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 (http://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.
1.
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
Overview
Enzymes 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:
EC 1.‐.‐.‐ Oxidoreductases;
EC 2.‐.‐.‐ Transferases;
EC 3.‐.‐.‐ Hydrolases;
EC 4.‐.‐.‐ Lyases;
EC 5.‐.‐.‐ Isomerases;
EC 6.‐.‐.‐ Ligases.
Although there are many more enzymes than receptors in biology, and many drugs that target prokaryotic enzymes are effective medicines, overall the number of enzyme drug targets is relatively small [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.
The 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.
Many enzymes require additional entities for functional activity. Some of these are used in the catalytic steps, while others promote a particular conformational change. Co‐factors are tightly bound to the enzyme and include metal ions and heme groups. Co‐enzymes are typically small molecules which accept or donate functional groups to assist in the enzymatic reaction. Examples include ATP, NAD, NADP and S‐adenosylmethionine, as well as a number of vitamins, such as riboflavin (vitamin B1) and thiamine (vitamin B2). Where co‐factors/co‐enzymes have been identified, the Guide indicates their involvement.
Family structure
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S304 2.1.1.‐ Protein arginine N‐methyltransferases
S305 Arginine:glycine amidinotransferase
S305 Dimethylarginine dimethylaminohydrolases
S308 Carboxylases and decarboxylases
S313 Serine palmitoyltransferase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=791
S314 Sphingolipid ∆4‐desaturase
S315 Sphingomyelin phosphodiesterase
S316 Neutral sphingomyelinase coupling factors
S316 Ceramide glucosyltransferase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=981
S319 Chromatin modifying enzymes
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=869
S319 2.1.1.‐ Protein arginine N‐methyltransferases
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=871
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=872
S320 3.5.1.‐ Histone deacetylases (HDACs)
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=873
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=884
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=558
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=626
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=631
S321 Cyclic nucleotide turnover/signalling
S323 Exchange protein activated by cyclic AMP (EPACs)
S323 Phosphodiesterases, 3’,5’‐cyclic nucleotide (PDEs)
S331 CYP5, CYP7 and CYP8 families
S332 CYP11, CYP17, CYP19, CYP20 and CYP21 families
S333 CYP24, CYP26 and CYP27 families
S333 CYP39, CYP46 and CYP51 families
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1020
S336 N‐Acylethanolamine turnover
S337 2‐Acylglycerol ester turnover
S342 Leukotriene and lipoxin metabolism
S344 Glycerophospholipid turnover
S344 Phosphoinositide‐specific phospholipase C
S348 Phosphatidylcholine‐specific phospholipase D
S349 Lipid phosphate phosphatases
S349 Phosphatidylinositol kinases
S350 1‐phosphatidylinositol 4‐kinase family
S351 Phosphatidylinositol‐4‐phosphate 3‐kinase family
S351 Phosphatidylinositol 3‐kinase family
S351 Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase family
S352 1‐phosphatidylinositol‐3‐phosphate 5‐kinase family
S353 Type I PIP kinases (1‐phosphatidylinositol‐4‐phosphate 5‐kinase family)
S353 Type II PIP kinases (1‐phosphatidylinositol‐5‐phosphate 4‐kinase family)
S356 Phosphatidylinositol phosphate kinases
S358 Hydrogen sulphide synthesis
S360 Inositol phosphate turnover
S360 Inositol 1,4,5‐trisphosphate 3‐kinases
S360 Inositol polyphosphate phosphatases
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1004
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=677
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=454
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=500
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=573
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=283
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=507
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=508
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=937
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=583
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=587
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=604
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=284
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=285
S362 Protein kinase C (PKC) family
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=535
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=287
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=601
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=466
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=539
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=540
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=541
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=705
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=614
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=616
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=644
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=678
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=448
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=468
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=469
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=450
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=471
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=472
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=556
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=874
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=558
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=576
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=463
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=528
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=530
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=531
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=598
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=465
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=536
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=537
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=538
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=596
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=608
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=626
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=631
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=679
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=561
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=562
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=452
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=474
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=475
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=476
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=477
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=478
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=479
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=480
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=700
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=481
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=482
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=483
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=484
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=563
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=566
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=571
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=572
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=459
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=512
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=513
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=585
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=599
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=600
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=605
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=607
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=609
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=630
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=635
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=636
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=680
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=564
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=627
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=640
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=681
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=568
S365 Cyclin‐dependent kinase (CDK) family
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=485
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=492
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=495
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=496
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=497
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=489
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=494
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=490
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=498
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=491
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=570
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=455
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=503
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=504
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=505
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=506
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=457
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=288
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=514
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=515
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=518
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=519
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=520
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=612
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=620
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=682
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=683
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=451
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=473
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=557
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=559
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=560
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=565
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=567
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=577
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=578
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=580
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=584
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=586
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=588
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=589
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=590
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=591
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=592
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=593
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=594
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=595
S367 Polo‐like kinase (PLK) family
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=462
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=526
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=527
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=597
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=617
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=618
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=628
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=633
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=634
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=637
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=639
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=641
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=642
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=643
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=684
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=449
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=470
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=615
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=890
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=685
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=621
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=467
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=542
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=543
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=544
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=544
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=546
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=547
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=548
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=549
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=622
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=550
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=551
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=552
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=624
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=686
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=936
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=569
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=574
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=575
S369 Janus kinase (JakA) family
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=625
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=687
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=579
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=582
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=458
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=510
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=511
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=461
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=521
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=522
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=523
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=524
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=525
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=613
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=632
S372 Lanosterol biosynthesis pathway
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=928
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=993
S374 Nucleoside synthesis and metabolism
S377 Peptidases and proteinases
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=707
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=708
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=709
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=728
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=731
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=729
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=730
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=732
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=931
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=711
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=733
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=711
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=735
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=712
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=736
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=713
S379 M2: Angiotensin‐converting (ACE and ACE2)
S379 M10: Matrix metallopeptidase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=740
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=742
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=714
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=743
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=715
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=744
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=716
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=745
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=717
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=746
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=718
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=747
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=860
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=719
S381 M19: Membrane dipeptidase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=720
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=750
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=721
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=722
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=878
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=753
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=723
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=754
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=724
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=725
S383 S9: Prolyl oligopeptidase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=756
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=757
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=917
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=947
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=980
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=948
S383 Poly ADP‐ribose polymerases
S384 Sphingosine 1‐phosphate turnover
S386 Sphingosine 1‐phosphate phosphatase
S387 Sphingosine 1‐phosphate lyase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=988
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=840
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=922
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=912
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=899
S388 1.14.13.9 Kynurenine 3‐monooxygenase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=877
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=843
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=846
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=844
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=978
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1003
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=979
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=908
S389 2.5.1.58 Protein farnesyltransferase
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=926
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=994
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=880
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=850
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=841
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=909
S390 3.5.1.‐ Histone deacetylases (HDACs)
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=925
S391 3.5.3.15 Peptidyl arginine deiminases (PADI)
S391 3.6.5.2 Small monomeric GTPases
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=849
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=845
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=847
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=765
Overview
Acetylcholine 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
A number of organophosphorus compounds inhibit acetylcholinesterase and cholinesterase irreversibly, including pesticides such as chlorpyrifos‐oxon, and nerve agents such as tabun, soman and sarin. AChE is unusual in its exceptionally high turnover rate which has been calculated at 740 000/min/molecule [http://www.ncbi.nlm.nih.gov/pubmed/13785664?dopt=AbstractPlus].
Further reading on Acetylcholine turnover
Li Q et al. (2017) Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer's disease. Eur J Med Chem 132: 294–309 https://www.ncbi.nlm.nih.gov/pubmed/28371641?dopt=AbstractPlus
Lockridge O. (2015) Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol Ther 148: 34–46 https://www.ncbi.nlm.nih.gov/pubmed/25448037?dopt=AbstractPlus
Masson P et al. (2016) Slow‐binding inhibition of cholinesterases, pharmacological and toxicological relevance. Arch Biochem Biophys 593: 60–8 https://www.ncbi.nlm.nih.gov/pubmed/26874196?dopt=AbstractPlus
Rotundo RL. (2017) Biogenesis, assembly and trafficking of acetylcholinesterase. J Neurochem 142 Suppl 2: 52–58 https://www.ncbi.nlm.nih.gov/pubmed/28326552?dopt=AbstractPlus
Silman I et al. (2017) Recent developments in structural studies on acetylcholinesterase. J Neurochem 142 Suppl 2: 19–25 https://www.ncbi.nlm.nih.gov/pubmed/28503857?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=248
Overview
A 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
An 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].
Further reading on Adenosine turnover
Boison D. (2016) Adenosinergic signaling in epilepsy. Neuropharmacology 104: 131–9 https://www.ncbi.nlm.nih.gov/pubmed/26341819?dopt=AbstractPlus
Cortés A et al. (2015) Moonlighting adenosine deaminase: a target protein for drug development. Med Res Rev 35: 85–125 https://www.ncbi.nlm.nih.gov/pubmed/24933472?dopt=AbstractPlus
Nishikura K. (2016) A‐to‐I editing of coding and non‐coding RNAs by ADARs. Nat Rev Mol Cell Biol 17: 83–96 https://www.ncbi.nlm.nih.gov/pubmed/26648264?dopt=AbstractPlus
Sawynok J. (2016) Adenosine receptor targets for pain. Neuroscience 338: 1–18 https://www.ncbi.nlm.nih.gov/pubmed/26500181?dopt=AbstractPlus
Xiao Y et al. (2015) Role of S‐adenosylhomocysteine in cardiovascular disease and its potential epi‐genetic mechanism. Int. J. Biochem. Cell Biol. 67: 158–66 https://www.ncbi.nlm.nih.gov/pubmed/26117455?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=249
Overview
The 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.
Further reading on Amino acid hydroxylases
Bauer IE et al. (2015) Serotonergic gene variation in substance use pharmacotherapy: a systematic review. Pharmacogenomics 16: 1307–14 https://www.ncbi.nlm.nih.gov/pubmed/26265436?dopt=AbstractPlus
Daubner SC et al. (2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 508: 1–12 https://www.ncbi.nlm.nih.gov/pubmed/21176768?dopt=AbstractPlus
Flydal MI et al. (2013) Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life 65: 341–9 https://www.ncbi.nlm.nih.gov/pubmed/23457044?dopt=AbstractPlus
Roberts KM et al. (2013) Mechanisms of tryptophan and tyrosine hydroxylase. IUBMB Life 65: 350–7 https://www.ncbi.nlm.nih.gov/pubmed/23441081?dopt=AbstractPlus
Tekin I et al. (2014) Complex molecular regulation of tyrosine hydroxylase. J Neural Transm 121: 1451–81 https://www.ncbi.nlm.nih.gov/pubmed/24866693?dopt=AbstractPlus
Walen K et al. (2017) Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease. Expert Opin Ther Targets 21: 167–180 https://www.ncbi.nlm.nih.gov/pubmed/27973928?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=239
Overview
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=721 is a basic amino acid with a guanidino sidechain. As an amino acid, metabolism of L‐arginine to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=725, catalysed by arginase, forms the last step of the urea production cycle. L‐Ornithine may be utilised as a precursor of polyamines (see http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240) or recycled via http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5324 to L‐arginine. L‐Arginine http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240#Decarboxylases to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4127, although the prominence of this pathway in human tissues is uncertain. L‐Arginine may be used as a precursor for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5325 formation in the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4496 synthesis pathway under the influence of arginine:glycine amidinotransferase with L‐ornithine as a byproduct. Nitric oxide synthase uses L‐arginine to generate nitric oxide, with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 also as a byproduct. L‐Arginine in proteins may be subject to post‐translational modification through methylation, catalysed by protein arginine methyltransferases. Subsequent proteolysis can liberate asymmetric http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5229 (ADMA), which is an endogenous inhibitor of nitric oxide synthase activities. ADMA is hydrolysed by dimethylarginine dimethylhydrolase activities to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=722 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5177.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254
Overview
Protein 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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=250
Overview
Arginase (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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=250.
Comments
http://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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=251
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1246 |
| Common abbreviation | AGAT |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4175, http://www.uniprot.org/uniprot/P50440 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.1.4.1 |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=252
Overview
Dimethylarginine 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=253
Overview
Nitric 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
The 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.
Further reading on Nitric oxide synthases
Garcia‐Ortiz A and Serrador JM (2018) Nitric Oxide Signaling in T Cell‐Mediated Immunity Trends Mol Med 24: 412–427 https://www.ncbi.nlm.nih.gov/pubmed/29519621
Lundberg JO et al. (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14: 623–41 https://www.ncbi.nlm.nih.gov/pubmed/26265312?dopt=AbstractPlus
Oliveira‐Paula GH et al. (2016) Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene 575: 584–99 https://www.ncbi.nlm.nih.gov/pubmed/26428312?dopt=AbstractPlus
Stuehr DJ and Haque MM (2019) Nitric oxide synthase enzymology in the 20 years after the Nobel Prize. BrJPharmacol 176: 177–188 https://www.ncbi.nlm.nih.gov/pubmed/30402946
Wallace JL (2019) Nitric oxide in the gastrointestinal tract: opportunities for drug development. Br J Pharmacol 176: 147–154 https://www.ncbi.nlm.nih.gov/pubmed/30357812
Further reading on L‐Arginine turnover
Lai L et al. (2016) Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers. J Diabetes Res 2016: 1982096 https://www.ncbi.nlm.nih.gov/pubmed/26770984?dopt=AbstractPlus
Moncada S et al. (1997) International Union of Pharmacology Nomenclature in Nitric Oxide Re‐search. Pharmacol. Rev. 49: 137–42 https://www.ncbi.nlm.nih.gov/pubmed/9228663?dopt=AbstractPlus
Pekarova M et al. (2015) The crucial role of l‐arginine in macrophage activation: What you need to know about it. Life Sci. 137: 44–8 https://www.ncbi.nlm.nih.gov/pubmed/26188591?dopt=AbstractPlus
Pudlo M et al. (2017) Arginase Inhibitors: A Rational Approach Over One Century. Med Res Rev 37: 475–513 https://www.ncbi.nlm.nih.gov/pubmed/27862081?dopt=AbstractPlus
Sudar‐Milovanovic E et al. (2016) Benefits of L‐Arginine on Cardiovascular System. Mini Rev Med Chem 16: 94–103 https://www.ncbi.nlm.nih.gov/pubmed/26471966?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=842
Overview
Carbonic anhydrases facilitate the interconversion of water and carbon dioxide with bicarbonate ions and protons (EC 4.2.1.1), with over a dozen gene products identified in man. The enzymes function in acid‐base balance and the movement of carbon dioxide and water. They are targetted for therapeutic gain by particular antiglaucoma agents and diuretics.
Further reading on Carbonic anhydrases
Imtaiyaz Hassan M, Shajee B, Waheed A, Ahmad F and Sly WS. (2013) Structure, function and applications of carbonic anhydrase isozymes. Bioorg Med Chem 21: 1570–70 https://www.ncbi.nlm.nih.gov/pubmed/22607884
Supuran CT (2017) Advances in structure‐based drug discovery of carbonic anhydrase inhibitors. Expert Opin Drug Discov 12: 61–88 https://www.ncbi.nlm.nih.gov/pubmed/27783541
Supuran CT (2018) Carbonic anhydrase activators. Future Med Chem 10: 561–573 https://www.ncbi.nlm.nih.gov/pubmed/29478330
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=240
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=255
Overview
The 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
Dicarboxylic 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=256
Overview
The 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.
Further reading on Carboxylases and decarboxylases
Bale S et al. (2010) Structural biology of S‐adenosylmethionine decarboxylase. Amino Acids 38: 451–60 [https://www.ncbi.nlm.nih.gov/pubmed/19997761?dopt=AbstractPlus
Di Bartolomeo F et al. (2017) Cell biology, physiology and enzymology of phosphatidylserine decarboxylase. Biochim Biophys Acta Mol Cell Biol Lipids 1862: 25–38 https://www.ncbi.nlm.nih.gov/pubmed/27650064
Jitrapakdee S et al. (2008) Structure, mechanism and regulation of pyruvate carboxylase. Biochem. J. 413: 369–87 https://www.ncbi.nlm.nih.gov/pubmed/18613815?dopt=AbstractPlus
Lietzan AD et al. (2014) Functionally diverse biotin‐dependent enzymes with oxaloacetate decarboxylase activity. Arch. Biochem. Biophys. 544: 75–86 https://www.ncbi.nlm.nih.gov/pubmed/24184447?dopt=AbstractPlus
Sanchez‐Jimenez F et al. (2016) Structural and functional analogies and differences between histi‐dine decarboxylase and aromatic l‐amino acid decarboxylase molecular networks: Biomedical implications Pharmacol Res 114: 90–102 https://www.ncbi.nlm.nih.gov/pubmed/27769832
Salie MJ and Thelen JJ (2016) Regulation and structure of the heteromeric acetyl‐CoA carboxylase. Biochim Biophys Acta 1861: 1207–1213 https://www.ncbi.nlm.nih.gov/pubmed/27091637
Tong L. (2013) Structure and function of biotin‐dependent carboxylases. Cell. Mol. Life Sci. 70: 863–91 https://www.ncbi.nlm.nih.gov/pubmed/22869039?dopt=AbstractPlus
Vance JE et al. (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim. Biophys. Acta 1831: 543–54 https://www.ncbi.nlm.nih.gov/pubmed/22960354?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=766
Overview
Catecholamines are defined by the presence of two adjacent hydroxyls on a benzene ring with a sidechain containing an amine. The predominant catacholamines in mammalian biology are the neurotransmitter/hormones 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.
Further reading on Catecholamine turnover
Bastos P et al. (2017) Catechol‐O‐Methyltransferase (COMT): An Update on Its Role in Cancer, Neuro‐and Cardiovascular Diseases. Rev Biochem Pharmacol 173: 1–39 https://www.ncbi.nlm.nih.gov/pubmed/28456872
Deshwal S etal. (2017) Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 33: 64–69 https://www.ncbi.nlm.nih.gov/pubmed/28528298?dopt=AbstractPlus
Fisar Z. (2016) Drugs related to monoamine oxidase activity. Prog. Neuropsychopharmacol. Biol. Psychiatry 69: 112–24 https://www.ncbi.nlm.nih.gov/pubmed/26944656?dopt=AbstractPlus
Ramsay RR. (2016) Molecular aspects of monoamine oxidase B. Prog. Neuropsychopharmacol. Biol. Psychiatry 69: 81–9 https://www.ncbi.nlm.nih.gov/pubmed/26891670?dopt=AbstractPlus
Walen K et al. (2017) Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease. Expert Opin. Ther. Targets 21: 167–180 https://www.ncbi.nlm.nih.gov/pubmed/27973928?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=767
Overview
Ceramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates 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.
Ceramidase re‐forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=788
Overview
The functional enzyme is a heterodimer of SPT1 (LCB1) with either SPT2 (LCB2) or SPT3 (LCB2B); the small subunits of SPT (ssSPTa or ssSPTb) bind to the heterodimer to enhance enzymatic activity. The complexes of SPT1/SPT2/ssSPTa and SPT1/SPT2/ssSPTb were most active with palmitoylCoA as substrate, with the latter complex also showing some activity with stearoylCoA [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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=789
Overview
This family of enzymes, also known as sphingosine N‐acyltransferase, is located in the ER facing the cytosol with an as‐yet undefined topology and stoichiometry. Ceramide synthase in vitro is sensitive to inhibition by the fungal derived toxin, fumonisin B1.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=790
Overview
DEGS1 and DEGS2 are 4TM proteins.
Comments
DEGS1 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=774
Overview
Following translocation from the ER to the Golgi under the influence of the ceramide transfer protein, sphingomyelin synthases allow the formation of sphingomyelin by the transfer of phosphocholine from the phospholipid phosphatidylcholine. Sphingomyelin synthase‐related protein 1 is structurally related but lacks sphingomyelin synthase activity.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=773
Overview
Also known as sphingomyelinase.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=772
Overview
Protein 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=775
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2528 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12524, http://www.uniprot.org/uniprot/Q16739 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.4.1.80: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1783 + ceramide = http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1749 + glucosylceramide |
| Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4841 (pK i 5.1) [68] |
| Comments | Glycoceramides are an extended family of sphingolipids, differing in the content and organization of the sugar moieties, as well as the acyl sidechains. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=769
Overview
The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2491 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:735, http://www.uniprot.org/uniprot/Q13510 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:3.5.1.23: ceramide ‐> http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2452 + a fatty acid |
| Comments | This lysosomal enzyme is proteolysed to form the mature protein made up of two chains from the same gene product [http://www.ncbi.nlm.nih.gov/pubmed/8955159?dopt=AbstractPlus]. |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=770
Overview
The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2492 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2493 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18860, http://www.uniprot.org/uniprot/Q9NR71 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:23456, http://www.uniprot.org/uniprot/P0C7U1 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:3.5.1.23: ceramide ‐> http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2452 + a fatty acid | – |
| Comments | The enzyme is associated with the plasma membrane [http://www.ncbi.nlm.nih.gov/pubmed/12499379?dopt=AbstractPlus]. | – |
Comments
ASAH2B appears to be an enzymatically inactive protein, which may result from gene duplication and truncation.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=768
Overview
The six human ceramidases may be divided on the basis of pH optimae into acid, neutral and alkaline ceramidases, which also differ in their subcellular location.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=771
Comments
A 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).
Further reading on Ceramide turnover
Brachtendorf S et al. (2019) Ceramide synthases in cancer therapy and chemoresistance. Prog Lipid Res 74: 160‐185 https://www.ncbi.nlm.nih.gov/pubmed/30953657
Chen Y and Cao Y. (2017) The sphingomyelin synthase family: proteins, diseases, and inhibitors. Biol Chem 398: 1319‐1325 https://www.ncbi.nlm.nih.gov/pubmed/28742512
Fang Z et al. (2019) Ceramide and sphingosine 1‐phosphate in adipose dysfunction. Prog Lipid Res 74: 145‐159 https://www.ncbi.nlm.nih.gov/pubmed/30951736
Hernández‐Corbacho MJ et al. (2017) Sphingolipids in mitochondria. Biochim Biophys Acta 1862: 56‐68 https://www.ncbi.nlm.nih.gov/pubmed/27697478?dopt=AbstractPlus
Ilan Y. (2016) Compounds of the sphingomyelin‐ceramide‐glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 310: G1102‐17 https://www.ncbi.nlm.nih.gov/pubmed/27173510?dopt=AbstractPlus
Iqbal J et al. (2017) Sphingolipids and Lipoproteins in Health and Metabolic Disorders. Trends Endocrinol. Metab. 28: 506‐518 https://www.ncbi.nlm.nih.gov/pubmed/28462811?dopt=AbstractPlus
Kihara A. (2016) Synthesis and degradation pathways, functions, and pathology of ceramides and epidermal acylceramides. Prog. Lipid Res. 63: 50‐69 https://www.ncbi.nlm.nih.gov/pubmed/27107674?dopt=AbstractPlus
Ogretmen B (2018) Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18: 33‐50 https://www.ncbi.nlm.nih.gov/pubmed/29147025
Parashuraman S and D’Angelo. (2019) Visualizing sphingolipid biosynthesis in cells. Chem Phys Lipids 218: 103‐111 https://www.ncbi.nlm.nih.gov/pubmed/30476485
Rodriguez‐Cuenca S et al. (2017) Sphingolipids and glycerophospholipids ‐ The “ying and yang” of lipotoxicity in metabolic diseases. Prog. Lipid Res. 66: 14‐29 https://www.ncbi.nlm.nih.gov/pubmed/28104532?dopt=AbstractPlus
Snider et al. (2019) Approaches for probing and evaluating mammalian sphingolipid metabolism. Anal Biochem 575: 70‐86 https://www.ncbi.nlm.nih.gov/pubmed/30917945
Vogt D et al. (2017) Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism. Med Res Rev 37: 3‐51 https://www.ncbi.nlm.nih.gov/pubmed/27480072?dopt=AbstractPlus
Wegner MS et al. (2016) The enigma of ceramide synthase regulation in mammalian cells. Prog. Lipid Res. 63: 93‐119 https://www.ncbi.nlm.nih.gov/pubmed/27180613?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=865
Overview
Chromatin modifying enzymes, and other chromatin‐modifying proteins, fall into three broad categories: writers, readers and erasers. The function of these proteins is to dynamically maintain cell identity and regulate processes such as differentiation, development, proliferation and genome integrity via recognition of specific ’marks’ (covalent post‐translational modifications) on histone proteins and DNA [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).
To date at least eight distinct types of modifications are found on histones. These include small covalent modifications such as acetylation, methylation, and phosphorylation, the attachment of larger modifiers such as ubiquitination or sumoylation, and ADP ribosylation, proline isomerization and deimination. Chromatin modifications and the functions they regulate in cells are reviewed by Kouzarides (2007) [http://www.ncbi.nlm.nih.gov/pubmed/17320507?dopt=AbstractPlus].
Writer proteins include the histone methyltransferases, histone acetyltransferases, some kinases and ubiquitin ligases.
Readers include proteins which contain methyl‐lysinerecognition motifs such as bromodomains, chromodomains, tudor domains, PHD zinc fingers, PWWP domains and MBT domains.
Erasers include the histone demethylases and histone deacetylases (HDACs and sirtuins).
Dysregulated 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254
Overview
Protein 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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=254.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=848
Overview
Histone deacetylases act as erasers of epigenetic acetylation marks on lysine residues in histones. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression.
The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:
Class I contains HDACs 1, 2, 3 and 8
Class IIa contains HDACs 4, 5, 7 and 9
Class IIb contains HDACs 6 and 10
Class III contains the sirtuins (SIRT1‐7)
Class IV contains only HDAC11.
Classes I, II and IV use Zn+ as a co‐factor, whereas catalysis by Class III enzymes requires NAD+ as a co‐factor, and members of this subfamily have ADP‐ribosylase activity in addition to protein deacetylase function [http://www.ncbi.nlm.nih.gov/pubmed/20132909?dopt=AbstractPlus].
HDACs 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].
Dysregulated 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].
Further reading on 3.5.1.‐ Histone deacetylases (HDACs)
Ellmeier W et al. (2018) Histone deacetylase function in CD4+ T cells. Nat. Rev. Immunol. 18: 617‐634 https://www.ncbi.nlm.nih.gov/pubmed/30022149?dopt=AbstractPlus
Maolanon AR et al. (2017) Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes. Chembiochem 18: 5‐49 https://www.ncbi.nlm.nih.gov/pubmed/27748555?dopt=AbstractPlus
Micelli C et al. (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today 20: 718‐35 https://www.ncbi.nlm.nih.gov/pubmed/25687212?dopt=AbstractPlus
Millard CJ et al. (2017) Targeting Class I Histone Deacetylases in a "Complex" Environment. Trends Pharmacol Sci 38: 363‐377 https://www.ncbi.nlm.nih.gov/pubmed/28139258?dopt=AbstractPlus
Roche J et al. (2016) Inside HDACs with more selective HDAC inhibitors. Eur J Med Chem 121: 451‐483 https://www.ncbi.nlm.nih.gov/pubmed/27318122?dopt=AbstractPlus
Zagni C et al. (2017) The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat. Med Res Rev 37: 1373‐1428 https://www.ncbi.nlm.nih.gov/pubmed/28181261?dopt=AbstractPlus
Further reading on Chromatin modifying enzymes
Angus SP et al. (2018) Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer. Annu Rev Pharmacol Toxicol 58: 209‐229 https://www.ncbi.nlm.nih.gov/pubmed/28934561?dopt=AbstractPlus
Bennett RL et al. (2018) Targeting Epigenetics in Cancer. Annu Rev Pharmacol Toxicol 58: 187‐207 https://www.ncbi.nlm.nih.gov/pubmed/28992434?dopt=AbstractPlus
Lauschke VM et al. (2018) Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities. Annu Rev Pharmacol Toxicol 58: 161‐185 https://www.ncbi.nlm.nih.gov/pubmed/29029592?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=241
Overview
Cyclic nucleotides are second messengers generated by cyclase enzymes from precursor triphosphates and hydrolysed by phosphodiesterases. The cellular actions of these cyclic nucleotides are mediated through activation of protein kinases (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).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=257
Overview
Adenylyl 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
Many 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.
Further reading on Adenylyl cyclases (ACs)
Dessauer CW et al. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol. Rev. 69: 93‐139 https://www.ncbi.nlm.nih.gov/pubmed/28255005?dopt=AbstractPlus
Halls ML et al. (2017) Adenylyl cyclase signalling complexes ‐ Pharmacological challenges and opportunities. Pharmacol. Ther. 172: 171‐180 https://www.ncbi.nlm.nih.gov/pubmed/28132906?dopt=AbstractPlus
Wiggins SV et al. (2018) Pharmacological modulation of the CO2/HCO‐ 3/pH‐, calcium‐, and ATP‐sensing soluble adenylyl cyclase. Pharmacol Ther 190: 173‐186 https://www.ncbi.nlm.nih.gov/pubmed/29807057
Wu L et al. (2016) Adenylate cyclase 3: a new target for anti‐obesity drug development. Obes Rev 17: 907‐14 https://www.ncbi.nlm.nih.gov/pubmed/27256589?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=259
Overview
Epacs 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].
Further reading on Exchange protein activated by cyclic AMP (EPACs)
Fujita T et al. (2017) The role of Epac in the heart. Cell. Mol. Life Sci. 74: 591‐606 https://www.ncbi.nlm.nih.gov/pubmed/27549789?dopt=AbstractPlus
Robichaux WG and Cheng X. (2018) Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiol Rev 98: 919‐1053 https://www.ncbi.nlm.nih.gov/pubmed/29537337
Wang P et al. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg. Med. Chem. Lett. 27: 1633‐1639 https://www.ncbi.nlm.nih.gov/pubmed/28283242?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=260
Overview
3’,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
PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane‐bound homodimer. PDE3A and PDE3B are membrane‐bound.
PDE4 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.
PDE6 is a membrane‐bound tetramer composed of two catalytic chains (PDE6A or PDE6C and PDE6B), an inhibitory chain (PDE6G or PDE6H) and the PDE6D chain. The enzyme is essentially 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.
Further reading on Phosphodiesterases, 3’,5’‐cyclic nucleotide (PDEs)
Klussmann E. (2016) Protein‐protein interactions of PDE4 family members ‐ Functions, interactions and therapeutic value. Cell. Signal. 28: 713‐8 https://www.ncbi.nlm.nih.gov/pubmed/26498857?dopt=AbstractPlus
Korkmaz‐Icöz S et al. (2018) Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure. Br. J. Pharmacol. 175: 223‐231 https://www.ncbi.nlm.nih.gov/pubmed/28213937?dopt=AbstractPlus
Li H et al. (2018) Phosphodiesterase‐4 Inhibitors for the Treatment of Inflammatory Diseases. Front Pharmacol 9: 1048 https://www.ncbi.nlm.nih.gov/pubmed/30386231
Mehta A and Patel BM. (2019) Therapeutic opportunities in colon cancer: Focus on phosphodiesterase inhibitors. Life Sci 230: 150‐161 https://www.ncbi.nlm.nih.gov/pubmed/31125564
Ntontsi P et al. (2019) Experimental and investigational phosphodiesterase inhibitors in development for asthma. Expert Opin Investig Drugs 28: 261‐266 https://www.ncbi.nlm.nih.gov/pubmed/30678501
Pauls MM. (2018) The effect of phosphodiesterase‐5 inhibitors on cerebral blood flow in humans: A systematic review. J Cereb Blood Flow Metab 38: 189‐203 https://www.ncbi.nlm.nih.gov/pubmed/29256324
Peng T et al. (2018) Inhibitors of phosphodiesterase as cancer therapeutics. Eur J Med Chem 150: 742‐756 https://www.ncbi.nlm.nih.gov/pubmed/29574203
Svensson F et al. (2018) Fragment‐Based Drug Discovery of Phosphodiesterase Inhibitors. J Med Chem 61: 1415–1424 https://www.ncbi.nlm.nih.gov/pubmed/28800229
Wahlang B et al. (2018) Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 49: 105‐115 https://www.ncbi.nlm.nih.gov/pubmed/29902522
Zagorska A et al. (2018) Phosphodiesterase 10 Inhibitors ‐ Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery. Curr Med Chem 25: 3455‐3481 https://www.ncbi.nlm.nih.gov/pubmed/29521210
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242
Overview
The cytochrome P450 enzyme family (CYP450), E.C. 1.14.‐.‐, were originally defined by their strong absorbance at 450 nm due to the reduced carbon monoxide‐complexed haem component of the cytochromes. They are an extensive family of haemcontaining monooxygenases with a huge range of both endogenous and exogenous substrates. These include sterols, fat‐soluble vitamins, pesticides and carcinogens as well as drugs. The substrates of some orphan CYP are not known. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologuemay not catalyse the metabolism of the same substrates. Although the majority of CYP450 enzyme activities are concentrated in the liver, the extrahepatic enzyme activities also contribute to patho/physiological processes. Genetic variation of CYP450 isoforms is widespread and likely underlies a significant proportion of the individual variation to drug administration.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=261
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=262
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=263
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=264
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=265
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=266
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=267
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=268
Further reading on Cytochrome P450
Backman JT et al. (2016) Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev 68: 168‐241 https://www.ncbi.nlm.nih.gov/pubmed/26721703?dopt=AbstractPlus
Davis CM et al. (2017) Cytochrome P450 eicosanoids in cerebrovascular function and disease. Pharmacol Ther 179: 31‐46 https://www.ncbi.nlm.nih.gov/pubmed/28527918?dopt=AbstractPlus
Ghosh D et al. (2016) Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure‐Function Perspective. J Med Chem. 59: 5131‐48 https://www.ncbi.nlm.nih.gov/pubmed/26689671?dopt=AbstractPlus
Go RE et al. (2015) Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol. 147: 24‐30 https://www.ncbi.nlm.nih.gov/pubmed/25448748?dopt=AbstractPlus
Guengerich FP et al. (2016) Recent Structural Insights into Cytochrome P450 Function. Trends Pharmacol Sci 37: 625‐640 https://www.ncbi.nlm.nih.gov/pubmed/27267697?dopt=AbstractPlus
Imig JD. (2018) Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics. Pharmacol Ther 192: 1‐19 https://www.ncbi.nlm.nih.gov/pubmed/29964123?dopt=AbstractPlus
Isvoran A et al. (2017) Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism. Drug Discov Today 22: 366‐376 https://www.ncbi.nlm.nih.gov/pubmed/27693711?dopt=AbstractPlus
Jamieson KL et al. (2017) Cytochrome P450‐derived eicosanoids and heart function. Pharmacol Ther 179: 47–83 https://www.ncbi.nlm.nih.gov/pubmed/28551025?dopt=AbstractPlus
Mak PJ et al. (2018) Spectroscopic studies of the cytochrome P450 reaction mechanisms. Biochim Biophys Acta 1866: 178‐204 https://www.ncbi.nlm.nih.gov/pubmed/28668640?dopt=AbstractPlus
Moutinho M et al. (2016) Cholesterol 24‐hydroxylase: Brain cholesterol metabolism and beyond. Biochim Biophys Acta 1861: 1911‐1920 https://www.ncbi.nlm.nih.gov/pubmed/27663182?dopt=AbstractPlus
Shalan H et al. (2018) Keeping the spotlight on cytochrome P450. Biochim Biophys Acta 1866: 80‐87 https://www.ncbi.nlm.nih.gov/pubmed/28599858?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=851
Overview
DNA topoisomerases regulate the supercoiling of nuclear DNA to influence the capacity for replication or transcription. The enzymatic function of this series of enzymes involves cutting the DNA to allow unwinding, followed by re‐attachment to reseal the backbone. Members of the family are targetted in anti‐cancer chemotherapy.
Further reading on DNA topoisomerases
Bansal S et al. (2017) Topoisomerases: Resistance versus Sensitivity, How Far We Can Go? Med Res Rev 37: 404‐438 https://www.ncbi.nlm.nih.gov/pubmed/27687257?dopt=AbstractPlus
Capranico G et al. (2017) Type I DNA Topoisomerases. J. Med. Chem. 60: 2169‐2192 https://www.ncbi.nlm.nih.gov/pubmed/28072526?dopt=AbstractPlus
Nagaraja V et al. (2017) DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov. Today 22: 510‐518 https://www.ncbi.nlm.nih.gov/pubmed/27856347?dopt=AbstractPlus
Pommier Y et al. (2016) Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat. Rev. Mol. Cell Biol. 17: 703‐721 https://www.ncbi.nlm.nih.gov/pubmed/27649880?dopt=AbstractPlus
Seol Y et al. (2016) The dynamic interplay between DNA topoisomerases and DNA topology. Biophys Rev 8: 101‐111 https://www.ncbi.nlm.nih.gov/pubmed/28510219?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=943
Overview
The 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=273
Comments
Routes for N‐acylethanolamine biosynthesis other than through NAPE‐PLD activity have been identified [http://www.ncbi.nlm.nih.gov/pubmed/23394527?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=944
Overview
ABHD12 is a 398‐aa protein, with serine hydrolase activity. It has a molecular weight of 45 kDa. A single TM is predicted at 75‐95, with an extracellular catalytic domain. ABHD12 is a monoacylglycerol hydrolase [http://www.ncbi.nlm.nih.gov/pubmed/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
Many of the compounds described as inhibitors are irreversible and so potency estimates will vary with incubation time. FAAH2 is not found in rodents [http://www.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].
Further reading on Endocannabinoid turnover
Blankman JL et al. (2013) Chemical probes of endocannabinoid metabolism. Pharmacol. Rev. 65: 849–71 https://www.ncbi.nlm.nih.gov/pubmed/23512546?dopt=AbstractPlus
Cao JK et al. (2019) ABHD6: Its Place in Endocannabinoid Signaling and Beyond. Trends Pharmacol Sci 40: 267–277 https://www.ncbi.nlm.nih.gov/pubmed/30853109
Di Marzo V. (2018) New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov 17: 623–639 https://www.ncbi.nlm.nih.gov/pubmed/30116049
Fowler CJ. (2017) Endocannabinoid Turnover. Adv Pharmacol 80: 31–66 https://www.ncbi.nlm.nih.gov/pubmed/28826539
Janssen FJ et al. (2016) Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders. Bioorg Med Chem Lett 26: 3831–7 https://www.ncbi.nlm.nih.gov/pubmed/27394666?dopt=AbstractPlus
Maccarrone M. (2017) Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years. Front Mol Neurosci 10: 166 https://www.ncbi.nlm.nih.gov/pubmed/28611591?dopt=AbstractPlus
Nicolussi S et al. (2015) Endocannabinoid transport revisited. Vitam Horm 98: 441–85 https://www.ncbi.nlm.nih.gov/pubmed/25817877?dopt=AbstractPlus
Tsuboi K et al. (2018) Endocannabinoids and related N‐acylethanolamines: biological activities and metabolism. Inflamm Regen 38: 28 https://www.ncbi.nlm.nih.gov/pubmed/30288203
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=243
Overview
Eicosanoids 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=269
Overview
Prostaglandin (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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=270
Overview
Subsequent 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
http://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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=271
Overview
The lipoxygenases (LOXs) are a structurally related family of non‐heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. For http://www.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
An 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=272
Overview
Leukotriene 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
LTA4H 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.
Further reading on Eicosanoid turnover
Ackermann JA et al. (2017) The double‐edged role of 12/15‐lipoxygenase during inflammation and immunity. Biochim. Biophys. Acta 1862: 371–381 https://www.ncbi.nlm.nih.gov/pubmed/27480217?dopt=AbstractPlus
Grosser T et al. (2017) The Cardiovascular Pharmacology of Nonsteroidal Anti‐Inflammatory Drugs. Trends Pharmacol. Sci. 38: 733–748 https://www.ncbi.nlm.nih.gov/pubmed/28651847?dopt=AbstractPlus
Haeggstrom JZ. (2018) Leukotriene biosynthetic enzymes as therapeutic targets. J Clin Invest 128: 2680–2690 https://www.ncbi.nlm.nih.gov/pubmed/30108195
Hafner AK et al. (2019) Beyond leukotriene formation‐The noncanonical functions of 5‐lipoxygenase. Prostaglandins Other Lipid Mediat 142: 24–32 https://www.ncbi.nlm.nih.gov/pubmed/30930090
Mitchell JA and Kirkby NS. (2019) Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. Br J Pharmacol 176: 1038–1050 https://www.ncbi.nlm.nih.gov/pubmed/29468666
Koeberle A et al. (2015) Perspective of microsomal prostaglandin E2 synthase‐1 as drug target in inflammation‐related disorders. Biochem. Pharmacol. 98: 1–15 https://www.ncbi.nlm.nih.gov/pubmed/26123522?dopt=AbstractPlus
Kuhn H et al. (2015) Mammalian lipoxygenases and their biological relevance. Biochim. Biophys. Acta 1851: 308–30 https://www.ncbi.nlm.nih.gov/pubmed/25316652?dopt=AbstractPlus
Patrignani P et al. (2015) Cyclooxygenase inhibitors: From pharmacology to clinical read‐outs. Biochim. Biophys. Acta 1851: 422–32 https://www.ncbi.nlm.nih.gov/pubmed/25263946?dopt=AbstractPlus
Rådmark O et al. (2015) 5‐Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim. Biophys. Acta 1851: 331–9 https://www.ncbi.nlm.nih.gov/pubmed/25152163?dopt=AbstractPlus
Sasaki Y et al. (2017) Role of prostacyclin synthase in carcinogenesis. Prostaglandins Other Lipid Mediat. 133: 49–52 https://www.ncbi.nlm.nih.gov/pubmed/28506876?dopt=AbstractPlus
Seo MJ et al. (2017) Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis. Prog. Lipid Res. 66: 50–68 https://www.ncbi.nlm.nih.gov/pubmed/28392405?dopt=AbstractPlus
Vitale P et al. (2016) COX‐1 Inhibitors: Beyond Structure Toward Therapy. Med Res Rev 36: 641–71 https://www.ncbi.nlm.nih.gov/pubmed/27111555?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=764
Overview
The 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.
Further reading on GABA turnover
Koenig MK et al. (2017) Phenotype of GABA‐transaminase deficiency. Neurology 88: 1919–1924 https://www.ncbi.nlm.nih.gov/pubmed/28411234?dopt=AbstractPlus
Lee H et al. (2015) Ornithine aminotransferase versus GABA aminotransferase: implications for the design of new anticancer drugs. Med Res Rev 35: 286–305 https://www.ncbi.nlm.nih.gov/pubmed/25145640?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244
Overview
Phospholipids are the basic barrier components of membranes in eukaryotic cells divided into glycerophospholipids (phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol and its phosphorylated derivatives) and sphingolipids (ceramide phosphorylcholine and ceramide phosphorylethanolamine).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=274
Overview
Phosphoinositide‐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
A 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].
Further reading on Phosphoinositide‐specific phospholipase C
Cocco L et al. (2015) Phosphoinositide‐specific phospholipase C in health and disease. J. Lipid Res.56: 1853–60 https://www.ncbi.nlm.nih.gov/pubmed/25821234?dopt=AbstractPlus
Cockcroft S et al. (2016) Topological organisation of the phosphatidylinositol 4,5‐bisphosphatephospholipase C resynthesis cycle: PITPs bridge the ER‐PM gap. Biochem. J. 473: 4289–4310 https://www.ncbi.nlm.nih.gov/pubmed/27888240?dopt=AbstractPlus
Litosch I. (2015) Regulating G protein activity by lipase‐independent functions of phospholipase C. Life Sci. 137: 116–24 https://www.ncbi.nlm.nih.gov/pubmed/26239437?dopt=AbstractPlus
Nakamura Y et al. (2017) Regulation and physiological functions of mammalian phospholipase C. J. Biochem. 161: 315–321 https://www.ncbi.nlm.nih.gov/pubmed/28130414?dopt=AbstractPlus
Swann K et al. (2016) The sperm phospholipase C‐ζ and Ca2+ signalling at fertilization in mammals. Biochem. Soc. Trans. 44: 267–72 https://www.ncbi.nlm.nih.gov/pubmed/26862214?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244#Phospholipase A2
Overview
Phospholipase 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
sPLA2‐1B, sPLA2‐2A, sPLA2‐2D, sPLA2‐2E, sPLA2‐2F, sPLA2‐3, sPLA2‐10 and sPLA2‐12A
Cytosolic, calcium‐dependent forms
cPLA2‐4A, cPLA2‐4B, cPLA2‐4C, cPLA2‐4D, cPLA2‐4E and cPLA2‐4F
Other forms
PLA2‐G5, iPLA2‐G6, PLA2‐G7 and PAFAH2 (platelet‐activating factor acetylhydrolase 2)
Comments
The 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.
A 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].
PLA2‐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).
Further reading on Phospholipase A2
Astudillo AM. (2019) Selectivity of phospholipid hydrolysis by phospholipase A2 enzymes in activated cells leading to polyunsaturated fatty acid mobilization. Biochim Biophys Acta Mol Cell Biol Lipids 1864: 772–783 https://www.ncbi.nlm.nih.gov/pubmed/30010011
Kita Y etal. (2019) Cytosolic phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids 1864: 838–845 https://www.ncbi.nlm.nih.gov/pubmed/30905348
Mouchlis VD and Dennis EA. (2019) Phospholipase A2 catalysis and lipid. mediator lipidomics. Biochim Biophys Acta Mol Cell Biol Lipids 1864: 766–771 https://www.ncbi.nlm.nih.gov/pubmed/30905345
Murakami M et al. (2019) Group IID, IIE, IIF and III secreted phospholipase A2s. Biochim Biophys Acta Mol Cell Biol Lipids. 1864: 803–818 https://www.ncbi.nlm.nih.gov/pubmed/30905347
Samuchiwal SK and Balestrieri B. (2019) Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions. Biochim Biophys Acta Mol Cell Biol Lipids 1864: 819–826 https://www.ncbi.nlm.nih.gov/pubmed/30308324
Shayman JA and Tesmer JJG. (2019) Lysosomal phospholipase A2. Biochim Biophys Acta Mol Cell Biol Lipids. 1864: 932–940 https://www.ncbi.nlm.nih.gov/pubmed/30077006
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=276
Overview
Phosphatidylcholine‐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
A 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].
Three 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.
Further reading on Phosphatidylcholine‐specific phospholipase D
Brown HA et al. (2017) Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov 16: 351‐367 https://www.ncbi.nlm.nih.gov/pubmed/28209987?dopt=AbstractPlus
Frohman MA. (2015) The phospholipase D superfamily as therapeutic targets. Trends Pharmacol. Sci. 36: 137‐44 https://www.ncbi.nlm.nih.gov/pubmed/25661257?dopt=AbstractPlus
Nelson RK et al. (2015) Physiological and pathophysiological roles for phospholipase D. J. Lipid Res. 56: 2229‐37 https://www.ncbi.nlm.nih.gov/pubmed/25926691?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=277
Overview
Lipid phosphate phosphatases, divided into phosphatidic acid phosphatases or lipins catalyse the dephosphorylation of phosphatidic acid (and other phosphorylated lipid derivatives) to generate inorganic phosphate and diacylglycerol. PTEN, a phosphatase and tensin homolog (BZS, MHAM, MMAC1, PTEN1, TEP1) is a phosphatidylinositol 3,4,5‐trisphosphate 3‐phosphatase which acts as a tumour suppressor by reducing cellular levels of PI 3,4,5‐P, thereby toning down activity of PDK1 and PKB. Loss‐of‐function mutations are frequently identified as somatic mutations in cancers.
Further reading on Lipid phosphate phosphatases
Knafo S and Esteban JA. (2017) PTEN: Local and Global Modulation of Neuronal Function in Health and Disease. Trends Neurosci 40: 83‐91 https://www.ncbi.nlm.nih.gov/pubmed/28081942
Lee YR et al. (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19: 547‐562 https://www.ncbi.nlm.nih.gov/pubmed/29858604
Yehia L et al. (2019) PTEN‐opathies: from biological insights to evidence‐based precision medicine. J Clin Invest 129: 452‐464 https://www.ncbi.nlm.nih.gov/pubmed/30614812
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=781
Overview
Phosphatidylinositol 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
Phosphatidylinositol 3‐kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3‐position of phosphatidylinositol (PI), phosphatidylinositol 4‐phosphate (PIP) or phosphatidylinositol 4,5‐bisphosphate (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.
Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5‐bisphosphate to generate phosphatidylinositol 3,4,5‐trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110ß and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linkedmore with GPCR signalling.
Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3‐phosphate (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.
The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).
Phosphatidylinositol 4‐kinases
Phosphatidylinositol 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=638
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=671
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=672
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2152 |
| Common abbreviation | VPS34 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8974, http://www.uniprot.org/uniprot/Q8NEB9 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.1.137 |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=673
Overview
PI3K 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=913
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2857 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:23785, http://www.uniprot.org/uniprot/Q9Y2I7 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.1.150: ATP + 1‐phosphatidyl‐1D‐myo‐inositol 3‐phosphate = ADP + 1‐phosphatidyl‐1D‐myo‐inositol 3,5‐bisphosphate |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=675
Overview
Type 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=674
Overview
Type 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.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2858 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2162 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2163 |
| Common abbreviation | PIP4K2A | PIP4K2B | PIP4K2C |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8997, http://www.uniprot.org/uniprot/P48426 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8998, http://www.uniprot.org/uniprot/P78356 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:23786, http://www.uniprot.org/uniprot/Q8TBX8 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.1.149 ATP + 1‐phosphatidyl‐1D‐myo‐inositol 5‐phosphate <=> ADP + 1‐phosphatidyl‐1D‐myo‐inositol 4,5‐bisphosphate | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.1.149 | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.1.149 |
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=787
Overview
SPHK1 and SPHK2 are encoded by different genes with some redundancy of function; genetic deletion of both Sphk1 and Sphk2, but not either alone, is embryonic lethal in mice. There are splice variants of each isoform (SphK1a‐c and SphK2a, b), distinguished by their N‐terminal sequences. SPHK1 and SPHK2 differ in tissue distribution, sub‐cellular localisation, biochemical properties and regulation. They regulate discrete pools of S1P. Receptor stimulation induces SPHK1 translocation from the cytoplasm to the plasma membrane. SPHK1 translocation is regulated by phosphorylation/dephosphorylation, specific protein:protein interactions and interaction with specific lipids at the plasma membrane. SPHK1 is a dimeric protein, as confirmed by its crystal structure which forms a positive cluster, between protomers, essential for interaction with anionic phospholipids in the plasma membrane. SPHK2 is localised to the ER or associated with mitochondria or shuttles in/out of the nucleus, regulated by phosphorylation. Intracellular targets of nuclear S1P include the catalytic subunit of telomerase (TERT) and regulators of gene expression including histone deacetylases (HDAC 1/2) and peroxisome proliferator‐activated receptor gamma (PPARγ). SPHK2 phosphorylates the pro‐drug FTY720 (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
http://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).
Further reading on Sphingosine kinase
Adams DR et al. (2016) Sphingosine Kinases: Emerging Structure‐Function Insights. Trends Biochem. Sci. 41: 395‐409 https://www.ncbi.nlm.nih.gov/pubmed/27021309?dopt=AbstractPlus
Lynch KR et al. (2016) Sphingosine kinase inhibitors: a review of patent literature (2006‐2015). Expert Opin Ther Pat 26: 1409‐1416 https://www.ncbi.nlm.nih.gov/pubmed/27539678?dopt=AbstractPlus
Pitman MR et al. (2016) Recent advances in the development of sphingosine kinase inhibitors. Cell. Signal. 28: 1349‐63 https://www.ncbi.nlm.nih.gov/pubmed/27297359?dopt=AbstractPlus
Pulkoski‐Gross MJ et al. (2018) An intrinsic lipid‐binding interface controls sphingosine kinase 1 function. J. Lipid Res. 59: 462‐474 https://www.ncbi.nlm.nih.gov/pubmed/29326159?dopt=AbstractPlus
Pyne NJ et al. (2017) Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol. Sci. 38: 581‐591 https://www.ncbi.nlm.nih.gov/pubmed/28606480?dopt=AbstractPlus
Pyne S et al. (2018) Sphingosine Kinases as Druggable Targets. Handb Exp Pharmacol https://www.ncbi.nlm.nih.gov/pubmed/29460151?dopt=AbstractPlus
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6060 also inhibits type III phosphatidylinositol 4‐kinases and polo‐like kinase [http://www.ncbi.nlm.nih.gov/pubmed/15664519?dopt=AbstractPlus]. PIK93 also inhibits PI 3‐kinases [http://www.ncbi.nlm.nih.gov/pubmed/16647110?dopt=AbstractPlus]. Adenosine activates http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=3.
Further reading on Phosphatidylinositol kinases
Raphael J et al. (2018) Phosphoinositide 3‐kinase inhibitors in advanced breast cancer: A systematic review and meta‐analysis. Eur J Cancer 91: 38‐46 https://www.ncbi.nlm.nih.gov/pubmed/29331750
Wang D et al. (2019) Upstream regulators of phosphoinositide 3‐kinase and their role in diseases. J Cell Physiol. https://www.ncbi.nlm.nih.gov/pubmed/30710358
Goncalves MD et al. (2018) Phosphatidylinositol 3‐Kinase, Growth Disorders, and Cancer. N Engl J Med 379: 2052‐2062 https://www.ncbi.nlm.nih.gov/pubmed/30462943
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=782
Overview
PIP2 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.
Further reading on Glycerophospholipid turnover
Cauvin C et al. (2015) Phosphoinositides: Lipids with informative heads and mastermind functions in cell division. Biochim. Biophys. Acta 1851: 832‐43 https://www.ncbi.nlm.nih.gov/pubmed/25449648?dopt=AbstractPlus
Irvine RF. (2016) A short history of inositol lipids. J. Lipid Res. 57: 1987‐1994 https://www.ncbi.nlm.nih.gov/pubmed/27623846?dopt=AbstractPlus
Poli A et al. (2016) Nuclear Phosphatidylinositol Signaling: Focus on Phosphatidylinositol Phosphate Kinases and Phospholipases C. J. Cell. Physiol. 231: 1645‐55 https://www.ncbi.nlm.nih.gov/pubmed/26626942?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=278
Overview
Haem 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.
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1441 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1442 |
| Common abbreviation | HO1 | HO2 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5013, http://www.uniprot.org/uniprot/P09601 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5014, http://www.uniprot.org/uniprot/P30519 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:1.14.14.18 Protoheme + 3 [reduced NADPH‐hemoprotein reductase] + 3 O(2) <=> biliverdin + Fe(2+) + CO + 3 [oxidized NADPH‐hemoprotein reductase] + 3 H(2)O | http://www.genome.jp/dbget‐bin/www_bget?ec:1.14.14.18 Protoheme + 3 [reduced NADPH–hemoprotein reductase] + 3 O(2) <=> biliverdin + Fe(2+) + CO + 3 [oxidized NADPH–hemoprotein reductase] + 3 H(2)O |
| Inhibitors | – | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8873 (pIC50 3.5) [http://www.ncbi.nlm.nih.gov/pubmed/16821802?dopt=AbstractPlus] – Rat |
Comments
The existence of a third non‐catalytic version of haem oxygenase, HO3, has been proposed, although this has been suggested to be a pseudogene [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].
Further reading on Haem oxygenase
Magierowska K et al. (2018) Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity. Pharmacol Res 129: 56‐64 https://www.ncbi.nlm.nih.gov/pubmed/29360501
Rochette L et al. (2018) Redox Functions of Heme Oxygenase‐1 and Biliverdin Reductase in Diabetes Trends. Endocrinol Metab. 29: 74‐85 https://www.ncbi.nlm.nih.gov/pubmed/29249571
Salerno L et al. (2017) Heme oxygenase‐1: A new druggable target in the management of chronic and acute myeloid leukemia. Eur J Med Chem. 142: 163‐178 https://www.ncbi.nlm.nih.gov/pubmed/28756878
Sebastian VP et al. (2018) Heme Oxygenase‐1 as a Modulator of Intestinal Inflammation Development and Progression. Front Immunol. 9: 1956 https://www.ncbi.nlm.nih.gov/pubmed/30258436
Tomczyk M et al. (2019) Modulation of the monocyte/macrophage system in heart failure by targeting heme oxygenase‐1. Vascul Pharmacol. 112: 79‐90 https://www.ncbi.nlm.nih.gov/pubmed/30213580
Vijayan V et al. (2018) The macrophage heme‐heme oxygenase‐1 system and its role in inflammation. Biochem Pharmacol. 153: 159‐167 https://www.ncbi.nlm.nih.gov/pubmed/29452096
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=279
Overview
Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (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].
Further reading on Hydrogen sulphide synthesis
Asimakopoulou A et al. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 169: 922‐32 https://www.ncbi.nlm.nih.gov/pubmed/23488457?dopt=AbstractPlus
Szabo C et al. (2017) International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmacol. Rev. 69: 497‐564 https://www.ncbi.nlm.nih.gov/pubmed/28978633?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=799
Overview
Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (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.
Further reading on Hydrolases
Allard B et al.. (2017) The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol Rev. 276: 121‐144 https://www.ncbi.nlm.nih.gov/pubmed/28258700
Kishore BK et al. (2018) CD39‐adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal 14: 109‐120 https://www.ncbi.nlm.nih.gov/pubmed/29332180
Rasmussen HB et al. (2018) Carboxylesterase 1 genes: systematic review and evaluation of existing genotyping procedures. Drug Metab Pers Ther 33: 3‐14 https://www.ncbi.nlm.nih.gov/pubmed/29427553
Zou LW et al. (2018) Carboxylesterase Inhibitors: An Update. Curr Med Chem. 25: 1627‐1649 https://www.ncbi.nlm.nih.gov/pubmed/29210644
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=245
Overview
The 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]).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=280
Overview
Inositol 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].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=280.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=281
Overview
Members 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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=281.
Comments
In vitro analysis suggested http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4222 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5202 were poor substrates for SKIP, synaptojanin 1 and synaptojanin 2, but suggested that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2387 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2353 were more efficiently hydrolysed [http://www.ncbi.nlm.nih.gov/pubmed/15474001?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=282
Overview
Inositol 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
Polymorphisms 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].
Further reading on Inositol phosphate turnover
Irvine R. (2016) A tale of two inositol trisphosphates. Biochem. Soc. Trans. 44: 202‐11 https://www.ncbi.nlm.nih.gov/pubmed/26862207?dopt=AbstractPlus
Livermore TM et al. (2016) Phosphate, inositol and polyphosphates. Biochem. Soc. Trans. 44: 253‐9 https://www.ncbi.nlm.nih.gov/pubmed/26862212?dopt=AbstractPlus
Miyamoto A et al. (2017) Probes for manipulating and monitoring IP_3. Cell Calcium 64: 57‐64 https://www.ncbi.nlm.nih.gov/pubmed/27887748?dopt=AbstractPlus
Windhorst S et al. (2017) Inositol‐1,4,5‐trisphosphate 3‐kinase‐A (ITPKA) is frequently over‐expressed and functions as an oncogene in several tumor types. Biochem. Pharmacol. 137: 1‐9 https://www.ncbi.nlm.nih.gov/pubmed/28377279?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=698
Overview
Protein 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.
Most inhibitors of these enzymes have been assessed in cell‐free investigations and so may appear to ’lose’ potency and selectivity in intact cell assays. In particular, ambient 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=289
Overview
Rho 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].
Further reading on Rho kinase
Feng Y et al. (2016) Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J. Med. Chem. 59: 2269‐300 https://www.ncbi.nlm.nih.gov/pubmed/26486225?dopt=AbstractPlus
Nishioka T et al. (2015) Developing novel methods to search for substrates of protein kinases such as Rho‐kinase. Biochim. Biophys. Acta 1854: 1663‐6 https://www.ncbi.nlm.nih.gov/pubmed/25770685?dopt=AbstractPlus
Shimokawa H et al. (2016) RhoA/Rho‐Kinase in the Cardiovascular System. Circ. Res. 118: 352‐66 https://www.ncbi.nlm.nih.gov/pubmed/26838319?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=286
Overview
Protein 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).
Classical 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.
Novel 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.
Atypical protein kinase C isoforms: PKC ι, PKC ζ.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=532
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=533
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=534
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1486 |
| Common abbreviation | PKC∈ |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9401, http://www.uniprot.org/uniprot/Q02156 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:2.7.11.13 |
| Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7946 (pIC50 8.2) [http://www.ncbi.nlm.nih.gov/pubmed/19827831?dopt=AbstractPlus] |
Further reading on Protein kinase C (PKC) family
Igumenova TI. (2015) Dynamics and Membrane Interactions of Protein Kinase C. Biochemistry 54: 4953‐68 https://www.ncbi.nlm.nih.gov/pubmed/26214365?dopt=AbstractPlus
Newton AC et al. (2017) Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor. Trends Pharmacol. Sci. 38: 438‐447 https://www.ncbi.nlm.nih.gov/pubmed/28283201?dopt=AbstractPlus
Salzer E et al. (2016) Protein Kinase C δ: a Gatekeeper of Immune Homeostasis. J. Clin. Immunol. 36: 631‐40 https://www.ncbi.nlm.nih.gov/pubmed/27541826?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=529
Further reading on FRAP subfamily
Hukelmann JL et al. (2016) The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17: 104‐12 https://www.ncbi.nlm.nih.gov/pubmed/26551880?dopt=AbstractPlus
Saxton RA et al. (2017) mTOR Signaling in Growth, Metabolism, and Disease. Cell 169: 361‐371 https://www.ncbi.nlm.nih.gov/pubmed/28388417?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=453
Overview
Five of the cyclin‐dependent kinases (CDKs: 7, 8, 9, 12, and 13) are involved in the phosphorylation of serine residues in the C‐terminal domain of RNA polymerase II, the enzyme that is responsible for the transcription of protein‐coding genes into mRNA in eukaryotes. Phosphorylation of RNA polymerase II at Ser5 is essential for transcriptional initiation, and phosphorylation of Ser 2 contributes to transcriptional elongation and termination. 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=488
Comments on Cyclin‐dependent kinase (CDK) family
The 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/.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=509
Further reading on GSK subfamily
Beurel E et al. (2015) Glycogen synthase kinase‐3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 148: 114‐31 https://www.ncbi.nlm.nih.gov/pubmed/25435019?dopt=AbstractPlus
Domoto T et al. (2016) Glycogen synthase kinase‐3β is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci. 107: 1363‐1372 https://www.ncbi.nlm.nih.gov/pubmed/27486911?dopt=AbstractPlus
Khan I et al. (2017) Natural and synthetic bioactive inhibitors of glycogen synthase kinase. Eur J Med Chem 125: 464‐477 https://www.ncbi.nlm.nih.gov/pubmed/27689729?dopt=AbstractPlus
Maqbool M et al. (2016) Pivotal role of glycogen synthase kinase‐3: A therapeutic target for Alzheimer's disease. Eur J Med Chem 107: 63‐81 https://www.ncbi.nlm.nih.gov/pubmed/26562543?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=602
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=623
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=553
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=554
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=581
Overview
Janus 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=619
Overview
Activation of Src‐family kinases leads to both stimulatory and inhibitory signaling responses, with cell‐specific and signaling pathway‐specific outcomes and redundancy of kinase function.
Immune system
In immune cells Src kinases are involved in many signalling pathways, including ITAM‐ and ITIM‐domain‐containing receptor signaling, integrin signaling, and responses to chemokines/chemoattractants, cytokines, innate immune stimuli and a large variety of non‐immune cell specific stimuli (UV irradiation, heat, osmotic shock etc.). In many cases Src kinases signal to MAP kinase or NF‐κB pathways, but they can also modulate other pathways through less well characterized mechanisms.
The 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=629
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=610
Further reading on Kinases (EC 2.7.x.x)
Eglen R et al. (2011) Drug discovery and the human kinome: recent trends. Pharmacol. Ther. 130: 144‐56 https://www.ncbi.nlm.nih.gov/pubmed/21256157?dopt=AbstractPlus
Graves LM et al. (2013) The dynamic nature of the kinome. Biochem. J. 450: 1‐8 https://www.ncbi.nlm.nih.gov/pubmed/23343193?dopt=AbstractPlus
Liu Q et al. (2013) Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol. 20: 146‐59 https://www.ncbi.nlm.nih.gov/pubmed/23438744?dopt=AbstractPlus
Martin KJ et al. (2012) Selective kinase inhibitors as tools for neuroscience research. Neuropharmacology 63: 1227–37 https://www.ncbi.nlm.nih.gov/pubmed/22846224?dopt=AbstractPlus
Tarrant MK et al. (2009) The chemical biology of protein phosphorylation. Annu. Rev. Biochem. 78: 797‐825 https://www.ncbi.nlm.nih.gov/pubmed/19489734?dopt=AbstractPlus
Wu‐Zhang AX et al. (2013) Protein kinase C pharmacology: refining the toolbox. Biochem. J. 452: 195‐209 https://www.ncbi.nlm.nih.gov/pubmed/23662807?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=104
Overview
Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG‐CoA reductase pathway. The first two steps (formation of 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.
Further reading on Lanosterol biosynthesis pathway
Moutinho M et al. (2017) The mevalonate pathway in neurons: It's not just about cholesterol. Exp. Cell Res. 360: 55–60 https://www.ncbi.nlm.nih.gov/pubmed/28232115?dopt=AbstractPlus
Mullen PJ et al. (2016) The interplay between cell signalling and the mevalonate pathway in cancer. Nat. Rev. Cancer 16: 718–731 https://www.ncbi.nlm.nih.gov/pubmed/27562463?dopt=AbstractPlus
Ness GC. (2015) Physiological feedback regulation of cholesterol biosynthesis: Role of translational control of hepatic HMG‐CoA reductase and possible involvement of oxylanosterols. Biochim. Biophys. Acta 1851: 667–73 https://www.ncbi.nlm.nih.gov/pubmed/25701719?dopt=AbstractPlus
Porter TD. (2015) Electron Transfer Pathways in Cholesterol Synthesis. Lipids 50: 927–36 https://www.ncbi.nlm.nih.gov/pubmed/26344922?dopt=AbstractPlus
Samaras K et al. (2016) Does statin use cause memory decline in the elderly? Trends Cardiovasc. Med. 26: 550–65 https://www.ncbi.nlm.nih.gov/pubmed/27177529?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=920
Overview
The 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
TYMS allows the interconversion of dUMP and dTMP, thereby acting as a crucial step in DNA synthesis. PNP allows separation of a nucleoside into the nucleobase and ribose phosphate for nucleotide salvage. XDH generates urate in the purine degradation pathway. Post‐translational modifications of XDH convert the enzymatic reaction to a xanthine oxidase, allowing the interconversion of hypoxanthine and xanthine, with the production (or consumption) of reactive oxygen species.
Further reading on Nucleoside synthesis and metabolism
Day RO et al. (2016) Xanthine oxidoreductase and its inhibitors: relevance for gout. Clin Sci (Lond). 130: 2167–2180 https://www.ncbi.nlm.nih.gov/pubmed/27798228
Okafor ON et al. (2017) Allopurinol as a therapeutic option in cardiovascular disease. Pharmacol Ther. 172: 139–150 https://www.ncbi.nlm.nih.gov/pubmed/27916655
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1018
Overview
Paraoxonases (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.
Further reading on Paraoxonase
Dardiotis E et al. (2019) Paraoxonase‐1 genetic polymorphisms in organophosphate metabolism. Toxicology. 411: 24–31 https://www.ncbi.nlm.nih.gov/pubmed/30359673
Lioudaki S et al. (2019) Paraoxonase‐1: Characteristics and Role in Atherosclerosis and Carotid Artery Disease. Curr Vasc Pharmacol. 17: 141–146 https://www.ncbi.nlm.nih.gov/pubmed/29189170
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=759
Overview
Peptidases 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.‐).
Since it is beyond the scope of the Guide to list all peptidase and proteinase activities, this summary focuses on selected enzymes of significant pharmacological interest that have ligands (mostly small‐molecules) directed against them. For those interested in detailed background we recommend the MEROPS database [493] (with whom we collaborate) as an information resource [http://www.ncbi.nlm.nih.gov/pubmed/26527717?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=726
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=727
Overview
Presenilin (PS)‐1 or ‐2 act as the catalytic component/ essential co‐factor of the γ‐secretase complex responsible for the final carboxy‐terminal cleavage of amyloid precursor protein (APP) [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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=727.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=734
Overview
Caspases, (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.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=734.
Comments
CARD16 (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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=737
Overview
Aminopeptidases 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].
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=741
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=738
Overview
Matrix 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).
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1629 | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1632 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7166, http://www.uniprot.org/uniprot/P08253 | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7175, http://www.uniprot.org/uniprot/P22894 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:3.4.24.24 | http://www.genome.jp/dbget‐bin/www_bget?ec:3.4.24.34 |
| Selective inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5140 [http://www.ncbi.nlm.nih.gov/pubmed/16483784?dopt=AbstractPlus] | – |
| Comments | MMP2 is categorised as a gelatinase with substrate specificity for gelatinase A. | MMP8 is categorised as a collagenase. |
Comments
A 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.
Tissue 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)
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=739
Overview
ADAM (A Disintegrin And Metalloproteinase domain containing proteins) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.
ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell‐surface or transmembrane proteins to generate soluble and membrane‐limited products.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=739.
Comments
Additional 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).
Other ADAMTS family members include AC104758.12‐5 (FLJ00317 protein Fragment ENSG00000231463), AC139425.3‐1 (ENSG00000225577), and AC126339.6‐1 (ENSG00000225734).
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=748
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1606 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3788, http://www.uniprot.org/uniprot/Q04609 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:3.4.17.21 |
| Antibodies | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6878 (Binding) |
| Comments | Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N‐acetaspartylglutamate to form N‐acetylaspartate and L‐glutamate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369). 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. |
Comments
Folate hydrolase is also known as NAALADase as it is responsible for the hydrolysis of N‐acetaspartylglutamate to form N‐acetylaspartate and L‐glutamate. In the gut, the enzyme assists in the assimilation of folate by hydrolysing dietary poly‐gamma‐glutamylfolate. The enzyme is highly expressed in the prostate, and its expression is up‐regulated in cancerous tissue. A tagged version of the antibody http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6878 has been used for imaging purposes.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=749
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=751
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=752
Overview
The 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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=755
Overview
One member of this family has garnered intense interest as a clinical drug target. As liver PCSK9 acts to maintain cholesterol homeostasis, it has become a target of intense interest for clinical drug development. Inhibition of PCSK9 can lower low‐density cholesterol (LDL‐C) by clearing LDLR‐bound LDL particles, thereby lowering circulating cholesterol levels. It is hypothesised that this action may improve outcomes in patients with atherosclerotic cardiovascular disease [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].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=755.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=758
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=883
Overview
The Poly ADP‐ribose polymerase family is a series of enzymes, where the best characterised members are nuclear proteins which are thought to function by binding to single strand breaks in DNA, allowing the recruitment of repair enzymes by the synthesis of NAD‐derived ADP‐ribose polymers, which are subsequently degraded by a glycohydrolase (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8605, http://www.uniprot.org/uniprot/Q86W56).
Further reading on Poly ADP‐ribose polymerases
Berger NA et al. (2018) Opportunities for the repurposing of PARP inhibitors for the therapy of non‐oncological diseases. Br J Pharmacol. 175: 192‐222 https://www.ncbi.nlm.nih.gov/pubmed/28213892
Faraoni I et al. (2019) Targeting ADP‐ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders. Biochem Pharmacol https://www.ncbi.nlm.nih.gov/pubmed/31028744
Zeniou M et al. (2019) Therapeutic considerations of PARP in stem cell biology: Relevance in cancer and beyond. Biochem Pharmacol https://www.ncbi.nlm.nih.gov/pubmed/31202733
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=900
Overview
Hypoxia‐inducible factors (HIFs) are rapidly‐responding sensors of reductions in local oxygen tensions, prompting changes in gene transcription. Listed here are the 4‐prolyl hydroxylase family, members of which have been identified to hydroxylate proline residues in HIF1α (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.
Further reading on Prolyl hydroxylases
Joharapurkar AA et al. (2018) Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases. J Med Chem 61: 6964‐6982 https://www.ncbi.nlm.nih.gov/pubmed/29712435
Lanigan SM and O’Connor JJ. (2019) Prolyl hydroxylase domain inhibitors: can multiple mechanisms be an opportunity for ischemic stroke? Neuropharmacology 148: 117‐130 https://www.ncbi.nlm.nih.gov/pubmed/30578795
Singh L et al. (2018) Prolyl hydroxylase 2: a promising target to inhibit hypoxia‐induced cellular metabolism in cancer cells. Drug Discov Today 23: 1873‐1882 https://www.ncbi.nlm.nih.gov/pubmed/29772209
Vasta JD and Raines RT et al. (2018) Collagen Prolyl 4‐Hydroxylase as a Therapeutic Target. J Med Chem 61: 10403‐10411 https://www.ncbi.nlm.nih.gov/pubmed/29986141
Watts ER and Walmsley SR. (2019) Inflammation and Hypoxia: HIF and PHD Isoform Selectivity. Trends Mol Med 25: 33‐46 https://www.ncbi.nlm.nih.gov/pubmed/30442494
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=776
Overview
S1P (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.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=777
Overview
SPHK1 and SPHK2 are encoded by different genes with some redundancy of function; genetic deletion of both Sphk1 and Sphk2, but not either alone, is embryonic lethal in mice. There are splice variants of each isoform (SphK1a‐c and SphK2a, b), distinguished by their N‐terminal sequences. SPHK1 and SPHK2 differ in tissue distribution, sub‐cellular localisation, biochemical properties and regulation. They regulate discrete pools of S1P. Receptor stimulation induces SPHK1 translocation from the cytoplasm to the plasma membrane. SPHK1 translocation is regulated by phosphorylation/dephosphorylation, specific protein:protein interactions and interaction with specific lipids at the plasma membrane. SPHK1 is a dimeric protein, as confirmed by its crystal structure which forms a positive cluster, between protomers, essential for interaction with anionic phospholipids in the plasma membrane. SPHK2 is localised to the ER or associated with mitochondria or shuttles in/out of the nucleus, regulated by phosphorylation. Intracellular targets of nuclear S1P include the catalytic subunit of telomerase (TERT) and regulators of gene expression including histone deacetylases (HDAC 1/2) and peroxisome proliferator‐activated receptor gamma (PPARγ). SPHK2 phosphorylates the pro‐drug FTY720 (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
http://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).
Further reading on Sphingosine kinase
Adams DR et al. (2016) Sphingosine Kinases: Emerging Structure‐Function Insights. Trends Biochem. Sci. 41: 395‐409 https://www.ncbi.nlm.nih.gov/pubmed/27021309?dopt=AbstractPlus
Lynch KR et al. (2016) Sphingosine kinase inhibitors: a review of patent literature (2006‐2015). Expert Opin Ther Pat 26: 1409‐1416 https://www.ncbi.nlm.nih.gov/pubmed/27539678?dopt=AbstractPlus
Pitman MR et al. (2016) Recent advances in the development of sphingosine kinase inhibitors. Cell. Signal. 28: 1349‐63 https://www.ncbi.nlm.nih.gov/pubmed/27297359?dopt=AbstractPlus
Pulkoski‐Gross MJ et al. (2018) An intrinsic lipid‐binding interface controls sphingosine kinase 1 function. J. Lipid Res. 59: 462‐474 https://www.ncbi.nlm.nih.gov/pubmed/29326159?dopt=AbstractPlus
Pyne NJ et al. (2017) Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors. Trends Pharmacol. Sci. 38: 581‐591 https://www.ncbi.nlm.nih.gov/pubmed/28606480?dopt=AbstractPlus
Pyne S et al. (2018) Sphingosine Kinases as Druggable Targets. Handb Exp Pharmacol https://www.ncbi.nlm.nih.gov/pubmed/29460151?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=778
Comments
SGPP1 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].
Further reading on Sphingosine 1‐phosphate phosphatase
Allende ML et al. (2013) Sphingosine‐1‐phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis. J. Biol. Chem. 288: 18381‐91 https://www.ncbi.nlm.nih.gov/pubmed/23637227?dopt=AbstractPlus
Huang WC et al. (2016) Sphingosine‐1‐phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J. 30: 2945‐58 https://www.ncbi.nlm.nih.gov/pubmed/27130484?dopt=AbstractPlus
Lépine S et al. (2011) Sphingosine‐1‐phosphate phosphohydrolase‐1 regulates ER stress‐induced autophagy. Cell Death Differ. 18: 350‐61 https://www.ncbi.nlm.nih.gov/pubmed/20798685?dopt=AbstractPlus
Mandala SM et al. (2000) Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine‐1‐ phosphate and induces cell death. Proc. Natl. Acad. Sci. U.S.A. 97: 7859‐64 https://www.ncbi.nlm.nih.gov/pubmed/10859351?dopt=AbstractPlus
Taguchi Y et al. (2016) Sphingosine‐1‐phosphate Phosphatase 2 Regulates Pancreatic Islet β‐Cell Endoplasmic Reticulum Stress and Proliferation. J. Biol. Chem. 291: 12029‐38 https://www.ncbi.nlm.nih.gov/pubmed/27059959?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=777
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6626 (2‐Acetyl‐5‐tetrahydroxybutyl imidazole) inhibits the enzyme activity in intact cell preparations [http://www.ncbi.nlm.nih.gov/pubmed/16151014?dopt=AbstractPlus]. Recessive mutations in the S1P lyase (SGPL1) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS) [http://www.ncbi.nlm.nih.gov/pubmed/30274713?dopt=AbstractPlus]. A Phase 2 clinical trial of LX3305 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9851) for rheumatoid arthritis has been completed (see https://clinicaltrials.gov/ct2/show/NCT00903383).
Further reading on Sphingosine 1‐phosphate lyase
Bamborschke D et al. (2018) A novel mutation in sphingosine‐1‐phosphate lyase causing congenital brain malformation. Brain Dev. 40: 480‐483 https://www.ncbi.nlm.nih.gov/pubmed/29501407?dopt=AbstractPlus
Choi YJ et al. (2019) Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. Adv Biol Regul 71: 128‐140 https://www.ncbi.nlm.nih.gov/pubmed/30274713
Lovric S et al. (2017) Mutations in sphingosine‐1‐phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J. Clin. Invest. 127: 912‐928 https://www.ncbi.nlm.nih.gov/pubmed/28165339?dopt=AbstractPlus
Prasad R et al. (2017) Sphingosine‐1‐phosphate lyase mutations cause primary adrenal insufficiency and steroid‐resistant nephrotic syndrome. J. Clin. Invest. 127: 942‐953 https://www.ncbi.nlm.nih.gov/pubmed/28165343?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=779
Overview
The 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
These 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.
Further reading on Thyroid hormone turnover
Darras VM et al. (2015) Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor‐mediated impact on vertebrate development. Biochim. Biophys. Acta 1849: 130‐41 https://www.ncbi.nlm.nih.gov/pubmed/24844179?dopt=AbstractPlus
Gereben B et al. (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11: 642‐652 https://www.ncbi.nlm.nih.gov/pubmed/26416219?dopt=AbstractPlus
Mondal S et al. (2017) Novel thyroid hormone analogues, enzyme inhibitors andmimetics, and their action. Mol. Cell. Endocrinol. 458: 91‐104 https://www.ncbi.nlm.nih.gov/pubmed/28408161?dopt=AbstractPlus
Schweizer U et al. (2015) New insights into the structure and mechanism of iodothyronine deiodinases. J. Mol. Endocrinol. 55: R37‐52 https://www.ncbi.nlm.nih.gov/pubmed/26390881?dopt=AbstractPlus
van der Spek AH et al. (2017) Thyroid hormone metabolism in innate immune cells. J. Endocrinol. 232: R67‐R81 https://www.ncbi.nlm.nih.gov/pubmed/27852725?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=923
| Nomenclature | http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2886 |
| HGNC, UniProt | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6381, http://www.uniprot.org/uniprot/O15229 |
| EC number | http://www.genome.jp/dbget‐bin/www_bget?ec:1.14.13.9 L‐kynurenine + NADPH + O2 <=> 3‐hydroxy‐L‐kynurenine + NADP(+) + H2O |
| Comments | Kynurenine 3‐monooxygenase participates in metabolism of the essential amino acid tryptophan. |
Further reading on 1.14.13.9 Kynurenine 3‐monooxygenase
Dounay AB et al. (2015) Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway. J. Med. Chem. 58: 8762‐82 https://www.ncbi.nlm.nih.gov/pubmed/26207924?dopt=AbstractPlus
Erhardt S et al. (2017) The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology 112: 297‐306 https://www.ncbi.nlm.nih.gov/pubmed/27245499?dopt=AbstractPlus
Fujigaki H et al. (2017) L‐Tryptophan‐kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences. Neuropharmacology 112: 264‐274 https://www.ncbi.nlm.nih.gov/pubmed/26767951?dopt=AbstractPlus
Smith JR et al. (2016) Kynurenine‐3‐monooxygenase: a review of structure, mechanism, and inhibitors. Drug Discov. Today 21: 315‐24 https://www.ncbi.nlm.nih.gov/pubmed/26589832?dopt=AbstractPlus
Song P et al. (2017) Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell. Mol. Life Sci. 74: 2899‐2916 https://www.ncbi.nlm.nih.gov/pubmed/28314892?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=898
Overview
Farnesyltransferase is a member of the prenyltransferases family which also includes geranylgeranyltransferase types I (EC 2.5.1.59) and II (EC 2.5.1.60) [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.
Substrates 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.
In relation to the causative association between oncogenic Ras proteins and cancer, farnesyltransferase has become an important mechanistic drug discovery target.
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=898.
Further reading on 2.5.1.58 Protein farnesyltransferase
Gao S et al. (2016) The Role of Geranylgeranyltransferase I‐Mediated Protein Prenylation in the Brain. Mol. Neurobiol. 53: 6925‐6937 https://www.ncbi.nlm.nih.gov/pubmed/26666664?dopt=AbstractPlus
Shen M et al. (2015) Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling. Drug Discov. Today 20: 267‐76 https://www.ncbi.nlm.nih.gov/pubmed/25450772?dopt=AbstractPlus
Shen Y et al. (2015) The Recent Development of Farnesyltransferase Inhibitors as Anticancer and Antimalarial Agents. Mini Rev Med Chem 15: 837‐57 https://www.ncbi.nlm.nih.gov/pubmed/25963569?dopt=AbstractPlus
Wang M et al. (2016) Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17: 110‐22 https://www.ncbi.nlm.nih.gov/pubmed/26790532?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=848
Overview
Histone deacetylases act as erasers of epigenetic acetylation marks on lysine residues in histones. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression.
The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:
Class I contains HDACs 1, 2, 3 and 8
Class IIa contains HDACs 4, 5, 7 and 9
Class IIb contains HDACs 6 and 10
Class III contains the sirtuins (SIRT1‐7)
Class IV contains only HDAC11.
Classes I, II and IV use Zn+ as a co‐factor, whereas catalysis by Class III enzymes requires NAD+ as a co‐factor, and members of this subfamily have ADP‐ribosylase activity in addition to protein deacetylase function [http://www.ncbi.nlm.nih.gov/pubmed/20132909?dopt=AbstractPlus].
HDACs 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].
Dysregulated 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].
Further reading on 3.5.1.‐ Histone deacetylases (HDACs)
Ellmeier W et al. (2018) Histone deacetylase function in CD4+ T cells. Nat. Rev. Immunol. 18: 617‐634 https://www.ncbi.nlm.nih.gov/pubmed/30022149?dopt=AbstractPlus
Maolanon AR et al. (2017) Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes. Chembiochem 18: 5‐49 https://www.ncbi.nlm.nih.gov/pubmed/27748555?dopt=AbstractPlus
Micelli C et al. (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov. Today 20: 718‐35 https://www.ncbi.nlm.nih.gov/pubmed/25687212?dopt=AbstractPlus
Millard CJ et al. (2017) Targeting Class I Histone Deacetylases in a "Complex" Environment. Trends Pharmacol. Sci. 38: 363‐377 https://www.ncbi.nlm.nih.gov/pubmed/28139258?dopt=AbstractPlus
Roche J et al. (2016) Inside HDACs with more selective HDAC inhibitors. Eur J Med Chem 121: 451‐483 https://www.ncbi.nlm.nih.gov/pubmed/27318122?dopt=AbstractPlus
Zagni C et al. (2017) The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat. Med Res Rev 37: 1373‐1428 https://www.ncbi.nlm.nih.gov/pubmed/28181261?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=918
Overview
In 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].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=918.
Further reading on 3.5.3.15 Peptidyl arginine deiminases (PADI)
Koushik S et al. (2017) PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin. Ther. Targets 21: 433‐447 https://www.ncbi.nlm.nih.gov/pubmed/28281906?dopt=AbstractPlus
Tu R et al. (2016) Peptidyl Arginine Deiminases and Neurodegenerative Diseases. Curr. Med. Chem. 23: 104‐14 https://www.ncbi.nlm.nih.gov/pubmed/26577926?dopt=AbstractPlus
Whiteley CG. (2014) Arginine metabolising enzymes as targets against Alzheimers’ disease. Neurochem. Int. 67: 23‐31 https://www.ncbi.nlm.nih.gov/pubmed/24508404?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=896
Overview
small G‐proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G‐protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G‐proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best‐known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=897
Overview
The 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.
The RAS proto‐oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP‐hydrolysing ability of the proteins causing constitutive activation [http://www.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].
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=897.
Further reading on RAS subfamily
Dorard C et al. (2017) Deciphering the RAS/ERK pathway in vivo. Biochem. Soc. Trans. 45: 27‐36 https://www.ncbi.nlm.nih.gov/pubmed/28202657?dopt=AbstractPlus
Keeton AB et al. (2017) The RAS‐Effector Interaction as a Drug Target. Cancer Res. 77: 221‐226 https://www.ncbi.nlm.nih.gov/pubmed/28062402?dopt=AbstractPlus
Lu S et al. (2016) Ras Conformational Ensembles, Allostery, and Signaling. Chem. Rev. 116: 6607‐65 https://www.ncbi.nlm.nih.gov/pubmed/26815308?dopt=AbstractPlus
Ostrem JM et al. (2016) Direct small‐molecule inhibitors of KRAS: from structural insights to mechanism‐based design. Nat Rev Drug Discov 15: 771‐785 https://www.ncbi.nlm.nih.gov/pubmed/27469033?dopt=AbstractPlus
Papke B et al. (2017) Drugging RAS: Know the enemy. Science 355: 1158‐1163 https://www.ncbi.nlm.nih.gov/pubmed/28302824?dopt=AbstractPlus
Quah SY et al. (2016) Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti‐Ras drugs. Pharmacol. Ther. 162: 35‐57 https://www.ncbi.nlm.nih.gov/pubmed/27016467?dopt=AbstractPlus
Simanshu DK et al. (2017) RAS Proteins and Their Regulators in Human Disease. Cell 170: 17‐33 https://www.ncbi.nlm.nih.gov/pubmed/28666118?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=938
Overview
The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface ( see http://www.genenames.org/cgi‐bin/genefamilies/set/388, http://www.genenames.org/cgi‐bin/genefamilies/set/388 ).
Information on members of this family may be found in the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=938.
Alexander Stephen PH, Fabbro Doriano, Kelly Eamonn, Mathie Alistair, Peters John A, Veale Emma L, Armstrong Jane F, Faccenda Elena, Harding Simon D, Pawson Adam J, Sharman Joanna L, Southan Christopher, Davies Jamie A and CGTP Collaborators (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Enzymes. British Journal of Pharmacology, 176: S297–S396. doi: 10.1111/bph.14752.
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