitors under clinical evaluation.

Overview

413Peptidases and proteinases hydrolyse peptide bonds, and can be simply divided on the basis of whether terminal peptide bonds are cleaved (exopeptidases and exoproteinases) at the amino terminus (aminopeptidases) or carboxy terminus (carboxypeptidases). Non‐terminal peptide bonds are cleaved by endopeptidases and endoproteinases, which are divided into serine endopeptidases (EC 3.4.21.‐), cysteine endopeptidases (EC 3.4.22.‐), aspartate endopeptidases (EC 3.4.23.‐), metalloendopeptidases (EC 3.4.24.‐) and threonine endopeptidases (EC 3.4.25.‐).

414Since 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 [450] (with whom we collaborate) as an information resource [432].

415Presenilin (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) [260] in the generation of amyloid beta (Aβ) [7, 510]. 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 [187]. 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 (total Aβ, Aβ40 and Aβ42) both in vitro and when infused in to the brains of APP transgenic mice [119]. The most active small peptides in this report were P4 and P8, from the amino‐terminal domain of PS‐1.

416Information on members of this family may be found in the online database.

417Caspases, (E.C. 3.4.22.‐) 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.

418Information on members of this family may be found in the online database.

Comments

419CARD16 (Caspase recruitment domain‐containing protein 16, caspase‐1 inhibitor COP, CARD only domain‐containing protein 1, pseudo interleukin‐1β converting enzyme, pseudo‐ICE, ENSG00000204397) shares sequence similarity with some of the caspases.

Overview

420Aminopeptidases catalyze the cleavage of amino acids from the amino (N) terminus of protein or peptide substrates, and are involved in many essential cellular functions. Members of this enzyme family may be monomeric or multi‐subunit complexes, and many are zinc metalloenzymes [522].

421Information on members of this family may be found in the online database.

422Matrix metalloproteinases (MMP) are calcium‐ and zinc‐dependent proteinases regulating the extracellular matrix and are often divided (e.g. [545]) on functional and structural bases into gelatinases, collagenases, stromyelinases and matrilysins, as well as membrane type‐MMP (MT‐MMP).

Comments

423A number of small molecule ‘broad spectrum’ inhibitors of MMP have been described, including marimastat and batimastat.

424Tissue inhibitors of metalloproteinase (TIMP) proteins are endogenous inhibitors acting to chelate MMP proteins: TIMP1(TIMP1, P01033), TIMP2(TIMP2, P16035), TIMP3(TIMP3, P35625), TIMP4(TIMP4, Q99727)

Overview

425ADAM (A Disintegrin And Metalloproteinase domain containing proteins) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.

426ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.

427Information on members of this family may be found in the online database.

Comments

428Additional ADAM family members include AC123767.2 (cDNA FLJ58962, moderately similar to mouse ADAM3, ENSG00000231168), AL160191.3 (ADAM21‐like protein, ENSG00000235812), AC136428.3‐2 (ENSG00000185520) and ADAMDEC1 (decysin 1, ENSG00000134028).

429Other ADAMTS family members include AC104758.12‐5 (FLJ00317 protein Fragment ENSG00000231463), AC139425.3‐1 (ENSG00000225577), and AC126339.6‐1 (ENSG00000225734).

430Folate 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.

Overview

431The T1 macropain beta subunits form the catalytic proteinase core of the 20S proteasome complex [93]. 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 bortezomib.

432One 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 [315, 452, 501]. Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry. Several monoclonal antibodies including alirocumab, evolocumab, bococizumab, RG‐7652 and LY3015014 are under development. One RNAi therapeutic, code named ALN‐PCS02, is also in development [106, 147, 155].

433Information on members of this family may be found in the online database.

434Acetylcholine is familiar as a neurotransmitter in the central nervous system and in the periphery. In the somatic nervous system, it activates nicotinic acetylcholine receptors at the skeletal neuromuscular junction. It is also employed in the autonomic nervous system, in both parasympathetic and sympathetic branches; in the former, at the smooth muscle neuromuscular junction, activating muscarinic acetylcholine receptors. In the latter, acetylcholine is involved as a neurotransmitter at the ganglion, activating nicotinic acetylcholine receptors. Acetylcholine is synthesised in neurones through the action of choline O‐acetyltransferase and metabolised after release through the extracellular action of acetylcholinesterase and cholinesterase. Choline is accumulated from the extracellular medium by selective transporters (see SLC5A7 and the SLC44 family). Acetylcholine is accumulated in synaptic vesicles through the action of the vesicular acetylcholine transporter SLC18A3.

Comments

435A 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 [570].

Overview

441A multifunctional, ubiquitous molecule, adenosine acts at cell‐surface G protein‐coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto‐5'‐nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co‐substrate). Intracellular adenosine may be produced by cytosolic 5'‐nucleotidases or through S‐adenosylhomocysteine hydrolase (also producing L‐homocysteine).

Comments

442An extracellular adenosine deaminase activity, termed ADA2 or adenosine deaminase growth factor (ADGF, CECR1, Q9NZK5) has been identified [101, 331], which is insensitive to EHNA[595]. Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: ADAT1(Q9BUB4) deaminates transfer RNA; ADAR(EC 3.5.4.37, also known as 136 kDa double‐stranded RNA‐binding protein, P136, K88DSRBP, Interferon‐inducible protein 4); ADARB1 (EC 3.5.‐.‐,, also known as dsRNA adenosine deaminase) and ADARB2 (EC 3.5.‐.‐, also known as dsRNA adenosine deaminase B2, RNA‐dependent adenosine deaminase 3) 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 (EC 3.4.14.5, DPP4, also known as T‐cell activation antigen CD26, TP103, adenosine deaminase complexing protein 2) to form a cell‐surface activity [259].

Overview

448The 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.

Overview

455L‐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.

456L‐Arginine in proteins may be subject to post‐translational modification through methylation, catalysed by protein arginine methyltransferases. Subsequent proteolysis can liberate asymmetric NG,NG‐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.

Overview

461Protein arginine N‐methyltransferases (PRMT, EC 2.1.1.‐) encompass histone arginine N‐methyltransferases (PRMT4, PRMT7, EC 2.1.1.125) and myelin basic protein N‐methyltransferases (PRMT7, EC 2.1.1.126). They are dimeric or 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 (NG,NG‐dimethyl‐L‐arginine) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.

462Information on members of this family may be found in the online database.

463Arginase (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.

464Information on members of this family may be found in the online database.

Comments

465Nω‐hydroxyarginine, an intermediate in NOS metabolism of L‐arginine acts as a weak inhibitor and may function as a physiological regulator of arginase activity. Although isoform‐selective inhibitors of arginase are not available, examples of inhibitors selective for arginase compared to NOS are Nω‐hydroxy‐nor‐L‐arginine[525], S‐(2‐boronoethyl)‐L‐cysteine[97, 268] and 2(S)‐amino‐6‐boronohexanoic acid [24, 97].

Overview

466Dimethylarginine dimethylaminohydrolases (DDAH, EC 3.5.3.18) are cytoplasmic enzymes which hydrolyse NG,NG‐dimethyl‐L‐arginine to form dimethylamine and L‐citrulline.

467Nitric 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 [363] 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+/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 IC50 values in the micromolar range.

Comments

468The reductase domain of NOS catalyses the reduction of cytochrome c and other redox‐active dyes [345]. NADPH:O2 oxidoreductase catalyses the formation of superoxide anion/H2O2 in the absence of L‐arginine and sapropterin.

Overview

474The carboxylases allow the production of new carbon‐carbon bonds by introducing HCO3 ‐ 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 biotin (EC 6.4.1.‐) or vitamin K hydroquinone (EC 4.1.1.‐).

Comments

475Dicarboxylic acids including citric acid 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.

Overview

476The decarboxylases generate CO2 and the indicated products from acidic substrates, requiring pyridoxal phosphate or pyruvic acid as a co‐factor.

Overview

483Catecholamines 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.

Overview

489Ceramides 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 sphinganine(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.

490The 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 [202]. 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 [202].

491This 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.

492DEGS1 and DEGS2 are 4TM proteins.

Comments

493DEGS1 activity is inhibited by a number of natural products, including curcumin and Δ9‐tetrahydrocannabinol[138].

Overview

494Following 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.

495Sphingomyelin synthase‐related protein 1 is structurally related but lacks sphingomyelin synthase activity.

496Also known as sphingomyelinase.

497Protein FAN [3] and polycomb protein EED [410] allow coupling between TNF receptors and neutral sphingomyelinase phosphodiesterases.

498The 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.

499The 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

500ASAH2B appears to be an enzymatically inactive protein, which may result from gene duplication and truncation.

Overview

501The 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

502A ceramide kinase‐like protein has been identified in the human genome (CERKL, Q49MI3).

Overview

517Chromatin 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 [280]. 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).

518To 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) [280].

519Writer proteins include the histone methyltransferases, histone acetyltransferases, some kinases and ubiquitin ligases.

520Readers include proteins which contain methyl‐lysine‐recognition motifs such as bromodomains, chromodomains, tudor domains, PHD zinc fingers, PWWP domains and MBT domains.

521Erasers include the histone demethylases and histone deacetylases (HDACs and sirtuins).

522Dysregulated epigenetic control can be associated with human diseases such as cancer [137], where a wide variety of cellular and protein abberations are known to perturb chromatin structure, gene transcription and ultimately cellular pathways [27, 477]. 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 [175, 565]) and erasers (e.g. the HDAC inhibitors vorinostat, romidepsin and belinostat for the treatment of T‐cell lymphomas [153, 265]) 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 [61]. Current progress in this field is reviewed by Simó‐Riudalbas and Esteller (2015) [478].

523Protein arginine N‐methyltransferases (PRMT, EC 2.1.1.‐) encompass histone arginine N‐methyltransferases (PRMT4, PRMT7, EC 2.1.1.125) and myelin basic protein N‐methyltransferases (PRMT7, EC 2.1.1.126). They are dimeric or 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 (NG,NG‐dimethyl‐L‐arginine) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.

524Information on members of this family may be found in the online database.

525Histone 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.

526The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:

527Class I contains HDACs 1, 2, 3 and 8

528Class IIa contains HDACs 4, 5, 7 and 9

529Class IIb contains HDACs 6 and 10

530Class III contains the sirtuins (SIRT1‐7)

531Class IV contains only HDAC11.

532Classes 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 [456].

533HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins [90] such as microtubules [233], the hsp90 chaperone [281] and the tumour suppressor p53 [322].

534Dysregulated HDAC activity has been identified in cancer cells and tumour tissues [305, 444], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [567]. 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) [478].

535Information on members of this family may be found in the online database.

536Cyclic 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).

537Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane‐bound adenylyl cyclases are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators forskolin, NKH477(except AC9, [419]) and Gα s(the stimulatory G protein α subunit). Adenosine and its derivatives (e.g. 2',5'‐dideoxyadenosine), acting through the P‐site, appear to be physiological inhibitors of adenylyl cyclase activity [527]. Three families of adenylyl cyclase are distinguishable: calmodulin(CALM1 CALM2 CALM3, P62158)‐stimulated (AC1, AC3 and AC8), Ca2+‐inhibitable (AC5, AC6 and AC9) and Ca2+‐insensitive (AC2, AC4 and AC7) forms.

Comments

538Nitric oxide has been proposed to inhibit AC5 and AC6 selectively [223], although it is unclear whether this phenomenon is of physiological significance. A soluble adenylyl cyclase has been described (ADCY10, Q96PN6 [54]), unaffected by either Gα or Gβ γ subunits, which has been suggested to be a cytoplasmic bicarbonate (pH‐insensitive) sensor [82]. It can be inhibited selectively by KH7 (pIC50 5.0‐5.5) [221].

Overview

542Epacs are members of a family of guanine nucleotide exchange factors (ENSFM00250000000899), which also includes RapGEF5(GFR, KIAA0277, MR‐GEF, Q92565) and RapGEFL1 (Link‐GEFII, Q9UHV5). They are activated endogenously by cyclic AMP and with some pharmacological selectivity by 8‐pCPT‐2'‐O‐Me‐cAMP[134]. Once activated, Epacs induce an enhanced activity of the monomeric G proteins, Rap1 and Rap2 by facilitating binding of guanosine‐5'‐triphosphate in place of guanosine 5'‐diphosphate, leading to activation of phospholipase C [459].

Overview

546Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase (GTP diphosphate‐lyase (cyclising)), E.C. 4.6.1.2, is a heterodimer comprising a β 1 subunit and one of two alpha subunits (α 1, α 2) giving rise to two functionally indistinguishable isoforms, GC‐1 (α 1 β 1) and GC‐2 (α 2 β 1) [449, 593]. A haem group is associated with the β subunit and is the target for the endogenous ligand NO, and, potentially, carbon monoxide [159]. The enzyme converts guanosine‐5'‐triphosphate to the intracellular second messenger cyclic guanosine‐3',5'‐monophosphate (cyclic GMP).

Comments

547ODQ also shows activity at other haem‐containing proteins [142], while YC‐1 may also inhibit cGMP‐hydrolysing phosphodiesterases [158, 169].

Overview

5523',5'‐Cyclic nucleotide phosphodiesterases (PDEs, 3',5'‐cyclic‐nucleotide 5'‐nucleotidohydrolase), E.C. 3.1.4.17, catalyse the hydrolysis of a 3',5'‐cyclic nucleotide (usually cyclic AMP or cyclic GMP). Isobutylmethylxanthine 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 (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

Comments

553PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane‐bound homodimer. PDE3A and PDE3B are membrane‐bound.

554PDE4 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 [224, 225]. PDE4A–D splice variants can be membrane‐bound or cytosolic [229]. PDE4 isoforms may be labelled with [3H]rolipram.

555PDE6 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.

Overview

564The 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 haem‐containing monooxygenases with a huge range of both endogenous and exogenous substrates. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologue may not mediate 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.

Comments

565Converts lauric acid to 12‐hydroxylauric acid.

Overview

576The principle endocannabinoids are 2‐acylglycerol esters, such as 2‐arachidonoylglycerol (2AG), and N‐acylethanolamines, such as anandamide(N‐arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re‐uptake of endocannabinoids (and related entities) are unclear, although candidates for intracellular transport have been suggested. For the generation of 2‐arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N‐acylphosphatidylethanolamine‐phospholipase D (NAPE‐PLD, [476]). A transacylation enzyme which forms N‐acylphosphatidylethanolamines has recently been identified as a cytosolic enzyme, PLA2G4E(Q3MJ16) [383]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [11, 154, 488].

Comments

577Routes for N‐acylethanolamine biosynthesis other than through NAPE‐PLD activity have been identified [536].

2‐Acylglycerol ester turnover

578Comments on Endocannabinoid turnover: Many of the compounds described as inhibitors are irreversible and so potency estimates will vary with incubation time. FAAH2 is not found in rodents [563] and a few of the inhibitors described have been assessed at this enzyme activity. 2‐arachidonoylglycerol has been reported to be hydrolysed by multiple enzyme activities from neural preparations, including ABHD2(P08910) [356], ABHD12(Q8N2K0) [44], neuropathy target esterase (PNPLA6, Q8IY17 [338]) and carboxylesterase 1 (CES1, P23141 [581]). ABHD2(P08910) has also been described as a triacylglycerol lipase and ester hydrolase [329], while ABHD12(Q8N2K0) is also able to hydrolyse lysophosphatidylserine [531]. ABHD12(Q8N2K0) has been described to be inhibited selectively by triterpenoids, such as betulinic acid [401].

Overview

583Eicosanoids 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.

584Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)‐icosa‐5,8,11,14‐tetraenoate,hydrogen‐donor: oxygen oxidoreductase) activity, catalyses the formation of PGG2 from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH2 from PGG2. COX‐1 and ‐2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indomethacin and paracetamol (acetaminophen). PGH2 may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue‐dependent manner.

585Subsequent to the formation of PGH2, the cytochrome P450 activities thromboxane synthase (CYP5A1, TBXAS1, P24557, EC 5.3.99.5) and prostacyclin synthase (CYP8A1, PTGIS, Q16647, EC 5.3.99.4) generate thromboxane A2 and prostacyclin (PGI2), respectively (see Cytochrome P450s). Additionally, multiple enzyme activities are able to generate prostaglandin E2(PGE2), prostaglandin D2(PGD2) and prostaglandin F2α(PGF2α). PGD2 can be metabolised to 9α,11β‐prostacyclin F2α through the multifunctional enzyme activity of AKR1C3. PGE2 can be metabolised to 9α,11β‐prostaglandin F2α through the 9‐ketoreductase activity of CBR1. Conversion of the 15‐hydroxyecosanoids, including prostaglandins, lipoxins and leukotrienes to their keto derivatives by the NAD‐dependent enzyme HPGD leads to a reduction in their biological activity.

Comments

586YS121 has been reported to inhibit mPGES1 and 5‐LOX with a pIC50value of 5.5 [276].

Overview

587The 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 arachidonic acid as substrate, these products are hydroperoxyeicosatetraenoic acids (HPETEs). In humans there are five lipoxygenases, the 5S‐(arachidonate: oxygen 5‐oxidoreductase), 12R‐(arachidonate 12‐lipoxygenase, 12R‐type), 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.

Comments

588An 8‐LOX (EC 1.13.11.40, arachidonate:oxygen 8‐oxidoreductase) may be the mouse orthologue of 15‐LOX‐2 [167]. Some general LOX inhibitors are nordihydroguiaretic acid and esculetin. Zileuton and caffeic acid are used as 5‐lipoxygenase inhibitors, while baicalein and CDC are 12‐lipoxygenase inhibitors. The specificity of these inhibitors has not been rigorously assessed with all LOX forms: baicalein, along with other flavonoids, such as fisetin and luteolin, also inhibits 15‐LOX‐1 [450].

Overview

589Leukotriene A4(LTA4), 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 LTA4 at the 6 position with reduced glutathione to generate LTC4 occurs under the influence of leukotriene C4 synthase, with the subsequent formation of LTD4 and LTE4, all three of which are agonists at CysLT receptors. LTD4 formation is catalysed by γ‐glutamyltransferase, and subsequently dipeptidase 2 removes the terminal glycine from LTD4 to generate LTE4. Leukotriene A4 hydrolase converts the 5,6‐epoxide LTA4 to the 5‐hydroxylated LTB4, an agonist for BLT receptors. LTA4 is also acted upon by 12S‐LOX to produce the trihydroxyeicosatetraenoic acids lipoxins LXA4 and LXB4. Treatment with a LTA4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA4 levels, in addition to reducing LTB4, in lung lavage fluid [429].

590LTA4 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 LTA4hydrolase converted chiral 5S(6)‐epoxide‐containing intermediates to resolvin E1 and 18S‐resolvin E1 [384].

Comments

591LTA4H 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 LTD4 appears not to be a substrate.

Overview

603The inhibitory neurotransmitter γ‐aminobutyrate (GABA, 4‐aminobutyrate) is generated in neurones by glutamic acid decarboxylase. GAD1 and GAD2 are differentially expressed during development, where GAD2 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 [136] where GABA is principally accumulated in vesicles through the action of the vesicular inhibitory amino acid transporter SLC32A1. 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 SLC6 family of transporters. 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.

Overview

607Phospholipids 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).

608Phosphoinositide‐specific phospholipase C (PLC, EC 3.1.4.11), catalyses the hydrolysis of PIP2 to IP3 and 1,2‐diacylglycerol, each of which have major second messenger functions. Two domains, X and Y, essential for catalytic activity, are conserved in the different forms of PLC. Isoforms of PLC‐β are activated primarily by G protein‐coupled receptors through members of the Gq/11 family of G proteins. The receptor‐mediated activation of PLC‐γ involves their phosphorylation by receptor tyrosine kinases (RTK) in response to activation of a variety of growth factor receptors and immune system receptors. PLC‐ϵ1 may represent a point of convergence of signalling via both G protein‐coupled and catalytic receptors. Ca2+ 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[23], although this mechanism of action has been questioned [284]. The aminosteroid U73122 has been described as an inhibitor of phosphoinositide‐specific PLC [485], although its selectivity among the isoforms is untested and it has been reported to occupy the H1 histamine receptor [235].

Comments

609A series of PLC‐like proteins (PLCL1, Q15111; PLCL2, Q9UPR0 and PLCH1, Q4KWH8) form a family with PLCδ and PLCζ1 isoforms, but appear to lack catalytic activity.

610PLC‐δ2 has been cloned from bovine sources [351].

Overview

616Phospholipase A2(PLA2, EC 3.1.1.4) cleaves the sn‐2 fatty acid of phospholipids, primarily phosphatidylcholine, to generate lysophosphatidylcholine and arachidonic acid. Most commonly‐used inhibitors (e.g. bromoenol lactone, arachidonyl trifluoromethyl ketone or methyl arachidonyl fluorophosphonate) are either non‐selective within the family of phospholipase A2 enzymes or have activity against other eicosanoid‐metabolising enzymes.

617Secreted or extracellular forms: sPLA2‐1B, sPLA2‐2A, sPLA2‐2D, sPLA2‐2E, sPLA2‐2F, sPLA2‐3, sPLA2‐10 and sPLA2‐12A

618Cytosolic, calcium‐dependent forms: cPLA2‐4A, cPLA2‐4B, cPLA2‐4C, cPLA2‐4D, cPLA2‐4E and cPLA2‐4F

619Other forms: PLA2‐G5, iPLA2‐G6, PLA2‐G7 and PAFAH2 (platelet‐activating factor acetylhydrolase 2)

Comments

623The sequence of PLA2‐2C suggests a lack of catalytic activity, while PLA2‐12B (GXIIB, GXIII sPLA2‐like) appears to be catalytically inactive [448]. A further fragment has been identified with sequence similarities to Group II PLA2 members. Otoconin 90 (OC90) shows sequence homology to PLA2‐G10.

624A binding protein for secretory phospholipase A2 has been identified which shows modest selectivity for sPLA2‐1B over sPLA2‐2A, and also binds snake toxin phospholipase A2[13]. 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 [29].

625PLA2‐G7 and PAFAH2 also express platelet‐activating factor acetylhydrolase activity (EC 3.1.1.47).

Overview

626Phosphatidylcholine‐specific phospholipase D (PLD, EC 3.1.4.4) catalyses the formation of phosphatidic acid from phosphatidylcholine. In addition, the enzyme can make use of alcohols, such as butanol in a transphosphatidylation reaction [428].

Comments

627A lysophospholipase D activity (ENPP2, Q13822, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2, phosphodiesterase I, nucleotide pyrophosphatase 2, autotaxin) has been described, which not only catalyses the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine, but also cleaves ATP (see Goding et al., 2003 [185]). Additionally, an N‐acylethanolamine‐specific phospholipase D (NAPEPLD, Q6IQ20) has been characterized, which appears to have a role in the generation of endocannabinoids/endovanilloids, including anandamide[388]. This enzyme activity appears to be enhanced by polyamines in the physiological range [311] and fails to transphosphatidylate with alcohols [408].

628Three further, less well‐characterised isoforms are PLD3 (PLD3, Q8IV08, other names Choline phosphatase 3, HindIII K4L homolog, Hu‐K4), PLD4 (PLD4, Q96BZ4, other names Choline phosphatase 4, Phosphatidylcholine‐hydrolyzing phospholipase, D4C14orf175 UNQ2488/PRO5775) and PLD5 (PLD5, Q8N7P1). PLD3 has been reported to be involved in myogenesis [391]. PLD4 is described not to have phospholipase D catalytic activity [588], but has been associated with inflammatory disorders [386, 507, 526]. Sequence analysis suggests that PLD5 is catalytically inactive.

Overview

632Lipid 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.

633Phosphatidylinositol may be phosphorylated at either 3‐ or 4‐ positions on the inositol ring by PI 3‐kinases or PI 4‐kinases, respectively.

Phosphatidylinositol 3‐kinases

634Phosphatidylinositol 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 (PIP2). 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. Structurally, PI3Ks have common motifs of at least one C2, calcium‐binding domain and helical domains, alongside structurally‐conserved catalytic domains. Wortmannin and LY 294002 are widely‐used inhibitors of PI3K activities. Wortmannin 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.

635Class 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, p110β 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 linked more with GPCR signalling.

636Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3‐phosphate (and possibly phosphatidylinositol 4‐phosphate to generate phosphatidylinositol 3,4‐bisphosphate). Three monomeric members exist, PI3K‐C2α, β and β, and include Ras‐binding, Phox homology and two C2domains.

637The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).

Phosphatidylinositol 4‐kinases

638Phosphatidylinositol 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.

Overview

639PIP2 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.

640Type I PIP kinases are required for the production of the second messenger phosphatidylinositol 4,5‐bisphosphate (PtdIns(4,5)P2) by phosphorylating PtdIns(4)P [426]. This enzyme family is also known as type I PIP(5)Ks.

641Type II PIP kinases are essential for the production of the second messenger phosphatidylinositol 4,5‐bisphosphate (PtdIns(4,5)P2) by phosphorylating PtdIns(5)P [426]. This enzyme family is also known as type II PIP(5)Ks.

Overview

649Haem oxygenase (heme,hydrogen‐donor:oxygen oxidoreductase (α‐methene‐oxidizing, hydroxylating)), E.C. 1.14.99.3, converts heme into biliverdin and carbon monoxide, utilizing NADPH as cofactor.

Comments

650The existence of a third non‐catalytic version of haem oxygenase, HO3, has been proposed, although this has been suggested to be a pseudogene [215]. The chemical tin protoporphyrin IX acts as a haem oxygenase inhibitor in rat liver with an IC50 value of 11 nM [128].

Overview

655Hydrogen 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 (H2S) 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 H2S; 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.

Overview

660Listed 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.

Overview

663The sugar alcohol D‐myo‐inositol is a component of the phosphatidylinositol signalling cycle, where the principal second messenger is inositol 1,4,5‐trisphosphate, IP3, which acts at intracellular ligand‐gated ion channels, IP3 receptors to elevate intracellular calcium. IP3 is recycled to inositol by phosphatases or phosphorylated to form other active inositol polyphosphates. Inositol produced from dephosphorylation of IP3 is recycled into membrane phospholipid under the influence of phosphatidyinositol synthase activity (CDP‐diacylglycerol‐inositol 3‐phosphatidyltransferase [EC 2.7.8.11]).

664Inositol 1,4,5‐trisphosphate 3‐kinases (E.C. 2.7.1.127, ENSFM00250000001260) catalyse the generation of inositol 1,3,4,5‐tetrakisphosphate (IP4) from IP3. IP3 kinase activity is enhanced in the presence of calcium/calmodulin(CALM1 CALM2 CALM3, P62158) [98].

665Information on members of this family may be found in the online database.

666Members of this family exhibit phosphatase activity towards IP3, as well as towards other inositol derivatives, including the phospholipids PIP2 and PIP3. With IP3 as substrate, 1‐phosphatase (EC 3.1.3.57) generates 4,5,‐IP2, 4‐phosphatases (EC 3.1.3.66, ENSFM00250000001432) generate 1,5,‐IP2 and 5‐phosphatases (E.C. 3.1.3.36 or 3.1.3.56) generate 1,4,‐IP2.

667Information on members of this family may be found in the online database.

Comments

668In vitro analysis suggested IP3 and IP4 were poor substrates for SKIP, synaptojanin 1 and synaptojanin 2, but suggested that PIP2 and PIP3 were more efficiently hydrolysed [458].

Overview

669Inositol monophosphatase (E.C. 3.1.3.25, IMPase, myo‐inositol‐1(or 4)‐phosphate phosphohydrolase) is a magnesium‐dependent homodimer which hydrolyses myo‐inositol monophosphate to generate myo‐inositol and phosphate. Glycerol may be a physiological phosphate acceptor. Li+ is a nonselective un‐competitive inhibitor more potent at IMPase 1 (pKica. 3.5, [347]; pIC50 3.2, [385]) than IMPase 2 (pIC50 1.8‐2.1, [385]). IMPase activity may be inhibited competitively by L690330(pKi 5.5, [347]), although the enzyme selectivity is not yet established.

Comments

670Polymorphisms in either of the genes encoding these enzymes have been linked with bipolar disorder [481, 482, 589]. Disruption of the gene encoding IMPase 1, but not IMPase 2, appears to mimic the effects of Li+ in mice [104, 105].

Overview

675Lanosterol 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.

Overview

681The de novo synthesis and salvage of nucleosides have been targetted for therapeutic advantage in the treatment of particular cancers and gout. Dihydrofolate reductase produces tetrahydrofolate, a cofactor required for synthesis of purines, pyrimidines and amino acids. GART allows formylation of phosphoribosylglycinamide, an early step in purine biosynthesis. Dihydroorotate dehydrogenase produces orotate, a key intermediate in pyrimidine synthesis. IMP dehydrogenase generates xanthosine monophosphate, an intermediate in GTP synthesis.

Comments

682Thymidylate synthetase allows the interconversion of dUMP and dTMP, thereby acting as a crucial step in DNA synthesis. Purine nucleoside phosphorylase allows separation of a nucleoside into the nucleobase and ribose phosphate for nucleotide salvage. Xanthine dehydrogenase generates urate in the purine degradation pathway. Post‐translational modifications of xanthine dehydrogenase convert the enzymatic reaction to a xanthine oxidase, allowing the interconversion of hypoxanthine and xanthine, with the production (or consumption) of reactive oxygen species. Ribonucleotide reductases allow the production of deoxyribonucleotides from ribonucleotides.

Overview

686S1P (sphingosine 1‐phosphate) is a pro‐survival signal, in contrast to ceramide. It is formed by the sphingosine kinase‐catalysed phosphorylation of sphingosine. S1P can be released from cells to act as an agonist at a family of five G protein‐coupled receptors (S1P1‐5) but also has intracellular targets. S1P can be dephosphorylated back to sphingosine or hydrolysed to form hexadecanal and phosphoethanolamine. Sphingosine choline phosphotransferase (EC 2.7.8.10) generates sphingosylphosphocholine from sphingosine and CDP‐choline. Sphingosine β‐galactosyltransferase (EC 2.4.1.23) generates psychosine from sphingosine in the presence of UDP‐α‐D‐galactose. The molecular identities of these enzymes have not been confirmed.

Overview

694The thyroid hormones triiodothyronine and thyroxine, usually abbreviated as triiodothyronine and T4, 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).

Tissue deiodinases

695These are 1 TM selenoproteins that remove an iodine from T4(3,3',5,5'‐tetraiodothyronine) to generate triiodothyronine(3,3',5‐triiodothyronine, a more potent agonist at thyroid hormone receptors) or rT3(rT3, 3,3',5'‐triiodothyronine, a relatively inactive analogue). DIO1 is also able to deiodinate RT3 to form 3,3'‐diidothyronine (T2). Iodotyrosine deiodinase is a 1TM homodimeric enzyme.

Overview

701Hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis [466]. At normal oxygen levels, the alpha subunit of HIF (HIF‐1α) is targeted for degradation by prolyl hydroxylation by the prolyl hydrolxyases PHD proteins 1‐3 (HIF‐PHs) whch are 2‐oxoglutarate oxygenases responsible for the post‐translational modification of a specific proline in each of the oxygen‐dependent degradation domains of HIF‐1α. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel‐Lindau ubiquitination complex [245]. Under hypoxic conditions, the hydroxylation reaction is blunted which results in decreased HIF degradation. The surviving HIFs are then available to translocate to the nucleus where they heterodimerize with HIF‐1β, effecting increased expression of hypoxia‐inducible genes.

702HIF‐PH enzymes are being investigated as pharmacological targets as their inhibition mimics the hypoxic state and switches on transcription of genes associated with processes such as erythropoiesis and vasculogenesis [151]. Small molecule HIF‐PH inhibitors are in clinical trial as novel therapies for the amelioration of anemia associated with chronic kidney disease [50].

Overview

713The 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).

Overview

719Farnesyltransferase 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) [72]. 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 (ie to the CaaX motif, where 'a' is an aliphatic amino acid and 'X' is usually serine, methionine, alanine or glutamine; leucine for EC 2.5.1.59) [165]. 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.

720Substrates of the prenyltransferases include Ras, Rho, Rab, other Ras‐related small GTP‐binding proteins, G‐protein γ‐subunits, nuclear lamins, centromeric proteins and many proteins involved in visual signal transduction.

721In relation to the causative association between oncogenic Ras proteins and cancer, farnesyltransferase has become an important mechanistic drug discovery target.

722Information on members of this family may be found in the online database.

Overview

727Histone 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.

728The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:

729Class I contains HDACs 1, 2, 3 and 8

730Class IIa contains HDACs 4, 5, 7 and 9

731Class IIb contains HDACs 6 and 10

732Class III contains the sirtuins (SIRT1‐7)

733Class IV contains only HDAC11.

734Classes 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 [456].

735HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins [91] such as microtubules [233], the hsp90 chaperone [281] and the tumour suppressor p53 [322].

736Dysregulated HDAC activity has been identified in cancer cells and tumour tissues [305, 444], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [567]. 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) [478].

737Information on members of this family may be found in the online database.

Overview

743In humans, the peptidyl arginine deiminases (PADIs; HGNC family link) are a family of five enzymes, PADI1‐4 and PADI6. PADIs catalyze the deimination of protein L‐arginine residues to L‐citrulline and ammonia, generating peptidyl‐citrulline on histones, fibrinogen, and other biologically relevant proteins. The human isozymes exhibit tissue‐specific expression patterns [256]. 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 [37]. Pharmacological PADI inhibition reverses protein‐hypercitrullination and disease in mouse models of multiple sclerosis [366].

744Information on members of this family may be found in the online database.

Overview

748The 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.

749The 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 [495], which leads to increased cell proliferation and decreased apoptosis [598]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [25].

750Information on members of this family may be found in the online database.

Overview

758Carbonic 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.

Overview

762DNA 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.

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THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes

Abstract

Full text

Conflict of interest

Overview

Family structure

Overview

Further reading on Rho kinases

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Further reading on Protein kinase C

Further reading on FRAP subfamily

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Further reading on GSK subfamily

Further reading on Kinases (EC 2.7.x.x)

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Further reading on Acetylcholine turnover

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Further reading on Adenosine turnover

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Further reading on Amino acid hydroxylases

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Further reading on L‐Arginine turnover

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Further reading on Nitric oxide synthases

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Further reading on Carboxylases and decarboxylases

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Further reading on Catecholamine turnover

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Further reading on Ceramide turnover

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Further reading on Adenylyl cyclases

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Further reading on Exchange protein activated by cyclic AMP (EPAC)

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Further reading on Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase

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Further reading on Phosphodiesterases, 3',5'‐cyclic nucleotide (PDEs)

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Further reading on Cytochrome P450

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2‐Acylglycerol ester turnover

Further reading on Endocannabinoid turnover

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Further reading on Eicosanoid turnover

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Further reading on GABA turnover

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Further reading on Phosphoinositide‐specific phospholipase C

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Further reading on Phospholipase A2