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
Related conditions
Related
- Xanthine oxidase
- Dihydrofolate reductase (DHFR)
- Thymidylate synthase
- IMP dehydrogenase (IMPDH)
- Dihydroorotate dehydrogenase (DHODH)
- Ribonucleotide reductase
- Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
- Adenosine deaminase (ADA)
- Uric acid
- dTMP (thymidine monophosphate)
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.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Allopurinol: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Febuxostat: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Methotrexate: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Fluorouracil Injection: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Hydroxyurea: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Mycophenolate: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Leflunomide: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Azathioprine: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Rasburicase Injection: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.