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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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.
* Key recommended reading is highlighted with an asterisk
* Battelli MG, Bolognesi A, Polito L. (2014) Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim. Biophys. Acta, 1842 (9): 1502-17. [PMID:24882753]
* Cantu-Medellin N, Kelley EE. (2013) Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: insights regarding where, when and how. Nitric Oxide, 34: 19-26. [PMID:23454592]
* Glander P, Hambach P, Liefeldt L, Budde K. (2012) Inosine 5'-monophosphate dehydrogenase activity as a biomarker in the field of transplantation. Clin. Chim. Acta, 413 (17-18): 1391-7. [PMID:21889500]
* Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL. (2013) On dihydroorotate dehydrogenases and their inhibitors and uses. J. Med. Chem., 56 (8): 3148-67. [PMID:23452331]
1. Biagi G, Costantini A, Costantino L, Giorgi I, Livi O, Pecorari P, Rinaldi M, Scartoni V. (1996) Synthesis and biological evaluation of new imidazole, pyrimidine, and purine derivatives and analogs as inhibitors of xanthine oxidase. J. Med. Chem., 39 (13): 2529-35. [PMID:8691450]
2. Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, Rogatko A, Wang H, Blanchard RL. (2005) UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin. Cancer Res., 11 (3): 1226-36. [PMID:15709193]
3. Elgemeie GH. (2003) Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites. Curr. Pharm. Des., 9 (31): 2627-42. [PMID:14529546]
4. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL. (2005) Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J. Med. Chem., 48 (16): 5329-36. [PMID:16078850]
5. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL. (2012) Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg. Med. Chem., 20 (14): 4217-25. [PMID:22739090]
6. Heikkilä T, Ramsey C, Davies M, Galtier C, Stead AM, Johnson AP, Fishwick CW, Boa AN, McConkey GA. (2007) Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J. Med. Chem., 50 (2): 186-91. [PMID:17228860]
7. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W. (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. Mol. Pharmacol., 38 (4): 567-72. [PMID:2233693]
8. Izbicka E, Diaz A, Streeper R, Wick M, Campos D, Steffen R, Saunders M. (2009) Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother. Pharmacol., 64 (5): 993-9. [PMID:19221750]
9. Khanna S, Burudkar S, Bajaj K, Shah P, Keche A, Ghosh U, Desai A, Srivastava A, Kulkarni-Almeida A, Deshmukh NJ et al.. (2012) Isocytosine-based inhibitors of xanthine oxidase: design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia. Bioorg. Med. Chem. Lett., 22 (24): 7543-6. [PMID:23122864]
10. Nelson PH, Eugui E, Wang CC, Allison AC. (1990) Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid. J. Med. Chem., 33 (2): 833-8. [PMID:1967654]
11. Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. (2003) An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J. Biol. Chem., 278 (3): 1848-55. [PMID:12421831]
12. Papageorgiou C, Albert R, Floersheim P, Lemaire M, Bitch F, Weber HP, Andersen E, Hungerford V, Schreier MH. (1998) Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations. J. Med. Chem., 41 (18): 3530-8. [PMID:9719606]
13. Papamichael D. (1999) The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status. Oncologist, 4 (6): 478-87. [PMID:10631692]
14. Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW, Shortnacy AT, Montgomery JA, Secrist 3rd JA, Bennett Jr LL. (1991) Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. Cancer Res., 51 (9): 2386-94. [PMID:1707752]
15. Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR. (1995) 2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii. J. Med. Chem., 38 (5): 745-52. [PMID:7877140]
16. Shao J, Zhou B, Zhu L, Bilio AJ, Su L, Yuan YC, Ren S, Lien EJ, Shih J, Yen Y. (2005) Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay. Biochem. Pharmacol., 69 (4): 627-34. [PMID:15670581]
17. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv. Enzyme Regul., 38: 135-52. [PMID:9762351]
18. Tseng WC, Derse D, Cheng YC, Brockman RW, Bennett Jr LL. (1982) In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol. Pharmacol., 21 (2): 474-7. [PMID:7048062]
19. Vethe NT, Bremer S, Bergan S. (2008) IMP dehydrogenase basal activity in MOLT-4 human leukaemia cells is altered by mycophenolic acid and 6-thioguanosine. Scand. J. Clin. Lab. Invest., 68 (4): 277-85. [PMID:18609073]
20. Wittine K, Stipković Babić M, Makuc D, Plavec J, Kraljević Pavelić S, Sedić M, Pavelić K, Leyssen P, Neyts J, Balzarini J et al.. (2012) Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations. Bioorg. Med. Chem., 20 (11): 3675-85. [PMID:22555152]
Database page citation:
Nucleoside synthesis and metabolism. Accessed on 24/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=920.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.