5-Fluorouracil (5-FU), used in colorectal cancer chemotherapy, is a pyrimidine antimetabolite. Its active metabolite 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) acts as an irreversible ('suicide') inhibitor of which enzyme?
- A Dihydrofolate reductase (DHFR)
- B Thymidylate synthase (TS) ✓
- C Ribonucleotide reductase
- D Uridine kinase
Explanation
FdUMP forms a covalent ternary complex with thymidylate synthase (TS) and its folate cofactor methylene-THF (5,10-methylene tetrahydrofolate), permanently inhibiting TS. TS normally converts dUMP to dTMP (thymidylate), the only de novo source of thymidine nucleotides needed for DNA synthesis. TS inhibition causes 'thymineless death' of rapidly dividing cells. Leucovorin (folinic acid) enhances 5-FU's activity by increasing intracellular methylene-THF levels, stabilising the ternary inhibitory complex. DHFR is inhibited by methotrexate; RNR is inhibited by hydroxyurea; FdUMP is specifically the suicide inhibitor of TS. FUFTP (another active metabolite) is also incorporated into RNA, further disrupting cancer cell function.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.