No retraction, correction or concern found when last checked on Oct 17, 2026.

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Enzymes

Stephen P H Alexander, Doriano Fabbro, Eamonn Kelly and 11 more

British Journal of Pharmacology · 2019 · Review

Abstract

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( 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.14752 . Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 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 disclose.

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 [http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24016212?dopt=AbstractPlus], which is not to say that they are of modest importance.

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

12– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=933

13S301 Acetylcholine turnover

14S302 Adenosine turnover

15S303 Amino acid hydroxylases

16S304 L‐Arginine turnover

17S304 2.1.1.‐ Protein arginine N‐methyltransferases

18S305 Arginase

19S305 Arginine:glycine amidinotransferase

20S305 Dimethylarginine dimethylaminohydrolases

21S306 Nitric oxide synthases

22S307 Carbonic anhydrases

23S308 Carboxylases and decarboxylases

24S308 Carboxylases

25S309 Decarboxylases

26S311 Catecholamine turnover

27S313 Ceramide turnover

28S313 Serine palmitoyltransferase

29– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=791

30S314 Ceramide synthase

31S314 Sphingolipid ∆4‐desaturase

32S315 Sphingomyelin synthase

33S315 Sphingomyelin phosphodiesterase

34S316 Neutral sphingomyelinase coupling factors

35S316 Ceramide glucosyltransferase

36S316 Acid ceramidase

37S317 Neutral ceramidases

38S317 Alkaline ceramidases

39S318 Ceramide kinase

40– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=981

41S319 Chromatin modifying enzymes

42– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=869

43S319 2.1.1.‐ Protein arginine N‐methyltransferases

44– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=871

45– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=872

46S320 3.5.1.‐ Histone deacetylases (HDACs)

47– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=873

48– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=884

49– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=558

50– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=626

51– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=631

52S321 Cyclic nucleotide turnover/signalling

53S321 Adenylyl cyclases (ACs)

54S323 Exchange protein activated by cyclic AMP (EPACs)

55S323 Phosphodiesterases, 3’,5’‐cyclic nucleotide (PDEs)

56S327 Cytochrome P450

57S327 CYP1 family

58S328 CYP2 family

59S329 CYP3 family

60S330 CYP4 family

61S331 CYP5, CYP7 and CYP8 families

62S332 CYP11, CYP17, CYP19, CYP20 and CYP21 families

63S333 CYP24, CYP26 and CYP27 families

64S333 CYP39, CYP46 and CYP51 families

65– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1020

66S334 DNA topoisomerases

67S335 Endocannabinoid turnover

68S336 N‐Acylethanolamine turnover

69S337 2‐Acylglycerol ester turnover

70S338 Eicosanoid turnover

71S338 Cyclooxygenase

72S339 Prostaglandin synthases

73S341 Lipoxygenases

74S342 Leukotriene and lipoxin metabolism

75S343 GABA turnover

76S344 Glycerophospholipid turnover

77S344 Phosphoinositide‐specific phospholipase C

78S346 Phospholipase A2

79S348 Phosphatidylcholine‐specific phospholipase D

80S349 Lipid phosphate phosphatases

81S349 Phosphatidylinositol kinases

82S350 1‐phosphatidylinositol 4‐kinase family

83S351 Phosphatidylinositol‐4‐phosphate 3‐kinase family

84S351 Phosphatidylinositol 3‐kinase family

85S351 Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase family

86S352 1‐phosphatidylinositol‐3‐phosphate 5‐kinase family

87S353 Type I PIP kinases (1‐phosphatidylinositol‐4‐phosphate 5‐kinase family)

88S353 Type II PIP kinases (1‐phosphatidylinositol‐5‐phosphate 4‐kinase family)

89S354 Sphingosine kinase

90S356 Phosphatidylinositol phosphate kinases

91S356 Haem oxygenase

92S358 Hydrogen sulphide synthesis

93S358 Hydrolases

94S360 Inositol phosphate turnover

95S360 Inositol 1,4,5‐trisphosphate 3‐kinases

96S360 Inositol polyphosphate phosphatases

97S361 Inositol monophosphatase

98– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1004

99S361 Kinases (EC 2.7.x.x)

100– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=677

101– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=454

102– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=500

103– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=573

104S362 Rho kinase

105– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=283

106– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=507

107– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=508

108– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=937

109– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=583

110– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=587

111– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=604

112– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=284

113– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=285

114S362 Protein kinase C (PKC) family

115S363 Alpha subfamily

116S363 Delta subfamily

117S364 Eta subfamily

118– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=535

119– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=287

120– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=601

121– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=466

122– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=539

123– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=540

124– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=541

125– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=705

126– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=614

127– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=616

128– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=644

129– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=678

130– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=448

131– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=468

132– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=469

133– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=450

134– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=471

135– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=472

136– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=556

137– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=874

138– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=558

139– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=576

140– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=463

141S264 FRAP subfamily

142– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=528

143– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=530

144– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=531

145– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=598

146– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=465

147– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=536

148– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=537

149– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=538

150– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=596

151– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=608

152– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=626

153– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=631

154– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=679

155– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=561

156– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=562

157– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=452

158– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=474

159– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=475

160– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=476

161– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=477

162– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=478

163– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=479

164– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=480

165– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=700

166– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=481

167– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=482

168– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=483

169– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=484

170– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=563

171– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=566

172– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=571

173– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=572

174– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=459

175– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=512

176– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=513

177– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=585

178– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=599

179– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=600

180– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=605

181– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=607

182– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=609

183– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=630

184– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=635

185– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=636

186– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=680

187– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=564

188– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=627

189– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=640

190– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=681

191– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=568

192S365 Cyclin‐dependent kinase (CDK) family

193– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=485

194– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=492

195S365 CDK4 subfamily

196– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=495

197– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=496

198– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=497

199– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=489

200– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=494

201– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=490

202– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=498

203– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=491

204– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=570

205– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=455

206– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=503

207– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=504

208– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=505

209– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=506

210– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=457

211S366 GSK subfamily

212– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=288

213– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=514

214– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=515

215– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=518

216– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=519

217– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=520

218– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=612

219– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=620

220– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=682

221– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=683

222– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=451

223– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=473

224– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=557

225– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=559

226– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=560

227– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=565

228– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=567

229– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=577

230– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=578

231– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=580

232– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=584

233– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=586

234– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=588

235– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=589

236– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=590

237– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=591

238– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=592

239– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=593

240– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=594

241– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=595

242S367 Polo‐like kinase (PLK) family

243– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=462

244– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=526

245– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=527

246– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=597

247– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=617

248– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=618

249– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=628

250– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=633

251– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=634

252– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=637

253– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=639

254– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=641

255– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=642

256– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=643

257– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=684

258– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=449

259– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=470

260– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=615

261– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=890

262– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=685

263S367 STE7 family

264– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=621

265– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=467

266– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=542

267– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=543

268– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=544

269– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=544

270– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=546

271– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=547

272– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=548

273– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=549

274– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=622

275– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=550

276– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=551

277– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=552

278– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=624

279– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=686

280– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=936

281S368 Abl family

282S368 Ack family

283– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=569

284– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=574

285– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=575

286S369 Janus kinase (JakA) family

287S369 Src family

288– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=625

289S370 Tec family

290– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=687

291– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=579

292– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=582

293– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=458

294– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=510

295– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=511

296– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=461

297– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=521

298– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=522

299– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=523

300– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=524

301– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=525

302S371 RAF family

303– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=613

304– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=632

305S372 Lanosterol biosynthesis pathway

306– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=928

307– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=993

308S374 Nucleoside synthesis and metabolism

309S376 Paraoxonase (PON) family

310S377 Peptidases and proteinases

311– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=707

312S377 A1: Pepsin

313– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=708

314S377 A22: Presenilin

315– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=709

316– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=728

317– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=731

318– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=729

319– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=730

320– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=732

321– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=931

322– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=711

323– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=733

324S378 C14: Caspase

325– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=711

326– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=735

327– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=712

328– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=736

329– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=713

330S378 M1: Aminopeptidase N

331S379 M2: Angiotensin‐converting (ACE and ACE2)

332S379 M10: Matrix metallopeptidase

333S380 M12: Astacin/Adamalysin

334– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=740

335– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=742

336– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=714

337– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=743

338– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=715

339– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=744

340– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=716

341– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=745

342– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=717

343– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=746

344– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=718

345– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=747

346– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=860

347S380 M28: Aminopeptidase Y

348– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=719

349S381 M19: Membrane dipeptidase

350– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=720

351– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=750

352– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=721

353S381 S1: Chymotrypsin

354– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=722

355– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=878

356S382 T1: Proteasome

357– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=753

358– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=723

359– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=754

360– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=724

361S382 S8: Subtilisin

362– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=725

363S383 S9: Prolyl oligopeptidase

364– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=756

365– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=757

366– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=917

367– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=947

368– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=980

369– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=948

370S383 Poly ADP‐ribose polymerases

371S384 Prolyl hydroxylases

372S384 Sphingosine 1‐phosphate turnover

373S385 Sphingosine kinase

374S386 Sphingosine 1‐phosphate phosphatase

375S387 Sphingosine 1‐phosphate lyase

376S387 Thyroid hormone turnover

377– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=988

378– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=840

379– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=922

380– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=912

381– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=899

382S388 1.14.13.9 Kynurenine 3‐monooxygenase

383– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=877

384– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=843

385– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=846

386– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=844

387– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=978

388– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1003

389– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=979

390– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=908

391S389 2.5.1.58 Protein farnesyltransferase

392– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=926

393– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=994

394– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=880

395– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=850

396– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=841

397– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=909

398S390 3.5.1.‐ Histone deacetylases (HDACs)

399– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=925

400S391 3.5.3.15 Peptidyl arginine deiminases (PADI)

401S391 3.6.5.2 Small monomeric GTPases

402S391 RAS subfamily

403S392 RAB subfamily

404– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=849

405– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=845

406– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=847

Overview

407Acetylcholine is familiar as a neurotransmitter in the central nervous system and in the periphery. In the somatic nervous system, it activates http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=76 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=2. 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=143#show_object_914 and the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=233 family). Acetylcholine is accumulated in synaptic vesicles through the action of the vesicular acetylcholine transporter http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193.

Comments

408A 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 [http://www.ncbi.nlm.nih.gov/pubmed/13785664?dopt=AbstractPlus].

Overview

414A multifunctional, ubiquitous molecule, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2844 acts at cell‐surface G protein‐coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Ex‐tracellular 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 as co‐substrate). Intracellular adenosine may be produced by cytosolic 5’‐nucleotidases or through S‐adenosylhomocysteine hydrolase (also producing http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5198).

Comments

415An extracellular adenosine deaminase activity, termed ADA2 or adenosine deaminase growth factor (ADGF, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1839, http://www.uniprot.org/uniprot/Q9NZK5) has been identified [http://www.ncbi.nlm.nih.gov/pubmed/24933472?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16245011?dopt=AbstractPlus], which is insensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5179 [http://www.ncbi.nlm.nih.gov/pubmed/20147294?dopt=AbstractPlus]. Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:228 (http://www.uniprot.org/uniprot/Q9BUB4) deaminates transfer RNA; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:225 (http://www.genome.jp/dbget‐bin/www_bget?ec:3.5.4.37, also known as 136 kDa double‐stranded RNA‐binding protein, P136, K88DSRBP, Interferon‐inducible protein 4); https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:226 (EC 3.5.‐.‐,, also known as dsRNA adenosine deaminase) andhttps://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:227 (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 (http://www.genome.jp/dbget‐bin/www_bget?ec:3.4.14.5, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3009, also known as T‐cell activation antigen CD26, TP103, adenosine deaminase complexing protein 2) to form a cell‐surface activity [http://www.ncbi.nlm.nih.gov/pubmed/8101391?dopt=AbstractPlus].

Overview

421The amino acid hydroxylases (monooxygenases), EC.1.14.16.‐, are iron‐containing enzymes which utilise molecular oxygen and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5276 as co‐substrate and co‐factor, respectively. In humans, as well as in other mammals, there are two distinct L‐Tryptophan hydroxylase 2 genes. In humans, these genes are located on chromosomes 11 and 12 and encode two different homologous enzymes, TPH1 and TPH2.

Overview

428http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 is a basic amino acid with a guanidino sidechain. As an amino acid, metabolism of L‐arginine to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725, catalysed by arginase, forms the last step of the urea production cycle. L‐Ornithine may be utilised as a precursor of polyamines (see http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240) or recycled via http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5324 to L‐arginine. L‐Arginine http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240#Decarboxylases to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4127, although the prominence of this pathway in human tissues is uncertain. L‐Arginine may be used as a precursor for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5325 formation in the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4496 synthesis pathway under the influence of arginine:glycine amidinotransferase with L‐ornithine as a byproduct. Nitric oxide synthase uses L‐arginine to generate nitric oxide, with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 also as a byproduct. L‐Arginine in proteins may be subject to post‐translational modification through methylation, catalysed by protein arginine methyltransferases. Subsequent proteolysis can liberate asymmetric http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229 (ADMA), which is an endogenous inhibitor of nitric oxide synthase activities. ADMA is hydrolysed by dimethylarginine dimethylhydrolase activities to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5177.

429Protein arginine N‐methyltransferases (PRMT, EC 2.1.1.‐) encompass histone arginine N‐methyltransferases (PRMT4, PRMT7, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.1.1.125) and myelin basic protein N‐methyltransferases (PRMT7, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.1.1.126). They are dimeric or tetrameric enzymes which use http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4786 as a methyl donor, generating http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5265 as a by‐product. They generate both mono‐methylated and di‐methylated products; these may be symmetric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5271) or asymmetric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.

430Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254.

431Arginase (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.5.3.1) are manganese‐containing isoforms, which appear to show differential distribution, where the ARG1 isoform predominates in the liver and erythrocytes, while ARG2 is associated more with the kidney.

432Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=250.

Comments

433http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5227, 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5091 [http://www.ncbi.nlm.nih.gov/pubmed/10637120?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5264 [http://www.ncbi.nlm.nih.gov/pubmed/11478904?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11258879?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5107 [http://www.ncbi.nlm.nih.gov/pubmed/10454520?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11478904?dopt=AbstractPlus].

Overview

434Dimethylarginine dimethylaminohydrolases (DDAH, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.5.3.18) are cytoplasmic enzymes which hydrolyse http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229 to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5177 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722.

435Nitric oxide synthases (NOS, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=1.14.13.39) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen‐dependent consumption of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 with the resultant by‐product, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post‐translation mechanisms regulating enzyme activity. The nomenclature suggested by NC‐IUPHAR of NOS I, II and III [http://www.ncbi.nlm.nih.gov/pubmed/9228663?dopt=AbstractPlus] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C‐terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4‐dependent reduction of heme bound oxygen for insertion into the substrate, L‐arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1442, http://www.uniprot.org/uniprot/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. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5213 and related modified arginine analogues are inhibitors of all three isoforms, with IC50 values in the micromolar range.

Comments

436The reductase domain of NOS catalyses the reduction of cytochrome c and other redox‐active dyes [http://www.ncbi.nlm.nih.gov/pubmed/9433128?dopt=AbstractPlus]. NADPH:O2 oxidoreductase catalyses the formation of superoxide anion/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2448 in the absence of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5276.

Overview

447Carbonic 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

451The 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 (EC 6.4.1.‐) or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5286 (EC 4.1.1.‐).

Comments

452Dicarboxylic acids including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2478 are able to activate ACC1/ACC2 activity allosterically. PCC is able to function in forward and reverse modes as a ligase (carboxylase) or lyase (decarboxylase) activity, respectively. Loss‐of‐function mutations in GGCX are associated with clotting disorders.

Overview

453The decarboxylases generate CO2 and the indicated products from acidic substrates, requiring http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5249 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4809 as a co‐factor.

Overview

462Catecholamines 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505 (norepinephrine) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 (epinephrine). These hormone/transmitters are synthesized by sequential metabolism from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3313 via http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4791. Hydroxylation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4791 generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3639, which is decarboxylated to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940. Hydroxylation of the ethylamine sidechain generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505 (norepinephrine), which can be methylated to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 (epinephrine). In particular neuronal and adrenal chromaffin cells, the catecholamines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 are accumulated into vesicles under the influence of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=193 (VMAT1/SLC18A1 and VMAT2/SLC18A2). After release into the synapse or the blood‐stream, catecholamines are accumulated through the action cell‐surface transporters, primarily the dopamine (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=144#Monoamine_transporter_subfamily) and norepinephrine transporter (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=144#Monoamine transporter subfamily). The primary routes of metabolism of these catecholamines are oxidation via monoamine oxidase activities of methylation via catechol O‐methyltransferase.

Overview

468Ceramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6654, which is reduced to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2453 (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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2205, http://www.uniprot.org/uniprot/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.

469Ceramidase 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.

470The 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 [http://www.ncbi.nlm.nih.gov/pubmed/19416851?dopt=AbstractPlus]. Complexes involving SPT3 appeared more broad in substrate selectivity, with incorporation of myristoylCoA prominent for SPT1/SPT3/ssSPTa complexes, while SP1/SPT3/ssSPTb complexes had similar activity with C16, C18 and C20 acylCoAs [http://www.ncbi.nlm.nih.gov/pubmed/19416851?dopt=AbstractPlus].

471This 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.

472DEGS1 and DEGS2 are 4TM proteins.

Comments

473DEGS1 activity is inhibited by a number of natural products, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7000 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424 [http://www.ncbi.nlm.nih.gov/pubmed/22200621?dopt=AbstractPlus].

Overview

474Following 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.

475Also known as sphingomyelinase.

476Protein FAN [http://www.ncbi.nlm.nih.gov/pubmed/8808629?dopt=AbstractPlus] and polycomb protein EED [http://www.ncbi.nlm.nih.gov/pubmed/20080539?dopt=AbstractPlus] allow coupling between TNF receptors and neutral sphingomyelinase phosphodiesterases.

477The 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.

478The 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

479ASAH2B appears to be an enzymatically inactive protein, which may result from gene duplication and truncation.

Overview

480The 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

481A ceramide kinase‐like protein has been identified in the human genome (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21699, http://www.uniprot.org/uniprot/Q49MI3).

Overview

495Chromatin 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 [http://www.ncbi.nlm.nih.gov/pubmed/17320507?dopt=AbstractPlus]. 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).

496To 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) [http://www.ncbi.nlm.nih.gov/pubmed/17320507?dopt=AbstractPlus].

497Writer proteins include the histone methyltransferases, histone acetyltransferases, some kinases and ubiquitin ligases.

498Readers include proteins which contain methyl‐lysinerecognition motifs such as bromodomains, chromodomains, tudor domains, PHD zinc fingers, PWWP domains and MBT domains.

499Erasers include the histone demethylases and histone deacetylases (HDACs and sirtuins).

500Dysregulated epigenetic control can be associated with human diseases such as cancer [http://www.ncbi.nlm.nih.gov/pubmed/18337604?dopt=AbstractPlus], where awide variety of cellular and protein abberations are known to perturb chromatin structure, gene transcription and ultimately cellular pathways [http://www.ncbi.nlm.nih.gov/pubmed/21941284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24104525?dopt=AbstractPlus]. 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. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6796 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6805 target the DNA methyltransferases DNMT1 and DNMT3 for the treatment of myelodysplastic syndromes [http://www.ncbi.nlm.nih.gov/pubmed/21220589?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24523604?dopt=AbstractPlus]) and erasers (e.g. the HDAC inhibitors http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6852, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7006 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496 for the treatment of T‐cell lymphomas [http://www.ncbi.nlm.nih.gov/pubmed/21493798?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22124371?dopt=AbstractPlus]) are already being used in the clinic. The search for the next generation of compounds with improved specificity against chromatin‐associated proteins is an area of intense basic and clinical research [http://www.ncbi.nlm.nih.gov/pubmed/25974248?dopt=AbstractPlus]. Current progress in this field is reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].

501Protein arginine N‐methyltransferases (PRMT, EC 2.1.1.‐) encompass histone arginine N‐methyltransferases (PRMT4, PRMT7, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.1.1.125) and myelin basic protein N‐methyltransferases (PRMT7, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.1.1.126). They are dimeric or tetrameric enzymes which use http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4786 as a methyl donor, generating http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5265 as a by‐product. They generate both mono‐methylated and dimethylated products; these may be symmetric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5271) or asym metric (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively.

502Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254.

503Histone 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.

504The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:

505Class I contains HDACs 1, 2, 3 and 8

506Class IIa contains HDACs 4, 5, 7 and 9

507Class IIb contains HDACs 6 and 10

508Class III contains the sirtuins (SIRT1‐7)

509Class IV contains only HDAC11.

510Classes 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 [http://www.ncbi.nlm.nih.gov/pubmed/20132909?dopt=AbstractPlus].

511HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins [http://www.ncbi.nlm.nih.gov/pubmed/19608861?dopt=AbstractPlus] such as microtubules [http://www.ncbi.nlm.nih.gov/pubmed/12024216?dopt=AbstractPlus], the hsp90 chaperone [http://www.ncbi.nlm.nih.gov/pubmed/15916966?dopt=AbstractPlus] and the tumour suppressor p53 [http://www.ncbi.nlm.nih.gov/pubmed/11099047?dopt=AbstractPlus].

512Dysregulated HDACactivity has been identified in cancer cells and tumour tissues [http://www.ncbi.nlm.nih.gov/pubmed/11704848?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19383284?dopt=AbstractPlus], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [http://www.ncbi.nlm.nih.gov/pubmed/24382387?dopt=AbstractPlus]. Several small molecule HDAC inhibitors are already approved for clinical use: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7006, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6852, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7489, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7009 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8305. HDACs and HDAC inhibitors currently in development as potential anti‐cancer therapeutics are reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].

Overview

522Cyclic 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 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=284‐ and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=287‐dependent protein kinases), ion channels (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=71, and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=71) and guanine nucleotide exchange factors (GEFs, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=259).

523Adenylyl cyclase, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=4.6.1.1, converts http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 and pyrophosphate. Mammalian membranedelimited adenylyl cyclases (nomenclature as approved by the NC‐IUPHAR Subcommittee on Adenylyl cyclases [http://www.ncbi.nlm.nih.gov/pubmed/28255005?dopt=AbstractPlus]) 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 Gαs (the stimulatory G protein α subunit) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5190 (except AC9, [http://www.ncbi.nlm.nih.gov/pubmed/8662814?dopt=AbstractPlus]). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2844 and its derivatives (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5108), acting through the P‐site,are inhibitors of adenylyl cyclase activity [http://www.ncbi.nlm.nih.gov/pubmed/11087399?dopt=AbstractPlus]. Four families of membranous adenylyl cyclase are distinguishable: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1442 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1445 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1449, http://www.uniprot.org/uniprot/P62158)‐stimulated (AC1, AC3 and AC8), Ca2+‐ and Gβγ‐inhibitable (AC5, AC6 and AC9), Gβγ‐stimulated and Ca2+‐insensitive (AC2, AC4 and AC7), and forskolin‐insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH‐insensitive) sensor [http://www.ncbi.nlm.nih.gov/pubmed/10915626?dopt=AbstractPlus].

Comments

524Many of the activators and inhibitors listed are only somewhat selective or have not been tested against all AC isoforms [http://www.ncbi.nlm.nih.gov/pubmed/24006339?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24008337?dopt=AbstractPlus]. AC3 shows only modest in vitro activation by Ca2+/CaM.

Overview

529Epacs are members of a family of guanine nucleotide exchange factors (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000000899), which also includes https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16862 (GFR, KIAA0277, MR‐GEF, http://www.uniprot.org/uniprot/Q92565) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17428 (Link‐GEFII, http://www.uniprot.org/uniprot/Q9UHV5). They are activated endogenously by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 and with some pharmacological selectivity by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5172 [http://www.ncbi.nlm.nih.gov/pubmed/12402047?dopt=AbstractPlus]. Once activated, Epacs induce an enhanced activity of the monomeric G proteins, Rap1 and Rap2 by facilitating binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1742 in place of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2410, leading to activation of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244 [http://www.ncbi.nlm.nih.gov/pubmed/11715024?dopt=AbstractPlus].

Overview

5333’,5’‐Cyclic nucleotide phosphodiesterases (PDEs, 3’,5’‐cyclic‐nucleotide 5’‐nucleotidohydrolase), http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.4.17, catalyse the hydrolysis of a 3’,5’‐cyclic nucleotide (usually http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=388 is a nonselective inhibitor with an IC50 value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2’,3’‐cyclic nucleotide 3’‐phosphodiesterase (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

Comments

534PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane‐bound homodimer. PDE3A and PDE3B are membrane‐bound.

535PDE4 isoforms are essentially http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 specific. The potency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5292 at other members of the PDE4 family has not been reported. PDE4B‐D long forms are inhibited by extracellular signal‐regulated kinase (ERK)‐mediated phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/10022832?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9639573?dopt=AbstractPlus]. PDE4A‐D splice variants can be membrane‐bound or cytosolic [http://www.ncbi.nlm.nih.gov/pubmed/12444918?dopt=AbstractPlus]. PDE4 isoforms may be labelled with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5313.

536PDE6 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 specific and is activated by the a‐subunit of transducin (Gat) and inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4743, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2919 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4807 with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness.

Overview

547The cytochrome P450 enzyme family (CYP450), E.C. 1.14.‐.‐, were originally defined by their strong absorbance at 450 nm due to the reduced carbon monoxide‐complexed haem component of the cytochromes. They are an extensive family of haemcontaining monooxygenases with a huge range of both endogenous and exogenous substrates. These include sterols, fat‐soluble vitamins, pesticides and carcinogens as well as drugs. The substrates of some orphan CYP are not known. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologuemay not catalyse the metabolism of the same substrates. Although the majority of CYP450 enzyme activities are concentrated in the liver, the extrahepatic enzyme activities also contribute to patho/physiological processes. Genetic variation of CYP450 isoforms is widespread and likely underlies a significant proportion of the individual variation to drug administration.

Overview

559DNA 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.

Overview

565The principle endocannabinoids are 2‐acylglycerol esters, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729 (2‐AG), and N‐acylethanolamines, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 (N‐arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re‐uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [http://www.ncbi.nlm.nih.gov/pubmed/29531087?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2535 (https://www.uniprot.org/uniprot/Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [http://www.ncbi.nlm.nih.gov/pubmed/28584105?dopt=AbstractPlus]. For the generation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 synthesis have been described, the best characterized of which involves N‐acylphosphatidylethanolamine‐phospholipase D (NAPE‐PLD, [http://www.ncbi.nlm.nih.gov/pubmed/20393650?dopt=AbstractPlus]). A transacylation enzyme which forms N‐acylphosphatidylethanolamines has been identified as a cytosolic enzyme, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24791 (http://www.uniprot.org/uniprot/Q3MJ16) [http://www.ncbi.nlm.nih.gov/pubmed/27399000?dopt=AbstractPlus]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [http://www.ncbi.nlm.nih.gov/pubmed/17876303?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17618306?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20133390?dopt=AbstractPlus].

Comments

566Routes for N‐acylethanolamine biosynthesis other than through NAPE‐PLD activity have been identified [http://www.ncbi.nlm.nih.gov/pubmed/23394527?dopt=AbstractPlus].

Overview

567ABHD12 is a 398‐aa protein, with serine hydrolase activity. It has a molecular weight of 45 kDa. A single TM is predicted at 75‐95, with an extracellular catalytic domain. ABHD12 is a monoacylglycerol hydrolase [http://www.ncbi.nlm.nih.gov/pubmed/22969151?dopt=AbstractPlus], but may also regulate lysophosphatidylserine levels [http://www.ncbi.nlm.nih.gov/pubmed/25580854?dopt=AbstractPlus]. Loss‐of‐function mutations in ABHD12 are associated with a disorder known as PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) [http://www.ncbi.nlm.nih.gov/pubmed/20797687?dopt=AbstractPlus].

Comments on Endocannabinoid turnover

568Many of the compounds described as inhibitors are irreversible and so potency estimates will vary with incubation time. FAAH2 is not found in rodents [http://www.ncbi.nlm.nih.gov/pubmed/17015445?dopt=AbstractPlus] and a limited range of inhibitors have been assessed at this enzyme activity. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729 has been reported to be hydrolysed by multiple enzyme activities from neural preparations [http://www.ncbi.nlm.nih.gov/pubmed/29751000?dopt=AbstractPlus], including https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21398 (http://www.uniprot.org/uniprot/Q9BV23) [http://www.ncbi.nlm.nih.gov/pubmed/26989199?dopt=AbstractPlus] and carboxylesterase 1 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1863, http://www.uniprot.org/uniprot/P23141 [http://www.ncbi.nlm.nih.gov/pubmed/21049984?dopt=AbstractPlus]). https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21398 (http://www.uniprot.org/uniprot/Q9BV23) has also been described as a triacylglycerol lipase and ester hydrolase [http://www.ncbi.nlm.nih.gov/pubmed/27247428?dopt=AbstractPlus], while https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15868 (http://www.uniprot.org/uniprot/Q8N2K0) is also able to hydrolyse lysophosphatidylserine [http://www.ncbi.nlm.nih.gov/pubmed/2397193?dopt=AbstractPlus]. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15868 (http://www.uniprot.org/uniprot/Q8N2K0) has been described to be inhibited selectively by pentacyclic triterpenoids, such as oleanolic acid [http://www.ncbi.nlm.nih.gov/pubmed/24879289?dopt=AbstractPlus].

Overview

577Eicosanoids are 20‐carbon fatty acids, where the usual focus is the polyunsaturated analogue http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 and its metabolites. Arachidonic acid is thought primarily to derive from http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244#Phospholipase A2 action on membrane phosphatidylcholine, andmay be re‐cycled to form phospholipid through conjugation with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3044 and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450‐like epoxygenases, particularly http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242#show_object_1332. 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 nonenzymaticmanner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.

578Prostaglandin (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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5245 from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391. Hydroperoxidase activity inherent in the enzyme catalyses the formation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4483 from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5245. COX‐1 and ‐2 can be nonselectively inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2713, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4795, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5230, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1909 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5239 (acetaminophen). PGH2 may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue‐dependent manner.

579Subsequent to the formation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4483, the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242 thromboxane synthase (CYP5A1, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11609, http://www.uniprot.org/uniprot/P24557, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=5.3.99.5) and prostacyclin synthase (CYP8A1, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9603, http://www.uniprot.org/uniprot/Q16647, http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=5.3.99.4) generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4482 and prostacyclin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1915), respectively. Additionally, multiple enzyme activities are able to generate prostaglandin E2 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1883), prostaglandin D2 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1881) and prostaglandin F2α (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1884). PGD2 can bemetabolised to 9α,11ß‐prostacyclin F2α through the multifunctional enzyme activity of AKR1C3. PGE2 can be metabolised to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5129 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

580http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5293 has been reported to inhibit mPGES1 and 5‐LOX with a pIC50 value of 5.5 [http://www.ncbi.nlm.nih.gov/pubmed/19053751?dopt=AbstractPlus].

Overview

581The lipoxygenases (LOXs) are a structurally related family of non‐heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. For http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 as substrate, these products are hydroperoxyeicosatetraenoic acids (HPETEs). In humans there are five lipoxygenases, the 5S‐(arachidonate: oxygen 5‐oxidoreductase), 12R‐(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

582An 8‐LOX(http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=1.13.11.40, arachidonate:oxygen 8‐oxidoreductase) may be the mouse orthologue of 15‐LOX‐2 [http://www.ncbi.nlm.nih.gov/pubmed/12432921?dopt=AbstractPlus]. Some general LOX inhibitors are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4265 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5180. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5297 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5155 are used as 5‐lipoxygenase inhibitors, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5144 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5162 are 12‐lipoxygenase inhibitors. The specificity of these inhibitors has not been rigorously assessed with all LOX forms: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5144, along with other flavonoids, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5182 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5215, also inhibits 15‐LOX‐1 [http://www.ncbi.nlm.nih.gov/pubmed/12628491?dopt=AbstractPlus].

Overview

583Leukotriene A4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214), produced by 5‐LOX activity, and lipoxins may be subject to further oxidative metabolism; ω‐hydroxylation is mediated by http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242#show_object_1344 and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242#show_object_1345, while ß‐oxidation in mitochondria and peroxisomes proceeds in a manner dependent on coenzyme A conjugation. Conjugation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214 at the 6 position with reduced glutathione to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3354 occurs under the influence of leukotriene C4 synthase, with the subsequent formation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3352, all three of which are agonists at http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 formation is catalysed by γ‐glutamyltransferase, and subsequently dipeptidase 2 removes the terminal http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3352. Leukotriene A4 hydrolase converts the 5,6‐epoxide LTA4 to the 5‐hydroxylated LTB4, an agonist for http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5214 is also acted upon by 12S‐LOX to produce the trihydroxyeicosatetraenoic acids lipoxins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1034 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5216. Treatment with a LTA4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA4 levels, in addition to reducing http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2487, in lung lavage fluid [http://www.ncbi.nlm.nih.gov/pubmed/20110560?dopt=AbstractPlus]. LTA4 hydrolase is also involved in biosynthesis of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=134. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4139 has been reported to increase endogenous formation of 18S‐hydroxyeicosapentaenoate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5105) compared with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3400, a resolvin precursor. Both enantiomers may be metabolised by human recombinant 5‐LOX; recombinant LTA4 hydrolase converted chiral 5S(6)‐epoxide‐containing intermediates to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3333 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5106 [http://www.ncbi.nlm.nih.gov/pubmed/21206090?dopt=AbstractPlus].

Comments

584LTA4H is a member of a family of arginyl aminopeptidases (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000001675), which also includes aminopeptidase B (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10078, http://www.uniprot.org/uniprot/9H4A4) and aminopeptidase B‐like 1 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10079, http://www.uniprot.org/uniprot/Q9HAU8). Dipeptidase 1 and 2 are members of a family of membrane dipeptidases, which also includes (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:23029, http://www.uniprot.org/uniprot/Q9H4B8) for which http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 appears not to be a substrate.

Overview

597The inhibitory neurotransmitter γ‐aminobutyrate (GABA, 4‐aminobutyrate) is generated in neurones by glutamic acid decarboxylase. GAD1 and GAD2 are differentially expressed during development, whereGAD2 is thought to subserve a trophic role in early life and is distributed throughout the cytoplasm. GAD1 is expressed in later life and is more associated with nerve terminals [http://www.ncbi.nlm.nih.gov/pubmed/8126575?dopt=AbstractPlus] where GABA is principally accumulated in vesicles through the action of the vesicular inhibitory amino acid transporter http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=219. The role of γ‐aminobutyraldehyde dehydrogenase (ALDH9A1) in neurotransmitter GABA synthesis is less clear. Following release from neurons, GABA may interact with either GABAA or GABAB receptors and may be accumulated in neurones and glia through the action of members of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=144. Successive metabolism through GABA transaminase and succinate semialdehyde dehydrogenase generates succinic acid, which may be further metabolized in the mitochondria in the tricarboxylic acid cycle.

Overview

600Phospholipids 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).

601Phosphoinositide‐specific phospholipase C (PLC, EC 3.1.4.11), catalyses the hydrolysis of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2387 to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 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‐ß 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304 in response to activation of a variety of growth factor receptors and immune system receptors. PLC‐ ∈1 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5097 [http://www.ncbi.nlm.nih.gov/pubmed/12695532?dopt=AbstractPlus], although this mechanism of action has been questioned [http://www.ncbi.nlm.nih.gov/pubmed/15302681?dopt=AbstractPlus]. The aminosteroid http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5283 has been described as an inhibitor of phosphoinositide‐specific PLC [http://www.ncbi.nlm.nih.gov/pubmed/2338654?dopt=AbstractPlus], although its selectivity among the isoforms is untested and it has been reported to occupy the H1 histamine receptor [http://www.ncbi.nlm.nih.gov/pubmed/11138848?dopt=AbstractPlus].

Comments

602A series of PLC‐like proteins (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9063, http://www.uniprot.org/uniprot/Q15111; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9064, http://www.uniprot.org/uniprot/Q9UPR0 and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29185, http://www.uniprot.org/uniprot/Q4KWH8) form a family with PLCδ and PLCζ1 isoforms, but appear to lack catalytic activity. PLC‐δ2 has been cloned from bovine sources [http://www.ncbi.nlm.nih.gov/pubmed/1848183?dopt=AbstractPlus].

Overview

608Phospholipase A2 (PLA2, EC 3.1.1.4) cleaves the sn‐2 fatty acid of phospholipids, primarily phosphatidylcholine, to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2508 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391. Most commonly‐used inhibitors (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5149, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5142 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5218) are either non‐selective within the family of phospholipase A2 enzymes or have activity against other eicosanoid‐metabolising enzymes.

Secreted or extracellular forms

609sPLA2‐1B, sPLA2‐2A, sPLA2‐2D, sPLA2‐2E, sPLA2‐2F, sPLA2‐3, sPLA2‐10 and sPLA2‐12A

Cytosolic, calcium‐dependent forms

610cPLA2‐4A, cPLA2‐4B, cPLA2‐4C, cPLA2‐4D, cPLA2‐4E and cPLA2‐4F

Other forms

611PLA2‐G5, iPLA2‐G6, PLA2‐G7 and PAFAH2 (platelet‐activating factor acetylhydrolase 2)

Comments

612The sequence of PLA2‐2C suggests a lack of catalytic activity, while PLA2‐12B (GXIIB, GXIII sPLA2‐like) appears to be catalytically inactive [http://www.ncbi.nlm.nih.gov/pubmed/14516201?dopt=AbstractPlus]. A further fragment has been identified with sequence similarities to Group II PLA2 members. Otoconin 90 (OC90) shows sequence homology to PLA2‐G10.

613A 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 [http://www.ncbi.nlm.nih.gov/pubmed/7548076?dopt=AbstractPlus]. The binding protein appears to have clearance function for circulating secretory phospholipase A2, as well as signalling functions, and is a candidate antigen for idiopathic membraneous nephropathy [http://www.ncbi.nlm.nih.gov/pubmed/19571279?dopt=AbstractPlus].

614PLA2‐G7 and PAFAH2 also express platelet‐activating factor acetylhydrolase activity (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.1.47).

Overview

621Phosphatidylcholine‐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 [http://www.ncbi.nlm.nih.gov/pubmed/2186929?dopt=AbstractPlus].

Comments

622A lysophospholipase D activity (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3357, http://www.uniprot.org/uniprot/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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2906) from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2508, but also cleaves http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 (see Goding et al., 2003 [http://www.ncbi.nlm.nih.gov/pubmed/12757929?dopt=AbstractPlus]). Additionally, an N‐acylethanolaminespecific phospholipase D (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:21683, http://www.uniprot.org/uniprot/Q6IQ20) has been characterized, which appears to have a role in the generation of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=273/endovanilloids, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 [http://www.ncbi.nlm.nih.gov/pubmed/14634025?dopt=AbstractPlus]. This enzyme activity appears to be enhanced by polyamines in the physiological range [http://www.ncbi.nlm.nih.gov/pubmed/12047899?dopt=AbstractPlus] and fails to transphosphatidylate with alcohols [http://www.ncbi.nlm.nih.gov/pubmed/10428468?dopt=AbstractPlus].

623Three further, less well‐characterised isoforms are PLD3 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17158, http://www.uniprot.org/uniprot/Q8IV08, other names Choline phosphatase 3, HindIII K4L homolog, Hu‐K4), PLD4 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:23792, http://www.uniprot.org/uniprot/Q96BZ4, other names Choline phosphatase 4, Phosphatidylcholine‐hydrolyzing phospholipase, D4C14orf175 UNQ2488/PRO5775) and PLD5 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:26879, http://www.uniprot.org/uniprot/Q8N7P1). PLD3 has been reported to be involved in myogenesis [http://www.ncbi.nlm.nih.gov/pubmed/22428023?dopt=AbstractPlus]. PLD4 is described not to have phospholipase D catalytic activity [http://www.ncbi.nlm.nih.gov/pubmed/21085684?dopt=AbstractPlus], but has been associated with inflammatory disorders [http://www.ncbi.nlm.nih.gov/pubmed/22446963?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23577190?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23124809?dopt=AbstractPlus]. Sequence analysis suggests that PLD5 is catalytically inactive.

Overview

627Lipid 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

631Phosphatidylinositol 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

632Phosphatidylinositol 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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:795 (http://www.uniprot.org/uniprot/Q13315) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3942 (http://www.uniprot.org/uniprot/P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3Krelated kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium‐binding domain and helical domains, alongside structurally‐conserved catalytic domains. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6004 are widely‐used inhibitors of PI3K activities. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.

633Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5‐bisphosphate to generate phosphatidylinositol 3,4,5‐trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110ß and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linkedmore with GPCR signalling.

634Class 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, PI3KC2α, ß and ß, and include Ras‐binding, Phox homology and two C2domains.

635The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).

636Phosphatidylinositol 4‐kinases

637Phosphatidylinositol 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

638PI3K activation is one of the most important signal transduction pathways used to transmit signals from cell‐surface receptors to regulate intracellular processes (cell growth, survival, proliferation and movement). PI3K catalytic (and regulatory) subunits play vital roles in normal cell function and in disease. Progress made in developing PI3K‐targeted agents as potential therapeutics for treating cancer and other diseases is reviewed by Fruman et al. (2017) [http://www.ncbi.nlm.nih.gov/pubmed/28802037?dopt=AbstractPlus].

639Type 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 [http://www.ncbi.nlm.nih.gov/pubmed/9367159?dopt=AbstractPlus]. This enzyme family is also known as type I PIP(5)Ks.

640Type 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 [http://www.ncbi.nlm.nih.gov/pubmed/9367159?dopt=AbstractPlus]. This enzyme family is also known as type II PIP(5)Ks.

641SPHK1 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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2407, which is used to treat some forms of multiple sclerosis) to a mimic of S1P and that acts as a functional antagonist of S1P1 receptors. Inhibitors of SPHK1 and SPHK2 have therapeutic potential in many diseases.

Comments

642http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10219 is competitive with ATP; other SPHK inhibitors are competitive with sphingosine. ABC294640 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6624) has known off‐target effects on dihydroceramide desaturase (DEGS1) [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26494858?dopt=AbstractPlus]) and induces proteasomal degradation of SK1 [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus]. ABC294640 is in clinical trials for advanced cholangiocarcinoma, advanced hepatocellular carcinoma and refractory/relapsed multiple myeloma (to view ClinicalTrials.gov list click https://clinicaltrials.gov/ct2/results?cond=&term=ABC294640).

Comments

649http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 also inhibits type III phosphatidylinositol 4‐kinases and polo‐like kinase [http://www.ncbi.nlm.nih.gov/pubmed/15664519?dopt=AbstractPlus]. PIK93 also inhibits PI 3‐kinases [http://www.ncbi.nlm.nih.gov/pubmed/16647110?dopt=AbstractPlus]. Adenosine activates http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=3.

Overview

653PIP2 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.

Overview

657Haem oxygenase (heme,hydrogen‐donor:oxygen oxidoreductase (α‐methene‐oxidizing, hydroxylating)), http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=1.14.99.3, converts http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4349 into http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5153 and carbonmonoxide, utilizing http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3041 as cofactor.

Comments

658The existence of a third non‐catalytic version of haem oxygenase, HO3, has been proposed, although this has been suggested to be a pseudogene [http://www.ncbi.nlm.nih.gov/pubmed/15246535?dopt=AbstractPlus]. The chemical http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5279 acts as a haem oxygenase inhibitor in rat liver with an IC50 value of 11 nM [http://www.ncbi.nlm.nih.gov/pubmed/6947237?dopt=AbstractPlus].

Overview

665Hydrogen 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. For an authoritative review on the pharmacological modulation of H2S levels, see Szabo and Papapetropoulos, 2017 [http://www.ncbi.nlm.nih.gov/pubmed/28978633?dopt=AbstractPlus].

Overview

668Listed 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 (http://www.uniprot.org/uniprot/P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone‐sensitive lipase is also a relatively non‐selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.

Overview

673The sugar alcohol D‐myo‐inositol is a component of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244, where the principal second messenger is inositol 1,4,5‐trisphosphate, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222, which acts at intracellular ligand‐gated ion channels, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=123 to elevate intracellular calcium. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 is recycled to inositol by phosphatases or phosphorylated to form other active inositol polyphosphates. Inositol produced from dephosphorylation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 is recycled into membrane phospholipid under the influence of phosphatidyinositol synthase activity (CDP‐diacylglycerol‐inositol 3‐phosphatidyltransferase [http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.8.11]).

674Inositol 1,4,5‐trisphosphate 3‐kinases (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.1.127, http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000001260) catalyse the generation of inositol 1,3,4,5‐tetrakisphosphate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5202) from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222. IP3 kinase activity is enhanced in the presence of calcium/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2351 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1442 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1445 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1449, http://www.uniprot.org/uniprot/P62158) [http://www.ncbi.nlm.nih.gov/pubmed/2559811?dopt=AbstractPlus].

675Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=280.

676Members of this family exhibit phosphatase activity towards IP3, as well as towards other inositol derivatives, including the phospholipids http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2387 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2353. With http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 as substrate, 1‐phosphatase (http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.57) generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5119, 4‐phosphatases (http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.66, http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000001432) generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5099 and 5‐phosphatases (http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.36 or http://www.genome.jp/dbget‐bin/www_bget?ec:3.1.3.56) generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5098.

677Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=281.

Comments

678In vitro analysis suggested http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5202 were poor substrates for SKIP, synaptojanin 1 and synaptojanin 2, but suggested that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2387 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2353 were more efficiently hydrolysed [http://www.ncbi.nlm.nih.gov/pubmed/15474001?dopt=AbstractPlus].

Overview

679Inositol monophosphatase (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=3.1.3.25, IMPase, myo‐inositol‐1(or 4)‐phosphate phosphohydrolase) is a magnesium‐dependent homodimer which hydrolyses myoinositol monophosphate to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4495 and phosphate. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5195 may be a physiological phosphate acceptor. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5212 is a nonselective un‐competitive inhibitor more potent at IMPase 1 (pKi ca. 3.5, [http://www.ncbi.nlm.nih.gov/pubmed/1377913?dopt=AbstractPlus]; pIC50 3.2, [http://www.ncbi.nlm.nih.gov/pubmed/17068342?dopt=AbstractPlus]) than IMPase 2 (pIC50 1.8‐2.1, [http://www.ncbi.nlm.nih.gov/pubmed/17068342?dopt=AbstractPlus]). IMPase activity may be inhibited competitively by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5208 (pKi 5.5, [http://www.ncbi.nlm.nih.gov/pubmed/1377913?dopt=AbstractPlus]), although the enzyme selectivity is not yet established.

Comments

680Polymorphisms in either of the genes encoding these enzymes have been linked with bipolar disorder [http://www.ncbi.nlm.nih.gov/pubmed/10822345?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9339367?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9322233?dopt=AbstractPlus]. Disruption of the gene encoding IMPase 1, but not IMPase 2, appears to mimic the effects of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5212 in mice [http://www.ncbi.nlm.nih.gov/pubmed/16841073?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17460611?dopt=AbstractPlus].

Overview

685Protein kinases (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=2.7.11.1) use the co‐substrate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 to phosphorylate serine and/or threonine residues on target proteins. Analysis of the human genome suggests the presence of 518 protein kinases in man (divided into 15 subfamilies), with over 100 protein kinase‐like pseudogenes [http://www.ncbi.nlm.nih.gov/pubmed/12471243?dopt=AbstractPlus]. It is beyond the scope of the Concise Guide to list all these protein kinase activities, but full listings are available on the ’Detailed page’ provided for each enzyme.

686Most 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 concentrations may be influential in responses to inhibitors, since the majority are directed at the ATP binding site [http://www.ncbi.nlm.nih.gov/pubmed/10998351?dopt=AbstractPlus].

687Rho 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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:681 (http://www.uniprot.org/uniprot/Q92888, p115‐RhoGEF), which in turn may be activated by Gα12/13 subunits [http://www.ncbi.nlm.nih.gov/pubmed/9641915?dopt=AbstractPlus].

Overview

691Protein kinase C is the target for the tumour‐promoting phorbol esters, such as tetradecanoyl‐β‐phorbol acetate (TPA, also known as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2341).

692Classical protein kinase C isoforms: PKCα, PKCβ, and PKCγ are activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=707 and diacylglycerol, and may be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5193, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5156, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5192, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5953 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5259.

693Novel protein kinase C isoforms: PKC δ, PKC ∈, PKC η, PKC ϑ and PKC μ are activated by diacylglycerol and may be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5156, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5192 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5953.

694Atypical protein kinase C isoforms: PKC ι, PKC ζ.

Overview

700Five 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. All five of the C‐terminal domain kinases can phosphorylate Ser5, but only CDK9, CDK12, and CDK13 can phosphorylate at Ser2 [http://www.ncbi.nlm.nih.gov/pubmed/24879308?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22512864?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25561469?dopt=AbstractPlus].

Comments on Cyclin‐dependent kinase (CDK) family

701The development of CDK inhibitors as anticancer drugs is reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/26115571?dopt=AbstractPlus], with detailed content covering CDK4 and CDK6 inhibitors that are under clinical evaluation. Data produced by Jorda et al. (2018) highlights the caution that must be used when deploying commercially available CDK inhibitors as pharmacological probes [http://www.ncbi.nlm.nih.gov/pubmed/30234987?dopt=AbstractPlus], as most of them are more promiscuous in their selectivity than indicated. To make their findings easily accessible the Jorda data is hosted on the http://rustreg.upol.cz/CDKiDB/.

Overview

706Janus kinases (JAKs) are a fam.ily of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). They are essential for cytokine signalling and are strongly linked to both cancer and inflammatory diseases.

707Activation 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

708In 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.

709The primary T cell Src kinases are Lck and Fyn; the main B cell Srcs are Lyn, Fyn and Blk. Mast cells express Fyn and Lyn, with low expression of Src.

Overview

716Lanosterol 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3039 and the mitochondrial generation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3040) are also associated with oxidation of fatty acids.

Overview

722The 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

723TYMS 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.

Overview

726Paraoxonases (PON) are calcium‐dependent esterases, whichmay be involved in lipoprotein turnover and the conversion of lactone statin prodrugs, as well as being targets of organophosphates, such as the insecticide paraoxon.

Overview

729Peptidases 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.‐).

730Since 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 [493] (with whom we collaborate) as an information resource [http://www.ncbi.nlm.nih.gov/pubmed/26527717?dopt=AbstractPlus].

731Presenilin (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) [http://www.ncbi.nlm.nih.gov/pubmed/2881207?dopt=AbstractPlus] in the generation of amyloid beta (Aβ) [http://www.ncbi.nlm.nih.gov/pubmed/21115843?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12660785?dopt=AbstractPlus]. Given that the accumulation and aggregation of Aβ in the brain is pivotal in the development of Alzheimer's disease (AD), inhibition of PS activity is one mechanism being investigated as a therapeutic option for AD [http://www.ncbi.nlm.nih.gov/pubmed/11378516?dopt=AbstractPlus]. Several small molecule inhibitors of PS‐1 have been investigated, with some reaching early clinical trials, but none have been formally approved. Dewji et al. (2015) have reported that small peptide fragments of human PS‐1 can significantly inhibit Aβ production (total Aβ, Aβ40 and Aβ42) both in vitro and when infused in to the brains of APP transgenic mice [http://www.ncbi.nlm.nih.gov/pubmed/25923432?dopt=AbstractPlus]. The most active small peptides in this report were http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8344 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8345, from the amino‐terminal domain of PS‐1.

732Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=727.

733Caspases, (http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=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.

734Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=734.

Comments

735CARD16 (Caspase recruitment domain‐containing protein 16, caspase‐1 inhibitor COP, CARD only domain‐containing protein 1, pseudo interleukin‐1β converting enzyme, pseudo‐ICE, http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000204397;r=11:104912053‐104972158) shares sequence similarity with some of the caspases.

Overview

736Aminopeptidases 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 [http://www.ncbi.nlm.nih.gov/pubmed/8440407?dopt=AbstractPlus].

737Matrix metalloproteinases (MMP) are calcium‐ and zinc‐dependent proteinases regulating the extracellular matrix and are often divided (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/17275314?dopt=AbstractPlus]) on functional and structural bases into gelatinases, collagenases, stromyelinases and matrilysins, as well as membrane type‐MMP (MT‐MMP).

Comments

738A number of small molecule ‘broad spectrum’ inhibitors of MMP have been described, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5220 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5145.

739Tissue inhibitors of metalloproteinase (TIMP) proteins are endogenous inhibitors acting to chelate MMP proteins: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5309 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11820, http://www.uniprot.org/uniprot/P01033), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5310 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11821, http://www.uniprot.org/uniprot/P16035), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5311 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11822, http://www.uniprot.org/uniprot/P35625), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5312 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11823, http://www.uniprot.org/uniprot/Q99727)

Overview

740ADAM (A Disintegrin And Metalloproteinase domain containing proteins) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.

741ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.

742Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=739.

Comments

743Additional ADAM family members include AC123767.2 (cDNA FLJ58962, moderately similar tomouse ADAM3, ENSG00000231168), AL160191.3 (ADAM21‐like protein, http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000235812;r=14:70712470‐70714518), AC136428.3‐2 (ENSG00000185520) and ADAMDEC1 (decysin 1, http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000134028;r=8:24241798‐24263526).

744Other ADAMTS family members include AC104758.12‐5 (FLJ00317 protein Fragment ENSG00000231463), AC139425.3‐1 (ENSG00000225577), and AC126339.6‐1 (ENSG00000225734).

745Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N‐acetaspartylglutamate to form N‐acetylaspartate and L‐glutamate. In the gut, the enzyme assists in the assimilation of folate by hydrolysing dietary poly‐gamma‐glutamylfolate. The enzyme is highly expressed in the prostate, and its expression is up‐regulated in cancerous tissue. A tagged version of the antibody http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6878 has been used for imaging purposes.

Overview

746The T1 macropain beta subunits form the catalytic proteinase core of the 20S proteasome complex [http://www.ncbi.nlm.nih.gov/pubmed/16142822?dopt=AbstractPlus]. This catalytic core enables the degradation of peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the cleavage site. The β5 subunit is the principal target of the approved drug proteasome inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6391.

747One 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 [http://www.ncbi.nlm.nih.gov/pubmed/18836590?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25083925?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19506257?dopt=AbstractPlus]. Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry. Several monoclonal antibodies including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6744, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7343, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7730, RG‐7652 and LY3015014 are under development. One RNAi therapeutic, code named ALN‐PCS02, is also in development [http://www.ncbi.nlm.nih.gov/pubmed/24145894?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24094767?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18695239?dopt=AbstractPlus].

748Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=755.

749The 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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8605, http://www.uniprot.org/uniprot/Q86W56).

Overview

753Hypoxia‐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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4910; https://www.uniprot.org/uniprot/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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:700; https://www.uniprot.org/uniprot/P27540), thereby allowing interaction with the genome as a transcription factor.

Overview

759S1P (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=911) 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.

760SPHK1 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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2407, which is used to treat some forms of multiple sclerosis) to a mimic of S1P and that acts as a functional antagonist of S1P1 receptors. Inhibitors of SPHK1 and SPHK2 have therapeutic potential in many diseases.

Comments

761http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10219 is competitive with ATP; other SPHK inhibitors are competitive with sphingosine. ABC294640 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6624) has known off‐target effects on dihydroceramide desaturase (DEGS1) [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26494858?dopt=AbstractPlus]) and induces proteasomal degradation of SK1 [http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus]. ABC294640 is in clinical trials for advanced cholangiocarcinoma, advanced hepatocellular carcinoma and refractory/relapsed multiple myeloma (to view ClinicalTrials.gov list click https://clinicaltrials.gov/ct2/results?cond=&term=ABC294640).

Comments

768SGPP1 and SGPP2 are non‐redundant endoplasmic reticulum enzymes that dephosphorylate intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=911. The phenotype of Sgpp1(‐/‐) mice differ with genetic background. Sgpp2(‐/‐) mice are also available. No specific SGPP inhibitors available [http://www.ncbi.nlm.nih.gov/pubmed/22052905?dopt=AbstractPlus].

Comments

774http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6626 (2‐Acetyl‐5‐tetrahydroxybutyl imidazole) inhibits the enzyme activity in intact cell preparations [http://www.ncbi.nlm.nih.gov/pubmed/16151014?dopt=AbstractPlus]. Recessive mutations in the S1P lyase (SGPL1) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS) [http://www.ncbi.nlm.nih.gov/pubmed/30274713?dopt=AbstractPlus]. A Phase 2 clinical trial of LX3305 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9851) for rheumatoid arthritis has been completed (see https://clinicaltrials.gov/ct2/show/NCT00903383).

Overview

779The thyroid hormones triiodothyronine and thyroxine, usually abbreviated as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635, respectively, are synthesized in the thyroid gland by sequential metabolism of tyrosine residues in the glycosylated homodimeric protein thyroglobulin (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11764, http://www.uniprot.org/uniprot/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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3423, http://www.uniprot.org/uniprot/P11678), lactoperoxidase (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6678, http://www.uniprot.org/uniprot/P22079) and myeloperoxidase (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7218, http://www.uniprot.org/uniprot/P05164). Circulating thyroid hormone is bound to thyroxine‐binding globulin (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11583, http://www.uniprot.org/uniprot/P05543).

Tissue deiodinases

780These are 1 TM selenoproteins that remove an iodine from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635 (3,3′,5,5′‐tetraiodothyronine) to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634 (3,3′,5‐triiodothyronine, a more potent agonist at thyroid hormone receptors) or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2636 (rT3, 3,3′,5′‐triiodothyronine, a relatively inactive analogue). DIO1 is also able to deiodinate RT3 to form 3,3′‐diidothyronine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6648). Iodotyrosine deiodinase is a 1TM homodimeric enzyme.

Overview

791Farnesyltransferase 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) [http://www.ncbi.nlm.nih.gov/pubmed/8621375?dopt=AbstractPlus]. Protein farnesyltransferase catalyses the post‐translational formation of a thioether linkage between the C‐1 of an isoprenyl group and a cysteine residue fourth from the C‐terminus of a protein (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) [http://www.ncbi.nlm.nih.gov/pubmed/7756316?dopt=AbstractPlus]. Farnesyltransferase is a dimer, composed of an alpha and beta subunit and requires Mg2+ and Zn2+ ions as cofactors. The active site is located between the subunits. Prenylation creates a hydrophobic domain on protein tails which acts as a membrane anchor.

792Substrates 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.

793In relation to the causative association between oncogenic Ras proteins and cancer, farnesyltransferase has become an important mechanistic drug discovery target.

794Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=898.

Overview

799Histone 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.

800The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:

801Class I contains HDACs 1, 2, 3 and 8

802Class IIa contains HDACs 4, 5, 7 and 9

803Class IIb contains HDACs 6 and 10

804Class III contains the sirtuins (SIRT1‐7)

805Class IV contains only HDAC11.

806Classes 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 [http://www.ncbi.nlm.nih.gov/pubmed/20132909?dopt=AbstractPlus].

807HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non‐histone proteins [http://www.ncbi.nlm.nih.gov/pubmed/19608861?dopt=AbstractPlus] such as microtubules [http://www.ncbi.nlm.nih.gov/pubmed/12024216?dopt=AbstractPlus], the hsp90 chaperone [http://www.ncbi.nlm.nih.gov/pubmed/15916966?dopt=AbstractPlus] and the tumour suppressor p53 [http://www.ncbi.nlm.nih.gov/pubmed/11099047?dopt=AbstractPlus].

808Dysregulated HDACactivity has been identified in cancer cells and tumour tissues [http://www.ncbi.nlm.nih.gov/pubmed/11704848?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19383284?dopt=AbstractPlus], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [http://www.ncbi.nlm.nih.gov/pubmed/24382387?dopt=AbstractPlus]. Several small molecule HDAC inhibitors are already approved for clinical use: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7006, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6852, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7489, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7496, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7009 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8305. HDACs and HDAC inhibitors currently in development as potential anti‐cancer therapeutics are reviewed by Simó‐Riudalbas and Esteller (2015) [http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus].

Overview

815In humans, the peptidyl arginine deiminases (PADIs; http://www.genenames.org/cgi‐bin/genefamilies/set/677) 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 [http://www.ncbi.nlm.nih.gov/pubmed/12606753?dopt=AbstractPlus]. Overexpression and/or increased PADI activity is observed in several diseases, including rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer [http://www.ncbi.nlm.nih.gov/pubmed/23175390?dopt=AbstractPlus]. Pharmacological PADI inhibition reverses protein‐hypercitrullination and disease in mouse models of multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/23118341?dopt=AbstractPlus].

816Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=918.

Overview

820small 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.

821The RAS proteins (HRAS, NRAS and KRAS) are small membrane‐localised G protein‐likemolecules of 21 kd. They act as an on/off switch linking receptor and non‐receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.

822The RAS proto‐oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP‐hydrolysing ability of the proteins causing constitutive activation [http://www.ncbi.nlm.nih.gov/pubmed/7900159?dopt=AbstractPlus], which leads to increased cell proliferation and decreased apoptosis [http://www.ncbi.nlm.nih.gov/pubmed/17721087?dopt=AbstractPlus]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [http://www.ncbi.nlm.nih.gov/pubmed/22004085?dopt=AbstractPlus].

823Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=897.

Overview

831The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface ( see http://www.genenames.org/cgi‐bin/genefamilies/set/388, http://www.genenames.org/cgi‐bin/genefamilies/set/388 ).

832Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=938.

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134.
Deng X et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24374347?dopt=AbstractPlus
Not in our library
135.
DePinto W et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/17121911?dopt=AbstractPlus
Not in our library
136.
Desai B et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23441572?dopt=AbstractPlus
Not in our library
137.
Dessauer CW et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28255005?dopt=AbstractPlus
Not in our library
138.
Desta Z et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12222994?dopt=AbstractPlus
Not in our library
139.
Dewji NN et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25923432?dopt=AbstractPlus
Not in our library
140.
Di Paolo JA et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21113169?dopt=AbstractPlus
Not in our library
141.
Di Santo R et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15974574?dopt=AbstractPlus
Not in our library
142.
Diel S et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16275644?dopt=AbstractPlus
Not in our library
143.
DiMauro EF et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17280833?dopt=AbstractPlus
Not in our library
144.
Ding Q et al (2006 ) Patent number: US7094896.
Not in our library
145.
Ding Q et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15385642?dopt=AbstractPlus
Not in our library
146.
Divanovic S et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23956430?dopt=AbstractPlus
Not in our library
147.
Dixon RA et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2300173?dopt=AbstractPlus
Not in our library
148.
Dodds HM et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9655905?dopt=AbstractPlus
Not in our library
149.
Doe C et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17018693?dopt=AbstractPlus
Not in our library
150.
Draganov DI et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15772423?dopt=AbstractPlus
Not in our library
151.
Drake FH et al (1989 ) http://www.ncbi.nlm.nih.gov/pubmed/2557897?dopt=AbstractPlus
Not in our library
152.
Drummond GS et al (1981 ) http://www.ncbi.nlm.nih.gov/pubmed/6947237?dopt=AbstractPlus
Not in our library
153.
Dunford JE et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18327899?dopt=AbstractPlus
Not in our library
154.
Dutour R et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28458135?dopt=AbstractPlus
Not in our library
155.
Eckhardt M et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/18052023?dopt=AbstractPlus
Not in our library
156.
Edmondson SD et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/14592490?dopt=AbstractPlus
Not in our library
157.
Engler TA et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15267232?dopt=AbstractPlus
Not in our library
158.
Enserink JM et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12402047?dopt=AbstractPlus
Not in our library
159.
Erba F et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11172730?dopt=AbstractPlus
Not in our library
160.
Esclapez M et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8126575?dopt=AbstractPlus
Not in our library
161.
Esteller M. (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18337604?dopt=AbstractPlus
Not in our library
162.
Evenäs J et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24508129?dopt=AbstractPlus
Not in our library
163.
Fabrias G et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22200621?dopt=AbstractPlus
Not in our library
164.
Faraci WS et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8937711?dopt=AbstractPlus
Not in our library
165.
Faul MM et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12749884?dopt=AbstractPlus
Not in our library
166.
Faull AW et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7861416?dopt=AbstractPlus
Not in our library
167.
Fawcett L et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10725373?dopt=AbstractPlus
Not in our library
168.
Fer M et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18577768?dopt=AbstractPlus
Not in our library
169.
Fischer L et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15197110?dopt=AbstractPlus
Not in our library
170.
Fisher DA et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9624146?dopt=AbstractPlus
Not in our library
171.
Fisher DA et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9618252?dopt=AbstractPlus
Not in our library
172.
Fiskerstrand T et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20797687?dopt=AbstractPlus
Not in our library
173.
Fitzgerald K et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24094767?dopt=AbstractPlus
Not in our library
174.
Folkes AJ et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18754654?dopt=AbstractPlus
Not in our library
175.
Fontana E et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16248836?dopt=AbstractPlus
Not in our library
176.
Forsyth T et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/23127890?dopt=AbstractPlus
Not in our library
177.
Foss FM et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21493798?dopt=AbstractPlus
Not in our library
178.
Foti RS et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22239545?dopt=AbstractPlus
Not in our library
179.
Fowler CJ. (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17618306?dopt=AbstractPlus
Not in our library
180.
Frank-Kamenetsky M et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18695239?dopt=AbstractPlus
Not in our library
181.
French KJ et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20061445?dopt=AbstractPlus
Not in our library
182.
Fruman DA et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28802037?dopt=AbstractPlus
Not in our library
183.
Fry DW et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15542782?dopt=AbstractPlus
Not in our library
184.
Fujishige K et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10373451?dopt=AbstractPlus
Not in our library
185.
Fukami T et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16636685?dopt=AbstractPlus
Not in our library
186.
Fuller RW et al (1981 ) http://www.ncbi.nlm.nih.gov/pubmed/6268095?dopt=AbstractPlus
Not in our library
187.
Furet P et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23726034?dopt=AbstractPlus
Not in our library
188.
Furfine ES et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7756316?dopt=AbstractPlus
Not in our library
189.
Furster C et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/9931427?dopt=AbstractPlus
Not in our library
190.
Fürstenberger G et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12432921?dopt=AbstractPlus
Not in our library
191.
Gainer JV et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15611369?dopt=AbstractPlus
Not in our library
192.
Galemmo RA Jr. et al (1996 ) Bioorg Med Chem Lett 6: 2913-2918
Not in our library
193.
Galli A et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8039548?dopt=AbstractPlus
Not in our library
194.
Gangjee A et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22739090?dopt=AbstractPlus
Not in our library
195.
Gao BN et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1946437?dopt=AbstractPlus
Not in our library
196.
Gao P et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22970244?dopt=AbstractPlus
Not in our library
197.
Gao X et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17110384?dopt=AbstractPlus
Not in our library
198.
Garbarg M et al (1980 ) http://www.ncbi.nlm.nih.gov/pubmed/7452304?dopt=AbstractPlus
Not in our library
199.
Garcia-Manero G et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21220589?dopt=AbstractPlus
Not in our library
200.
Gardner C et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10872825?dopt=AbstractPlus
Not in our library
201.
Garvey EP et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9030556?dopt=AbstractPlus
Not in our library
202.
Garvey EP et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/7523409?dopt=AbstractPlus
Not in our library
203.
Gehrmann T et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10101268?dopt=AbstractPlus
Not in our library
204.
Ghafouri N et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15492019?dopt=AbstractPlus
Not in our library
205.
Giacobini E. (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12675140?dopt=AbstractPlus
Not in our library
206.
Gilmartin AG et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21245089?dopt=AbstractPlus
Not in our library
207.
Giroux A et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19748780?dopt=AbstractPlus
Not in our library
208.
Glazer RI et al (1986 ) http://www.ncbi.nlm.nih.gov/pubmed/3457563?dopt=AbstractPlus
Not in our library
209.
Goding JW et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12757929?dopt=AbstractPlus
Not in our library
210.
Golas JM et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12543790?dopt=AbstractPlus
Not in our library
211.
Golde TE et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11378516?dopt=AbstractPlus
Not in our library
212.
Gomaa MS et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21838328?dopt=AbstractPlus
Not in our library
213.
Gorman RR et al (1983 ) http://www.ncbi.nlm.nih.gov/pubmed/6316421?dopt=AbstractPlus
Not in our library
214.
Graf C et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18612076?dopt=AbstractPlus
Not in our library
215.
Graham DW et al (1987 ) http://www.ncbi.nlm.nih.gov/pubmed/3495664?dopt=AbstractPlus
Not in our library
216.
Gray AP et al (1988 ) http://www.ncbi.nlm.nih.gov/pubmed/3351860?dopt=AbstractPlus
Not in our library
217.
Greenblatt DJ et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25923589?dopt=AbstractPlus
Not in our library
218.
Greengard O et al (1976 ) http://www.ncbi.nlm.nih.gov/pubmed/944951?dopt=AbstractPlus
Not in our library
219.
Griffith DA et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23981033?dopt=AbstractPlus
Not in our library
220.
Groarke DA et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11160875?dopt=AbstractPlus
Not in our library
221.
Gryglewski RJ et al (1976 ) http://www.ncbi.nlm.nih.gov/pubmed/824685?dopt=AbstractPlus
Not in our library
222.
Gryglewski RJ et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7778318?dopt=AbstractPlus
Not in our library
223.
Gschwendt M et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8772178?dopt=AbstractPlus
Not in our library
224.
Guengerich FP et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21737533?dopt=AbstractPlus
Not in our library
225.
Guengerich FP et al (1986 ) http://www.ncbi.nlm.nih.gov/pubmed/3514607?dopt=AbstractPlus
Not in our library
226.
Gupta R et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19149538?dopt=AbstractPlus
Not in our library
227.
Guranowski A et al (1981 ) http://www.ncbi.nlm.nih.gov/pubmed/7470463?dopt=AbstractPlus
Not in our library
228.
Gustafsson D et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9459334?dopt=AbstractPlus
Not in our library
229.
Haber MT et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1654825?dopt=AbstractPlus
Not in our library
230.
Haefely WE et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2122653?dopt=AbstractPlus
Not in our library
231.
Hagishita S et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8809154?dopt=AbstractPlus
Not in our library
232.
Haj-Dahmane S et al (2018 ) http://www.ncbi.nlm.nih.gov/pubmed/29531087?dopt=AbstractPlus
Not in our library
233.
Hammond SM et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9013646?dopt=AbstractPlus
Not in our library
234.
Han G et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19416851?dopt=AbstractPlus
Not in our library
235.
Han L et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17260973?dopt=AbstractPlus
Not in our library
236.
Hanan EJ et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/23061660?dopt=AbstractPlus
Not in our library
237.
Hanaoka K et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28079151?dopt=AbstractPlus
Not in our library
238.
Handratta VD et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15828836?dopt=AbstractPlus
Not in our library
239.
Hanke JH et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8557675?dopt=AbstractPlus
Not in our library
240.
Hansen JD et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18676143?dopt=AbstractPlus
Not in our library
241.
Harmon SD et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16820285?dopt=AbstractPlus
Not in our library
242.
Harris CM et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/27519818?dopt=AbstractPlus
Not in our library
243.
Hartung IV et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23474388?dopt=AbstractPlus
Not in our library
244.
Hatae T et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8766713?dopt=AbstractPlus
Not in our library
245.
Hatzelmann A et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8381000?dopt=AbstractPlus
Not in our library
246.
Hauel NH et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/11960487?dopt=AbstractPlus
Not in our library
247.
Hausser A et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16100512?dopt=AbstractPlus
Not in our library
248.
Hayakawa M et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17601739?dopt=AbstractPlus
Not in our library
249.
Hayashi M et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9784418?dopt=AbstractPlus
Not in our library
250.
Hayashi S et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15246535?dopt=AbstractPlus
Not in our library
251.
Hays SJ et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9544206?dopt=AbstractPlus
Not in our library
252.
He Y et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28135237?dopt=AbstractPlus
Not in our library
253.
Heikkilä T et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17228860?dopt=AbstractPlus
Not in our library
254.
Helsby NA et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2291871?dopt=AbstractPlus
Not in our library
255.
Hepler JR et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8314796?dopt=AbstractPlus
Not in our library
256.
Hess KC et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16054031?dopt=AbstractPlus
Not in our library
257.
Hieke M et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21873070?dopt=AbstractPlus
Not in our library
258.
Hill J et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10781930?dopt=AbstractPlus
Not in our library
259.
Hiraku S et al (1986 ) http://www.ncbi.nlm.nih.gov/pubmed/3093741?dopt=AbstractPlus
Not in our library
260.
Hoffmann R et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10022832?dopt=AbstractPlus
Not in our library
261.
Hoffmann R et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9639573?dopt=AbstractPlus
Not in our library
262.
Homma Y et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7835339?dopt=AbstractPlus
Not in our library
263.
Horbert R et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26061392?dopt=AbstractPlus
Not in our library
264.
Horio T et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17376680?dopt=AbstractPlus
Not in our library
265.
Houslay MD et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12444918?dopt=AbstractPlus
Not in our library
266.
Howard S et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19143567?dopt=AbstractPlus
Not in our library
267.
Hsieh AC et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22367541?dopt=AbstractPlus
Not in our library
268.
Hsu KL et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/23103940?dopt=AbstractPlus
Not in our library
269.
Huang WS et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20513156?dopt=AbstractPlus
Not in our library
270.
Hubbert C et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12024216?dopt=AbstractPlus
Not in our library
271.
Hughes RO et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19631533?dopt=AbstractPlus
Not in our library
272.
Hughes SA et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/11138848?dopt=AbstractPlus
Not in our library
273.
Illenberger D et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12441352?dopt=AbstractPlus
Not in our library
274.
Illenberger D et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12509427?dopt=AbstractPlus
Not in our library
275.
Imanishi J et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21745460?dopt=AbstractPlus
Not in our library
276.
Imiya M et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9361377?dopt=AbstractPlus
Not in our library
277.
Irikura D et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19131342?dopt=AbstractPlus
Not in our library
278.
Ishida H et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1400444?dopt=AbstractPlus
Not in our library
279.
Ishikawa Y et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1618857?dopt=AbstractPlus
Not in our library
280.
Istvan ES et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11349148?dopt=AbstractPlus
Not in our library
281.
Iverson C et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19706763?dopt=AbstractPlus
Not in our library
282.
Iwami G et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7759492?dopt=AbstractPlus
Not in our library
283.
Jacobowitz O et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8440678?dopt=AbstractPlus
Not in our library
284.
Jagrat M et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21680183?dopt=AbstractPlus
Not in our library
285.
Jain MR et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28452143?dopt=AbstractPlus
Not in our library
286.
Jameson 2nd JB et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/25111178?dopt=AbstractPlus
Not in our library
287.
Jarvis MF et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/11082453?dopt=AbstractPlus
Not in our library
288.
Jhon DY et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8454637?dopt=AbstractPlus
Not in our library
289.
Jirousek MR et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8709095?dopt=AbstractPlus
Not in our library
290.
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Not in our library
291.
Johansen PA et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8592157?dopt=AbstractPlus
Not in our library
292.
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Not in our library
293.
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Not in our library
294.
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Not in our library
295.
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Not in our library
296.
Jorda R et al (2018 ) http://www.ncbi.nlm.nih.gov/pubmed/30234987?dopt=AbstractPlus
Not in our library
297.
Joshi KS et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17363486?dopt=AbstractPlus
Not in our library
298.
Kahraman M et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15615534?dopt=AbstractPlus
Not in our library
299.
Kalgutkar AS et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/11844663?dopt=AbstractPlus
Not in our library
300.
Kamat SS et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25580854?dopt=AbstractPlus
Not in our library
301.
Kameoka J et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8101391?dopt=AbstractPlus
Not in our library
302.
Kang J et al (1987 ) http://www.ncbi.nlm.nih.gov/pubmed/2881207?dopt=AbstractPlus
Not in our library
303.
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Not in our library
304.
Kao YL et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9661650?dopt=AbstractPlus
Not in our library
305.
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Not in our library
306.
Kawabe J et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8206971?dopt=AbstractPlus
Not in our library
307.
Kedei N et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15126366?dopt=AbstractPlus
Not in our library
308.
Keith JM et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18693015?dopt=AbstractPlus
Not in our library
309.
Khan O et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22124371?dopt=AbstractPlus
Not in our library
310.
Kharasch ED et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18285471?dopt=AbstractPlus
Not in our library
311.
Kim JJ et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26206858?dopt=AbstractPlus
Not in our library
312.
Kim NN et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11258879?dopt=AbstractPlus
Not in our library
313.
Kimura S et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16105974?dopt=AbstractPlus
Not in our library
314.
Kitagawa D et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23279183?dopt=AbstractPlus
Not in our library
315.
Knight SD et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/24900173?dopt=AbstractPlus
Not in our library
316.
Knight ZA et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16647110?dopt=AbstractPlus
Not in our library
317.
Kobayashi T et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15040786?dopt=AbstractPlus
Not in our library
318.
Koch J et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8955159?dopt=AbstractPlus
Not in our library
319.
Kodimuthali A et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18686943?dopt=AbstractPlus
Not in our library
320.
Koeberle A et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/19053751?dopt=AbstractPlus
Not in our library
321.
Kohoutek J et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22512864?dopt=AbstractPlus
Not in our library
322.
Kondoh G et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15665832?dopt=AbstractPlus
Not in our library
323.
Kong F et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21438579?dopt=AbstractPlus
Not in our library
324.
Kotthaus J et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/19013076?dopt=AbstractPlus
Not in our library
325.
Kouzarides T. (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17320507?dopt=AbstractPlus
Not in our library
326.
Kovacs JJ et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15916966?dopt=AbstractPlus
Not in our library
327.
Kozasa T et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9641915?dopt=AbstractPlus
Not in our library
328.
Kramlinger VM et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/27059013?dopt=AbstractPlus
Not in our library
329.
Krapcho J et al (1988 ) http://www.ncbi.nlm.nih.gov/pubmed/2836590?dopt=AbstractPlus
Not in our library
330.
Krjukova J et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15302681?dopt=AbstractPlus
Not in our library
331.
Kunick C et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/14698171?dopt=AbstractPlus
Not in our library
332.
Kupperman E et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20160034?dopt=AbstractPlus
Not in our library
333.
Lafite P et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16495056?dopt=AbstractPlus
Not in our library
334.
Lahiri S et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16100120?dopt=AbstractPlus
Not in our library
335.
Lai HL et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10462552?dopt=AbstractPlus
Not in our library
336.
Lannutti BJ et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/20959606?dopt=AbstractPlus
Not in our library
337.
Laquerre S et al (2009 ) Mol Cancer Ther 8: B88
Not in our library
338.
Laviad EL et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18165233?dopt=AbstractPlus
Not in our library
339.
Lavieri RR et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20735042?dopt=AbstractPlus
Not in our library
340.
Lazer ES et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9083488?dopt=AbstractPlus
Not in our library
341.
Lee CH et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1322889?dopt=AbstractPlus
Not in our library
342.
Lefebvre HP et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17506720?dopt=AbstractPlus
Not in our library
343.
Lehmann TP et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23254310?dopt=AbstractPlus
Not in our library
344.
Leisle L et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16270062?dopt=AbstractPlus
Not in our library
345.
Lewis DF et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/20408502?dopt=AbstractPlus
Not in our library
346.
Li W et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17629278?dopt=AbstractPlus
Not in our library
347.
Li X et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24915291?dopt=AbstractPlus
Not in our library
348.
Li Y et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28802121?dopt=AbstractPlus
Not in our library
349.
Li Y et al (2018 ) http://www.ncbi.nlm.nih.gov/pubmed/29572189?dopt=AbstractPlus
Not in our library
350.
Li YL et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26314925?dopt=AbstractPlus
Not in our library
351.
Li-Hawkins J et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10748047?dopt=AbstractPlus
Not in our library
352.
Liang K et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25561469?dopt=AbstractPlus
Not in our library
353.
Libè R et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17395972?dopt=AbstractPlus
Not in our library
354.
Lim KG et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21620961?dopt=AbstractPlus
Not in our library
355.
Lin RJ et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11704848?dopt=AbstractPlus
Not in our library
356.
Lippert B et al (1977 ) http://www.ncbi.nlm.nih.gov/pubmed/856582?dopt=AbstractPlus
Not in our library
357.
Litvin TN et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12609998?dopt=AbstractPlus
Not in our library
358.
Liu F et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23594111?dopt=AbstractPlus
Not in our library
359.
Liu J et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23600958?dopt=AbstractPlus
Not in our library
360.
Liu KK et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/24900269?dopt=AbstractPlus
Not in our library
361.
Liu Q et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20860370?dopt=AbstractPlus
Not in our library
362.
Liu Q et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12047899?dopt=AbstractPlus
Not in our library
363.
Liu Q et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21322566?dopt=AbstractPlus
Not in our library
364.
Liu Y et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15664519?dopt=AbstractPlus
Not in our library
365.
Llerena A et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19102711?dopt=AbstractPlus
Not in our library
366.
Loetscher E et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23499842?dopt=AbstractPlus
Not in our library
367.
Long JZ et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19029917?dopt=AbstractPlus
Not in our library
368.
Lopez D. (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18836590?dopt=AbstractPlus
Not in our library
369.
Lopez I et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9582313?dopt=AbstractPlus
Not in our library
370.
Lotta T et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7703232?dopt=AbstractPlus
Not in our library
371.
Lou Y et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22394077?dopt=AbstractPlus
Not in our library
372.
Loughney K et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8557689?dopt=AbstractPlus
Not in our library
373.
Loveridge C et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20926375?dopt=AbstractPlus
Not in our library
374.
Luci DK et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24393039?dopt=AbstractPlus
Not in our library
375.
Ludwig J et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16610804?dopt=AbstractPlus
Not in our library
376.
Lunniss CJ et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19195882?dopt=AbstractPlus
Not in our library
377.
Luo J et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/11099047?dopt=AbstractPlus
Not in our library
378.
Luo JQ et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9207251?dopt=AbstractPlus
Not in our library
379.
Luo M et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15280375?dopt=AbstractPlus
Not in our library
380.
Luo W et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16570913?dopt=AbstractPlus
Not in our library
381.
Lustig KD et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8390980?dopt=AbstractPlus
Not in our library
382.
Lépine S et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/22052905?dopt=AbstractPlus
Not in our library
383.
Löhn M et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19597037?dopt=AbstractPlus
Not in our library
384.
M NK et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/27247428?dopt=AbstractPlus
Not in our library
385.
Ma L et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23584399?dopt=AbstractPlus
Not in our library
386.
Mahli A et al (2019 ) http://www.ncbi.nlm.nih.gov/pubmed/30380359?dopt=AbstractPlus
Not in our library
387.
Maier SA et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16245011?dopt=AbstractPlus
Not in our library
388.
Maira SM et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18606717?dopt=AbstractPlus
Not in our library
389.
Malerich JP et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/21106455?dopt=AbstractPlus
Not in our library
390.
Manning G et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12471243?dopt=AbstractPlus
Not in our library
391.
Mao C et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11356846?dopt=AbstractPlus
Not in our library
392.
Markman B et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22357447?dopt=AbstractPlus
Not in our library
393.
Marsell R et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22142634?dopt=AbstractPlus
Not in our library
394.
Martin MW et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16884310?dopt=AbstractPlus
Not in our library
395.
Martinez GR et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1311763?dopt=AbstractPlus
Not in our library
396.
Masferrer JL et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20378715?dopt=AbstractPlus
Not in our library
397.
Mason JM et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/25043604?dopt=AbstractPlus
Not in our library
398.
Matsuura K et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9792917?dopt=AbstractPlus
Not in our library
399.
Maurice DH et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24687066?dopt=AbstractPlus
Not in our library
400.
Mayer B et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9433128?dopt=AbstractPlus
Not in our library
401.
Mayhoub AS et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22386564?dopt=AbstractPlus
Not in our library
402.
McAllister G et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1377913?dopt=AbstractPlus
Not in our library
403.
McGaraughty S et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11160637?dopt=AbstractPlus
Not in our library
404.
McNaughton M et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/26934645?dopt=AbstractPlus
Not in our library
405.
Meanwell NA et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1321910?dopt=AbstractPlus
Not in our library
406.
Medvedev AE et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9564636?dopt=AbstractPlus
Not in our library
407.
Meldrum E et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1848183?dopt=AbstractPlus
Not in our library
408.
Meyers R et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9020160?dopt=AbstractPlus
Not in our library
409.
Michaeli T et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8389765?dopt=AbstractPlus
Not in our library
410.
Michaud A et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9187274?dopt=AbstractPlus
Not in our library
411.
Michie AM et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8730511?dopt=AbstractPlus
Not in our library
412.
Miller MR et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/26989199?dopt=AbstractPlus
Not in our library
413.
Mishra N et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21377879?dopt=AbstractPlus
Not in our library
414.
Miyake Y et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7794249?dopt=AbstractPlus
Not in our library
415.
Mizukami Y et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8389204?dopt=AbstractPlus
Not in our library
416.
Mizutani Y et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15823095?dopt=AbstractPlus
Not in our library
417.
Mlinar B et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/14511335?dopt=AbstractPlus
Not in our library
418.
Mochida H et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12450574?dopt=AbstractPlus
Not in our library
419.
Mohamed HA et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21189023?dopt=AbstractPlus
Not in our library
420.
Moncada S et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9228663?dopt=AbstractPlus
Not in our library
421.
Moore WM et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/7525961?dopt=AbstractPlus
Not in our library
422.
Mori S et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12939527?dopt=AbstractPlus
Not in our library
423.
Moscarello MA et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23118341?dopt=AbstractPlus
Not in our library
424.
Muftuoglu Y et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20413308?dopt=AbstractPlus
Not in our library
425.
Murthy SN et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10518533?dopt=AbstractPlus
Not in our library
426.
Nagahara N et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7608189?dopt=AbstractPlus
Not in our library
427.
Nagar B et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12154025?dopt=AbstractPlus
Not in our library
428.
Nakamura H et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19428245?dopt=AbstractPlus
Not in our library
429.
Nakano M et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19661213?dopt=AbstractPlus
Not in our library
430.
Nakashima T et al (1978 ) http://www.ncbi.nlm.nih.gov/pubmed/748042?dopt=AbstractPlus
Not in our library
431.
Nakaya Y et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/22829185?dopt=AbstractPlus
Not in our library
432.
Navia-Paldanius D et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22969151?dopt=AbstractPlus
Not in our library
433.
Nelson PH et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/1967654?dopt=AbstractPlus
Not in our library
434.
Nicholson AN et al (1981 ) http://www.ncbi.nlm.nih.gov/pubmed/6457252?dopt=AbstractPlus
Not in our library
435.
Nilsson T et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/19919823?dopt=AbstractPlus
Not in our library
436.
Niphakis MJ et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23731016?dopt=AbstractPlus
Not in our library
437.
Noshiro M et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2384150?dopt=AbstractPlus
Not in our library
438.
Nylander S et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22906130?dopt=AbstractPlus
Not in our library
439.
O'Hare T et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15930265?dopt=AbstractPlus
Not in our library
440.
Ochi T et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10720634?dopt=AbstractPlus
Not in our library
441.
Ogasawara D et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/26668358?dopt=AbstractPlus
Not in our library
442.
Ogasawara D et al (2019 ) http://www.ncbi.nlm.nih.gov/pubmed/30720278?dopt=AbstractPlus
Not in our library
443.
Ogura Y et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/27399000?dopt=AbstractPlus
Not in our library
444.
Oh SF et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21206090?dopt=AbstractPlus
Not in our library
445.
Ohnishi T et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17068342?dopt=AbstractPlus
Not in our library
446.
Okada M et al (2007 ) Oxazole compound and pharmaceutical composition Patent number: WO2007058338.
Not in our library
447.
Okada Y et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22446963?dopt=AbstractPlus
Not in our library
448.
Okamoto Y et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/14634025?dopt=AbstractPlus
Not in our library
449.
Onda T et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11602596?dopt=AbstractPlus
Not in our library
450.
Orning L et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1846352?dopt=AbstractPlus
Not in our library
451.
Osisami M et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22428023?dopt=AbstractPlus
Not in our library
452.
Oslund RC et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18605714?dopt=AbstractPlus
Not in our library
453.
Ottanà R et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15993594?dopt=AbstractPlus
Not in our library
454.
Overington JP et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus
Not in our library
455.
Pajunen AE et al (1979 ) http://www.ncbi.nlm.nih.gov/pubmed/438812?dopt=AbstractPlus
Not in our library
456.
Palanki MS et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17685602?dopt=AbstractPlus
Not in our library
457.
Pan Z et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17154430?dopt=AbstractPlus
Not in our library
458.
Panek RL et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9400019?dopt=AbstractPlus
Not in our library
459.
Park D et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8383116?dopt=AbstractPlus
Not in our library
460.
Parkkari T et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24879289?dopt=AbstractPlus
Not in our library
461.
Paterson JM et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10987815?dopt=AbstractPlus
Not in our library
462.
Pawelczyk T et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1497353?dopt=AbstractPlus
Not in our library
463.
Payne EJ et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19470632?dopt=AbstractPlus
Not in our library
464.
Penning TD et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9135032?dopt=AbstractPlus
Not in our library
465.
Perry MJ et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9631241?dopt=AbstractPlus
Not in our library
466.
Perzborn E et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20139357?dopt=AbstractPlus
Not in our library
467.
Petersen G et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10428468?dopt=AbstractPlus
Not in our library
468.
Pheneger J et al (2006 ) American College of Rheumatology. 2006 Annual Scientific Meeting. Abstract 794
Not in our library
469.
Philipp S et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20080539?dopt=AbstractPlus
Not in our library
470.
Piechulek T et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16172125?dopt=AbstractPlus
Not in our library
471.
Pinto DJ et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20503967?dopt=AbstractPlus
Not in our library
472.
Pinto-Bazurco Mendieta MA et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18672868?dopt=AbstractPlus
Not in our library
473.
Pireddu R et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/23275831?dopt=AbstractPlus
Not in our library
474.
Pitman MR et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25788259?dopt=AbstractPlus
Not in our library
475.
Plourde PV et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/7949201?dopt=AbstractPlus
Not in our library
476.
Pollard JR et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19320489?dopt=AbstractPlus
Not in our library
477.
Potter GA et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7608911?dopt=AbstractPlus
Not in our library
478.
Preininger AM et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16638972?dopt=AbstractPlus
Not in our library
479.
Premont RT et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8662814?dopt=AbstractPlus
Not in our library
480.
Purandare AV et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22015772?dopt=AbstractPlus
Not in our library
481.
Qiu W et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17166832?dopt=AbstractPlus
Not in our library
482.
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Not in our library
483.
Quintás-Cardama A et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20130243?dopt=AbstractPlus
Not in our library
484.
Rabionet M et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18308723?dopt=AbstractPlus
Not in our library
485.
Rai G et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/24672829?dopt=AbstractPlus
Not in our library
486.
Rai G et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20866075?dopt=AbstractPlus
Not in our library
487.
Rameh LE et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9367159?dopt=AbstractPlus
Not in our library
488.
Ramos-Espiritu L et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/27547922?dopt=AbstractPlus
Not in our library
489.
Randall MJ et al (1981 ) http://www.ncbi.nlm.nih.gov/pubmed/6795753?dopt=AbstractPlus
Not in our library
490.
Randall RW et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2186929?dopt=AbstractPlus
Not in our library
491.
Rao NL et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20110560?dopt=AbstractPlus
Not in our library
492.
Rask-Andersen M et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24016212?dopt=AbstractPlus
Not in our library
493.
Rawlings et al.. MEROPS
Not in our library
494.
Rawlings ND et al (2016 ) http://www.ncbi.nlm.nih.gov/pubmed/26527717?dopt=AbstractPlus
Not in our library
495.
Rawson DJ et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22100260?dopt=AbstractPlus
Not in our library
496.
Ray P et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21145740?dopt=AbstractPlus
Not in our library
497.
Raynaud FI et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19584227?dopt=AbstractPlus
Not in our library
498.
Reynisson J et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19303309?dopt=AbstractPlus
Not in our library
499.
Ribeiro A et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25874594?dopt=AbstractPlus
Not in our library
500.
Rice KD et al (2012 ) ACS Med Chem Lett 3: 416-421
Not in our library10.1021/ml300049d
501.
Riebeling C et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12912983?dopt=AbstractPlus
Not in our library
502.
Riendeau D et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15953724?dopt=AbstractPlus
Not in our library
503.
Riendeau D et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11160644?dopt=AbstractPlus
Not in our library
504.
Ring DB et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12606497?dopt=AbstractPlus
Not in our library
505.
Rivera VM et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21482695?dopt=AbstractPlus
Not in our library
506.
Robbins JD et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8709105?dopt=AbstractPlus
Not in our library
507.
Robinson DM et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17547476?dopt=AbstractPlus
Not in our library
508.
Ronn R et al (2016 ) Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof Patent number: WO20161778-45.
Not in our library
509.
Ropero S et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/19383284?dopt=AbstractPlus
Not in our library
510.
Rose KA et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9144166?dopt=AbstractPlus
Not in our library
511.
Rosowsky A et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7877140?dopt=AbstractPlus
Not in our library
512.
Rotstein DM et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1495014?dopt=AbstractPlus
Not in our library
513.
Rouault M et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/14516201?dopt=AbstractPlus
Not in our library
514.
Sadik CD et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12628491?dopt=AbstractPlus
Not in our library
515.
Saha AK et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10854420?dopt=AbstractPlus
Not in our library
516.
Sahebkar A et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/25083925?dopt=AbstractPlus
Not in our library
517.
Saldou N et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9720765?dopt=AbstractPlus
Not in our library
518.
Santo L et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22262760?dopt=AbstractPlus
Not in our library
519.
Sarri E et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12374567?dopt=AbstractPlus
Not in our library
520.
Sasaki T et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10814504?dopt=AbstractPlus
Not in our library
521.
Sauve AA. (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20132909?dopt=AbstractPlus
Not in our library
522.
Schafer PH et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24882690?dopt=AbstractPlus
Not in our library
523.
Schmid AC et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15474001?dopt=AbstractPlus
Not in our library
524.
Schmidt M et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11715024?dopt=AbstractPlus
Not in our library
525.
Schmöle AC et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20708937?dopt=AbstractPlus
Not in our library
526.
Schnute ME et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28231433?dopt=AbstractPlus
Not in our library
527.
Schnute ME et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22397330?dopt=AbstractPlus
Not in our library
528.
Schwab SR et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16151014?dopt=AbstractPlus
Not in our library
529.
Schümann J et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25630683?dopt=AbstractPlus
Not in our library
530.
Scott SA et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19136975?dopt=AbstractPlus
Not in our library
531.
Sedrani R et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9723437?dopt=AbstractPlus
Not in our library
532.
Semenas J et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/25071204?dopt=AbstractPlus
Not in our library
533.
Sethi KK et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23965175?dopt=AbstractPlus
Not in our library
534.
Sevrioukova IF et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26002732?dopt=AbstractPlus
Not in our library
535.
Seynaeve CM et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8022414?dopt=AbstractPlus
Not in our library
536.
Shahrokh K et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22677141?dopt=AbstractPlus
Not in our library
537.
Shak S et al (1985 ) http://www.ncbi.nlm.nih.gov/pubmed/2997155?dopt=AbstractPlus
Not in our library
538.
Sharma RK et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22628311?dopt=AbstractPlus
Not in our library
539.
Sharp JD et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8083230?dopt=AbstractPlus
Not in our library
540.
Shih C et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9762351?dopt=AbstractPlus
Not in our library
541.
Shiro T et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23623673?dopt=AbstractPlus
Not in our library
542.
Silverman RB. (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22168767?dopt=AbstractPlus
Not in our library
543.
Simon GM et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20393650?dopt=AbstractPlus
Not in our library
544.
Simó-Riudalbas L et al (2014 ) http://www.ncbi.nlm.nih.gov/pubmed/24104525?dopt=AbstractPlus
Not in our library
545.
Simó-Riudalbas L et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/25039449?dopt=AbstractPlus
Not in our library
546.
Sinnarajah S et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11234015?dopt=AbstractPlus
Not in our library
547.
Sircar I et al (1989 ) http://www.ncbi.nlm.nih.gov/pubmed/2536438?dopt=AbstractPlus
Not in our library
548.
Sjholt G et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10822345?dopt=AbstractPlus
Not in our library
549.
Sjholt G et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9339367?dopt=AbstractPlus
Not in our library
550.
Skarydová L et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19007764?dopt=AbstractPlus
Not in our library
551.
Smith CJ et al (1998 ) http://www.ncbi.nlm.nih.gov/pubmed/9789085?dopt=AbstractPlus
Not in our library
552.
Smith RJ et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2338654?dopt=AbstractPlus
Not in our library
553.
Smith SJ et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15371556?dopt=AbstractPlus
Not in our library
554.
Smrcka AV et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1846707?dopt=AbstractPlus
Not in our library
555.
Snider NT et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20133390?dopt=AbstractPlus
Not in our library
556.
Solanki M et al (2018 ) http://www.ncbi.nlm.nih.gov/pubmed/29695613?dopt=AbstractPlus
Not in our library
557.
Solorzano C et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19926854?dopt=AbstractPlus
Not in our library
558.
Song C et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11022048?dopt=AbstractPlus
Not in our library
559.
Sontag TJ et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/11997390?dopt=AbstractPlus
Not in our library
560.
Sperzel M et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17666018?dopt=AbstractPlus
Not in our library
561.
Sridhar J et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28698457?dopt=AbstractPlus
Not in our library
562.
Stanek J et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8340919?dopt=AbstractPlus
Not in our library
563.
Stanek J et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1573631?dopt=AbstractPlus
Not in our library
564.
Stanley LA. (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7900159?dopt=AbstractPlus
Not in our library
565.
Stanley WC et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9283721?dopt=AbstractPlus
Not in our library
566.
Stark K et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/18549450?dopt=AbstractPlus
Not in our library
567.
Steinberg D et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19506257?dopt=AbstractPlus
Not in our library
568.
Stevens T et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21791628?dopt=AbstractPlus
Not in our library
569.
Stoilov I et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9097971?dopt=AbstractPlus
Not in our library
570.
Su T et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/11016631?dopt=AbstractPlus
Not in our library
571.
Sudo T et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10644042?dopt=AbstractPlus
Not in our library
572.
Sun W et al (2008 ) http://www.ncbi.nlm.nih.gov/pubmed/17713573?dopt=AbstractPlus
Not in our library
573.
Sutherlin DP et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21981714?dopt=AbstractPlus
Not in our library
574.
Suzuki T et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23577190?dopt=AbstractPlus
Not in our library
575.
Szabo C et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28978633?dopt=AbstractPlus
Not in our library
576.
Sánchez-Martínez C et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26115571?dopt=AbstractPlus
Not in our library
577.
Tai AW et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21704602?dopt=AbstractPlus
Not in our library
578.
Taimi M et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/14532297?dopt=AbstractPlus
Not in our library
579.
Takasugi N et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12660785?dopt=AbstractPlus
Not in our library
580.
Takeuchi CS et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23394126?dopt=AbstractPlus
Not in our library
581.
Talley JJ et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/10715145?dopt=AbstractPlus
Not in our library
582.
Tanaka M et al (2017 ) http://www.ncbi.nlm.nih.gov/pubmed/28086912?dopt=AbstractPlus
Not in our library
583.
Tang WJ et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/2022671?dopt=AbstractPlus
Not in our library
584.
Tani M et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12499379?dopt=AbstractPlus
Not in our library
585.
Tani M et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19233134?dopt=AbstractPlus
Not in our library
586.
Tanizawa A et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8182764?dopt=AbstractPlus
Not in our library
587.
Tao YH et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16290145?dopt=AbstractPlus
Not in our library
588.
Taussig R et al (1993 ) http://www.ncbi.nlm.nih.gov/pubmed/8416978?dopt=AbstractPlus
Not in our library
589.
Taussig R et al (1994 ) http://www.ncbi.nlm.nih.gov/pubmed/8119955?dopt=AbstractPlus
Not in our library
590.
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Not in our library
591.
Temperini C et al (2009 ) http://www.ncbi.nlm.nih.gov/pubmed/19119014?dopt=AbstractPlus
Not in our library
592.
Tenu JP et al (1999 ) http://www.ncbi.nlm.nih.gov/pubmed/10637120?dopt=AbstractPlus
Not in our library
593.
Terao C et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23124809?dopt=AbstractPlus
Not in our library
594.
Tesmer JJ et al (2000 ) http://www.ncbi.nlm.nih.gov/pubmed/11087399?dopt=AbstractPlus
Not in our library
595.
Thilagavathi R et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/15686906?dopt=AbstractPlus
Not in our library
596.
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Not in our library
597.
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Not in our library
598.
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Not in our library
599.
Toprakçí M et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16137882?dopt=AbstractPlus
Not in our library
600.
Toullec D et al (1991 ) http://www.ncbi.nlm.nih.gov/pubmed/1874734?dopt=AbstractPlus
Not in our library
601.
Tsuboi K et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/14686878?dopt=AbstractPlus
Not in our library
602.
Tsuboi K et al (2013 ) http://www.ncbi.nlm.nih.gov/pubmed/23394527?dopt=AbstractPlus
Not in our library
603.
Tuccinardi T et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16483784?dopt=AbstractPlus
Not in our library
604.
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Not in our library
605.
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Not in our library
606.
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Not in our library
607.
Uehata M et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9353125?dopt=AbstractPlus
Not in our library
608.
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Not in our library
609.
Vemulapalli S et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8961086?dopt=AbstractPlus
Not in our library
610.
Venant H et al (2015 ) http://www.ncbi.nlm.nih.gov/pubmed/26494858?dopt=AbstractPlus
Not in our library
611.
Venkataraman K et al (2002 ) http://www.ncbi.nlm.nih.gov/pubmed/12105227?dopt=AbstractPlus
Not in our library
612.
Venkatesan AM et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20166697?dopt=AbstractPlus
Not in our library
613.
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Not in our library
614.
Verma RP et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17275314?dopt=AbstractPlus
Not in our library
615.
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Not in our library
616.
Vlahakis JZ et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16821802?dopt=AbstractPlus
Not in our library
617.
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Not in our library
618.
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Not in our library
619.
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Not in our library
620.
Walsky RL et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17682072?dopt=AbstractPlus
Not in our library
621.
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Not in our library
622.
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Not in our library
623.
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Not in our library
624.
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Not in our library
625.
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Not in our library
626.
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Not in our library
627.
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Not in our library
628.
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Not in our library
629.
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Not in our library
630.
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Not in our library
631.
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Not in our library
632.
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Not in our library
633.
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Not in our library
634.
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Not in our library
635.
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Not in our library
636.
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Not in our library
637.
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Not in our library
638.
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Not in our library
639.
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Not in our library
640.
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Not in our library
641.
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Not in our library
642.
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Not in our library
643.
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Not in our library
644.
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Not in our library
645.
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Not in our library
646.
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Not in our library
647.
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Not in our library
648.
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Not in our library
649.
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Not in our library
650.
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Not in our library
651.
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Not in our library
652.
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Not in our library
653.
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Not in our library
654.
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Not in our library
655.
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Not in our library
656.
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Not in our library
657.
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Not in our library
658.
Yaguchi S et al (2006 ) http://www.ncbi.nlm.nih.gov/pubmed/16622124?dopt=AbstractPlus
Not in our library
659.
Yamaguchi T et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21523318?dopt=AbstractPlus
Not in our library
660.
Yamano S et al (1990 ) http://www.ncbi.nlm.nih.gov/pubmed/2322567?dopt=AbstractPlus
Not in our library
661.
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Not in our library
662.
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Not in our library
663.
Yokomatsu T et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12482429?dopt=AbstractPlus
Not in our library
664.
Yoshida S et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/15110846?dopt=AbstractPlus
Not in our library
665.
Yoshikawa F et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/21085684?dopt=AbstractPlus
Not in our library
666.
Yoshikawa T et al (1997 ) http://www.ncbi.nlm.nih.gov/pubmed/9322233?dopt=AbstractPlus
Not in our library
667.
Yoshimura M et al (1992 ) http://www.ncbi.nlm.nih.gov/pubmed/1379717?dopt=AbstractPlus
Not in our library
668.
Youdim MB et al (2001 ) http://www.ncbi.nlm.nih.gov/pubmed/11159700?dopt=AbstractPlus
Not in our library
669.
Yu Z et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/12881489?dopt=AbstractPlus
Not in our library
670.
Zambon A et al (2012 ) http://www.ncbi.nlm.nih.gov/pubmed/22222036?dopt=AbstractPlus
Not in our library
671.
Zavialov AV et al (2010 ) http://www.ncbi.nlm.nih.gov/pubmed/20147294?dopt=AbstractPlus
Not in our library
672.
Zeldin DC et al (1995 ) http://www.ncbi.nlm.nih.gov/pubmed/7574697?dopt=AbstractPlus
Not in our library
673.
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Not in our library
674.
Zhang J et al (2007 ) http://www.ncbi.nlm.nih.gov/pubmed/17721087?dopt=AbstractPlus
Not in our library
675.
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Not in our library
676.
Zhou W et al (2003 ) http://www.ncbi.nlm.nih.gov/pubmed/14612531?dopt=AbstractPlus
Not in our library
677.
Zhou Y et al (2005 ) http://www.ncbi.nlm.nih.gov/pubmed/16107206?dopt=AbstractPlus
Not in our library
678.
Zhu MY et al (2004 ) http://www.ncbi.nlm.nih.gov/pubmed/14738999?dopt=AbstractPlus
Not in our library
679.
Zimmer C et al (2011 ) http://www.ncbi.nlm.nih.gov/pubmed/21129965?dopt=AbstractPlus
Not in our library
680.
Zimmermann G et al (1996 ) http://www.ncbi.nlm.nih.gov/pubmed/8900209?dopt=AbstractPlus
Not in our library
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THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Enzymes

Abstract

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Conflict of interest

Overview

Family structure

Overview

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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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Overview

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Further reading on Nitric oxide synthases

Further reading on L‐Arginine turnover

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Further reading on Carbonic anhydrases

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Overview

Further reading on Carboxylases and decarboxylases

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Further reading on Catecholamine turnover

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Overview

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Overview

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Further reading on Ceramide turnover

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Further reading on 3.5.1.‐ Histone deacetylases (HDACs)

Further reading on Chromatin modifying enzymes

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Further reading on Adenylyl cyclases (ACs)

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

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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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Further reading on DNA topoisomerases

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Overview

Comments on Endocannabinoid turnover

Further reading on Endocannabinoid turnover

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Overview

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Overview

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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

Overview

Secreted or extracellular forms

Cytosolic, calcium‐dependent forms

Other forms

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Further reading on Phospholipase A2

Overview

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Further reading on Phosphatidylcholine‐specific phospholipase D

Overview

Further reading on Lipid phosphate phosphatases

Overview

Phosphatidylinositol 3‐kinases