304PathwayAzathioprine Metabolism PathwayAzathioprine 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. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is 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.Drug MetabolismPW000621CenterPathwayVisualizationContext73411401300#000099PathwayVisualization186304Azathioprine PathwayAzathioprine 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. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is 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.Drug1663305SubPathway11069464Compound291422Nelson, D.L., & Cox, M.M. Lehninger Principles of Biochemistry (3rd ed.) (2000). New York: Worth Publishers.304Pathway142318506437Sahasranaman 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 28.304Pathway142418685564Stocco 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 6.304Pathway1CellCL:00000001Homo sapiens9606EukaryoteHuman1CytosolGO:000582911Extracellular SpaceGO:00056155CytoplasmGO:00057371LiverBTO:00007597292111PW_BS00000215111PW_BS00001529111PW_BS000029311511PW_BS0000319464MercaptopurineHMDB0015167Mercaptopurine is only found in individuals that have used or taken this drug. It is an antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. [PubChem]Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).50-44-2C017566674902208580869DB01033S=C1N=CNC2=C1NC=N2C5H4N4SInChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)GLVAUDGFNGKCSF-UHFFFAOYSA-N6,7-dihydro-3H-purine-6-thione152.177152.015666838-2.322mercaptopurine00DBMET00630Mercaptopurine monohydrate;Mercapurin;6 mp;Mp;6-mercaptopurine;1,7-dihydro-6h-purine-6-thione;3h-purine-6-thiol;6-mp;6-thiohypoxanthinePW_C009464Mcapprn362223791154076299429AzathioprineHMDB0015128Azathioprine is only found in individuals that have used or taken this drug. It is an immunosuppressive pro-drug. It is converted into 6-mercaptopurine in the body where it blocks purine metabolism and DNA synthesis.Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.446-86-6C06837226529482178DB00993CN1C=NC(=C1SC1=NC=NC2=C1NC=N2)[N+]([O-])=OC9H7N7O2SInChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13)LMEKQMALGUDUQG-UHFFFAOYSA-N6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine277.263277.038193193-2.411azathioprine00Azathioprin;Azothioprine;Azatioprin;6-((1-methyl-4-nitro-1h-imidazol-5-yl)thio)-1h-purine;6-(1'-methyl-4'-nitro-5'-imidazolyl)-mercaptopurine;ImuranPW_C009429Azathio407529461631406881-Methyl-4-nitroimidazoleHMDB00606591-Methyl-4-nitroimidazole belongs to the class of organic compounds known as nitroimidazoles. Nitroimidazoles are compounds containing an imidazole ring which bears a nitro group. 1-Methyl-4-nitroimidazole is slightly soluble (in water) and an extremely weak basic (essentially neutral) compound (based on its pKa). 1-Methyl-4-nitroimidazole has been found in human liver and kidney tissues, and has also been detected in multiple biofluids, such as urine and blood. In humans, 1-methyl-4-nitroimidazole is involved in the azathioprine metabolism pathway and the azathioprine action pathway.3034-41-1C166211820917198CN1C=NC(=C1)[N+]([O-])=OC4H5N3O2InChI=1S/C4H5N3O2/c1-6-2-4(5-3-6)7(8)9/h2-3H,1H3HSCOLDQJZRZQMV-UHFFFAOYSA-N1-methyl-4-nitro-1H-imidazole127.1014127.038176419-1.6101-methyl-4-nitroimidazole00PW_C0406881M4N4617312075falsePW_R002075Right738994291Compoundfalse739094641Compoundfalse8264406881Compoundtrue8200946429157false78056010regular2001909838942931157false25556010regular200190983940688313false67539510regular10011012340M880 750 C884 820 876 930 880 1005 5false18trueM 912.0096189432334 792.5 L 925 785 L 912.0096189432334 777.5false15489M780 655 C750 655 474 655 455 655 5false18trueM 887.0096189432334 347.5 L 900 340 L 887.0096189432334 332.5false15490M980 655 C1010 655 1041 18 1065 35 5true18trueM 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345false15491M725 505 C725 526 694 656 611 655 5false18trueM 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345false29411862075319302983815489Left9303820015490Right9304983915491Right74566318614false805100516regular707820012340Left5667225351.01.0029200145572M116 376 C116 326 166 276 216 276 C461 276 781 276 1026 276 C1076 276 1126 326 1126 376 C1126 497 1126 653 1126 774 C1126 824 1076 874 1026 874 C781 874 461 874 216 874 C166 874 116 824 116 774 C116 653 116 497 116 376 1true61010.0598.028578116582201186931441128711