Thymidylate synthase and folate-dependent enzymes (TS and folate-dependent enzymes)

Thymidylate synthase (TS) and associated folate-dependent enzymes, including dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), are central components of the de novo nucleotide synthesis pathway. TS is responsible for the reductive methylation of deoxyuridine monophosphate to thymidine monophosphate, providing the only de novo source of thymidylate for DNA synthesis. Folate-dependent enzymes in the purine pathway facilitate the incorporation of one-carbon units into the purine ring, essential for the production of adenine and guanine. Because rapidly dividing cells, such as cancer cells, have a high demand for nucleotides, these enzymes are prime therapeutic targets. Antifolate drugs like pemetrexed and methotrexate inhibit these enzymes to disrupt DNA replication and repair, leading to cell cycle arrest and apoptosis. Clinical use of these inhibitors is widespread in oncology, though resistance and systemic toxicities like myelosuppression remain significant challenges.

Other names

Antifolate targetsDe novo nucleotide synthesis enzymesFolate metabolism enzymesThymidylate synthaseDihydrofolate reductaseGlycinamide ribonucleotide formyltransferase

Inhibition of thymidylate synthase and other folate-dependent enzymes (such as DHFR and GARFT) prevents the formation of essential nucleotide precursors, specifically thymidine monophosphate (dTMP) and purines, thereby inhibiting DNA and RNA synthesis and inducing thymineless death in proliferating cells.