SMPDB

Pathway Description

Mercaptopurine Action Pathway

Homo sapiens

Drug Action Pathway

Created: 2013-08-22

Last Updated: 2025-01-29

Mercaptopurine is a purine antimetabolite prodrug that exerts cytotoxic effects via three mechanisms: via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA, inhibition of de novo synthesis of purine nucleotides, and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Mercaptopurine travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is then converted to thioguanosince diphosphate through a series of metabolic reactions that produces the metabolic intermediates, thioinosine 5’-monophosphate, thioxanthine monophosphate, and thioguanosine monophosphate. Thioguanosine diphosphate is then converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate, which is incorporated into DNA. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells. Finally, de novo synthesis of purine nucleotides is inhibited by the methyl-thioinosine 5’-monophosphate metabolite, which inhibits amidophosphoribosyl-transferase, the enzyme that catalyzes one of the first steps in this pathway.

References

Mercaptopurine Pathway References

Nelson, D.L., & Cox, M.M. Lehninger Principles of Biochemistry (3rd ed.) (2000). New York: Worth Publishers.

Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28.

Pubmed: 18506437

Stocco G, Cheok MH, Crews KR, Dervieux T, French D, Pei D, Yang W, Cheng C, Pui CH, Relling MV, Evans WE: Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther. 2009 Feb;85(2):164-72. doi: 10.1038/clpt.2008.154. Epub 2008 Aug 6.

Pubmed: 18685564

Jolly DJ, Okayama H, Berg P, Esty AC, Filpula D, Bohlen P, Johnson GG, Shively JE, Hunkapillar T, Friedmann T: Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase. Proc Natl Acad Sci U S A. 1983 Jan;80(2):477-81. doi: 10.1073/pnas.80.2.477.

Pubmed: 6300847

Edwards A, Voss H, Rice P, Civitello A, Stegemann J, Schwager C, Zimmermann J, Erfle H, Caskey CT, Ansorge W: Automated DNA sequencing of the human HPRT locus. Genomics. 1990 Apr;6(4):593-608.

Pubmed: 2341149

Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.

Pubmed: 14702039

Bowne SJ, Sullivan LS, Blanton SH, Cepko CL, Blackshaw S, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP: Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa. Hum Mol Genet. 2002 Mar 1;11(5):559-68. doi: 10.1093/hmg/11.5.559.

Pubmed: 11875050

Bowne SJ, Sullivan LS, Mortimer SE, Hedstrom L, Zhu J, Spellicy CJ, Gire AI, Hughbanks-Wheaton D, Birch DG, Lewis RA, Heckenlively JR, Daiger SP: Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006 Jan;47(1):34-42. doi: 10.1167/iovs.05-0868.

Pubmed: 16384941

Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K: Two distinct cDNAs for human IMP dehydrogenase. J Biol Chem. 1990 Mar 25;265(9):5292-5.

Pubmed: 1969416

Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA: t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. Blood. 2000 Dec 15;96(13):4360-2.

Pubmed: 11110714

Hirst M, Haliday E, Nakamura J, Lou L: Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. J Biol Chem. 1994 Sep 23;269(38):23830-7.

Pubmed: 8089153

Krynetski EY, Fessing MY, Yates CR, Sun D, Schuetz JD, Evans WE: Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library. Pharm Res. 1997 Dec;14(12):1672-8. doi: 10.1023/a:1012111325397.

Pubmed: 9453052

Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, Evans WE: Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet. 1996 Apr;58(4):694-702.

Pubmed: 8644731

Honchel R, Aksoy IA, Szumlanski C, Wood TC, Otterness DM, Wieben ED, Weinshilboum RM: Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. Mol Pharmacol. 1993 Jun;43(6):878-87.

Pubmed: 8316220

Didsbury J, Weber RF, Bokoch GM, Evans T, Snyderman R: rac, a novel ras-related family of proteins that are botulinum toxin substrates. J Biol Chem. 1989 Oct 5;264(28):16378-82.

Pubmed: 2674130

Drivas GT, Shih A, Coutavas E, Rush MG, D'Eustachio P: Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line. Mol Cell Biol. 1990 Apr;10(4):1793-8. doi: 10.1128/mcb.10.4.1793.

Pubmed: 2108320

Matos P, Skaug J, Marques B, Beck S, Verissimo F, Gespach C, Boavida MG, Scherer SW, Jordan P: Small GTPase Rac1: structure, localization, and expression of the human gene. Biochem Biophys Res Commun. 2000 Nov 2;277(3):741-51. doi: 10.1006/bbrc.2000.3743.

Pubmed: 11062023

Neumeier M, Weigert J, Schaffler A, Weiss TS, Schmidl C, Buttner R, Bollheimer C, Aslanidis C, Scholmerich J, Buechler C: Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. Biochem Biophys Res Commun. 2006 Nov 24;350(3):731-5. doi: 10.1016/j.bbrc.2006.09.101. Epub 2006 Sep 27.

Pubmed: 17022944

Fu C, Di L, Han X, Soderstrom C, Snyder M, Troutman MD, Obach RS, Zhang H: Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship. Drug Metab Dispos. 2013 Oct;41(10):1797-804. doi: 10.1124/dmd.113.053082. Epub 2013 Jul 15.

Pubmed: 23857892

Wright RM, Vaitaitis GM, Wilson CM, Repine TB, Terada LS, Repine JE: cDNA cloning, characterization, and tissue-specific expression of human xanthine dehydrogenase/xanthine oxidase. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10690-4. doi: 10.1073/pnas.90.22.10690.

Pubmed: 8248161

Iwahana H, Oka J, Mizusawa N, Kudo E, Ii S, Yoshimoto K, Holmes EW, Itakura M: Molecular cloning of human amidophosphoribosyltransferase. Biochem Biophys Res Commun. 1993 Jan 15;190(1):192-200. doi: 10.1006/bbrc.1993.1030.

Pubmed: 8380692

Brayton KA, Chen Z, Zhou G, Nagy PL, Gavalas A, Trent JM, Deaven LL, Dixon JE, Zalkin H: Two genes for de novo purine nucleotide synthesis on human chromosome 4 are closely linked and divergently transcribed. J Biol Chem. 1994 Feb 18;269(7):5313-21.

Pubmed: 8106516

Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.

Pubmed: 15489334

Purine Metabolism References

Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.

Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.

Garcia-Gil M, Camici M, Allegrini S, Pesi R, Petrotto E, Tozzi MG: Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors. Int J Mol Sci. 2018 Nov 14;19(11). pii: ijms19113598. doi: 10.3390/ijms19113598.

Pubmed: 30441833

Davies O, Mendes P, Smallbone K, Malys N: Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism. BMB Rep. 2012 Apr;45(4):259-64.

Pubmed: 22531138