Thymidylate synthase, Dihydrofolate reductase, and Glycinamide ribonucleotide formyltransferase (TS, DHFR, GARFT)

Thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase are essential folate-dependent enzymes in the de novo biosynthesis of purines and thymidine nucleotides, required for DNA synthesis and cell proliferation. All are validated targets for anticancer therapy, notably for antifolate drugs such as pemetrexed, methotrexate, and raltitrexed, among others. Targeting these enzymes disrupts nucleotide metabolism, inhibiting cell division and preferentially affecting rapidly dividing tumor or microbial cells. This entry represents a conflation of three distinct, non-redundant targets (TS, DHFR, GARFT), which are structurally and functionally individual proteins and should typically be treated as separate canonical entries.

Enzyme inhibition: Drugs act as competitive or multi-targeted inhibitors, directly blocking the respective enzyme's activity in the folate/purine/thymidine synthesis pathways. Results in cytostasis/cytotoxicity via inhibition of DNA synthesis and cell proliferation, particularly in S-phase. Most "antifolates" are optimized for one or multiple targets (e.g., pemetrexed is a multi-targeted antifolate).