Thymidylate synthase (TYMS) and folate-dependent one-carbon transfer enzymes (TYMS/Folate Pathway)

Thymidylate synthase (TS) is a key enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), a process requiring 5,10-methylenetetrahydrofolate as a cofactor (UniProt P04818). This reaction represents the sole de novo source of thymidylate, making it a critical rate-limiting step for DNA synthesis and repair (PubMed: 15591231). The broader folate-dependent one-carbon transfer pathway includes enzymes such as dihydrofolate reductase (DHFR) and glycinamide ribonucleotide transformylase (GART), which are essential for purine and pyrimidine biosynthesis (StatPearls: Folate Deficiency). Because cancer cells exhibit high rates of proliferation, they are heavily dependent on these pathways, leading to the development of numerous antimetabolite drugs (PubMed: 11412161). Agents like 5-fluorouracil and methotrexate target these enzymes to induce "thymineless death" and inhibit tumor growth (PubChem: CID 3385). However, these drugs also affect rapidly dividing healthy cells, resulting in significant side effects such as myelosuppression and gastrointestinal toxicity (PubMed: 19074561). Genetic variations in pathway components, such as MTHFR or DPYD, can significantly influence individual drug response and toxicity profiles (PubMed: 15138464).

Other names

Thymidylate synthase and other folate-dependent one-carbon transfer pathwaysThymidylate synthetaseTSTYMSOne-carbon metabolism pathwayFolate cycle enzymes

Inhibition of deoxythymidine monophosphate (dTMP) synthesis and depletion of reduced folate pools to disrupt DNA and purine biosynthesis.