[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Drugs acting on nucleotide metabolism [Biochemistry](https://durgical.com/en/biochemistry/) · Topic # Drugs acting on nucleotide metabolism Many drugs against cancer, gout and transplant rejection block one specific enzyme of nucleotide synthesis or breakdown. Updated 2026-11-01 ## Key facts - Gout: allopurinol and febuxostat inhibit xanthine oxidase; rasburicase (uricase) breaks down uric acid. - Folate: methotrexate inhibits DHFR (and ATIC); 5-fluorouracil, as FdUMP, inhibits thymidylate synthase. - Immunosuppressants: mycophenolate inhibits IMPDH; leflunomide inhibits DHODH; azathioprine releases 6-mercaptopurine. - Hydroxyurea inhibits ribonucleotide reductase (it destroys its tyrosyl radical). - Most act in S phase and harm fast-dividing tissues: bone marrow, gut mucosa, hair follicles. ## In detail - Allopurinol: a hypoxanthine analogue; xanthine oxidase oxidises it to oxypurinol, which stays bound to the molybdenum. Febuxostat: a non-purine inhibitor of the substrate channel. - Methotrexate: a folate analogue that inhibits DHFR; without THF there are no formyl groups for purines or methylene groups for dTMP. Folinic acid (leucovorin) rescues healthy cells. - 5-Fluorouracil: converted to FdUMP, which forms a covalent complex with thymidylate synthase and methylene-THF; leucovorin enhances it. Capecitabine is its oral prodrug. - Hydroxyurea: switches off ribonucleotide reductase; in sickle cell disease it also raises fetal haemoglobin. - Mycophenolate: inhibits IMPDH; lymphocytes depend on de novo guanine synthesis and run out of GTP. - Leflunomide: its metabolite teriflunomide inhibits mitochondrial DHODH and starves activated T cells of pyrimidines. - 6-Mercaptopurine and azathioprine: HGPRT activates them to thio-IMP; xanthine oxidase and TPMT inactivate them. Allopurinol and TPMT deficiency increase their toxicity. - Rasburicase: recombinant uricase that converts uric acid to allantoin and produces H₂O₂; it is contraindicated in G6PD deficiency. **Also called** Antimetabolites ## Clinical notes - DurgiPedia (Pharmacology) has its own pages on methotrexate, fluorouracil and antimetabolites. - Methotrexate and leflunomide are teratogenic; so is mycophenolate. - The common toxicity of antimetabolites is myelosuppression, mucositis and abnormal liver tests. ## Pathways - [De novo purine synthesis](https://durgical.com/en/biochemistry/pathways/de-novo-purine-synthesis/) - [Purine degradation and salvage](https://durgical.com/en/biochemistry/pathways/purine-degradation-and-salvage/) - [Pyrimidine synthesis](https://durgical.com/en/biochemistry/pathways/pyrimidine-synthesis/) ## Related conditions - [Gout](https://durgical.com/en/conditions/gout/) - [Tumour lysis syndrome](https://durgical.com/en/conditions/tumour-lysis-syndrome/) - [Rheumatoid arthritis](https://durgical.com/en/conditions/rheumatoid-arthritis/) - [Colorectal cancer](https://durgical.com/en/conditions/colorectal-cancer/) - [Breast cancer](https://durgical.com/en/conditions/breast-cancer/) ## Related - [Xanthine oxidase](https://durgical.com/en/biochemistry/enzymes/xanthine-oxidase/) - [Dihydrofolate reductase (DHFR)](https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/) - [Thymidylate synthase](https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/) - [IMP dehydrogenase (IMPDH)](https://durgical.com/en/biochemistry/enzymes/imp-dehydrogenase/) - [Dihydroorotate dehydrogenase (DHODH)](https://durgical.com/en/biochemistry/enzymes/dihydroorotate-dehydrogenase/) - [Ribonucleotide reductase](https://durgical.com/en/biochemistry/enzymes/ribonucleotide-reductase/) - [Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)](https://durgical.com/en/biochemistry/enzymes/hypoxanthine-guanine-phosphoribosyltransferase/) - [Adenosine deaminase (ADA)](https://durgical.com/en/biochemistry/enzymes/adenosine-deaminase/) - [Uric acid](https://durgical.com/en/biochemistry/molecules/uric-acid/) - [dTMP (thymidine monophosphate)](https://durgical.com/en/biochemistry/molecules/dtmp/) ## Test yourself Think of the answer, then tap the question to see it. ## Which enzyme does each drug inhibit: mycophenolate, leflunomide and hydroxyurea? Mycophenolate: IMPDH. Leflunomide: DHODH. Hydroxyurea: ribonucleotide reductase. ## Why does allopurinol increase azathioprine toxicity? Xanthine oxidase inactivates 6-mercaptopurine; when it is blocked, the active drug accumulates and suppresses the marrow. ## How does 5-fluorouracil inhibit thymidylate synthase? Its metabolite FdUMP stays covalently bound to the enzyme together with methylene-THF. ## Why is rasburicase avoided in G6PD deficiency? It produces H₂O₂ while breaking down uric acid; without G6PD the red cell cannot cope and haemolyses. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/topics/drugs-acting-on-nucleotide-metabolism/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [Allopurinol: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682673.html) (MedlinePlus, US National Library of Medicine, 2026); [Febuxostat: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a609020.html) (MedlinePlus, US National Library of Medicine, 2026); [Methotrexate: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682019.html) (MedlinePlus, US National Library of Medicine, 2026); [Fluorouracil Injection: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682708.html) (MedlinePlus, US National Library of Medicine, 2026); [Hydroxyurea: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682004.html) (MedlinePlus, US National Library of Medicine, 2026); [Mycophenolate: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a601081.html) (MedlinePlus, US National Library of Medicine, 2026); [Leflunomide: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a600032.html) (MedlinePlus, US National Library of Medicine, 2026); [Azathioprine: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682167.html) (MedlinePlus, US National Library of Medicine, 2026); [Rasburicase Injection: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a610008.html) (MedlinePlus, US National Library of Medicine, 2026). 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