Thymidylate synthase and other folate-dependent one-carbon transferases (TS and other folate-dependent enzymes)

Thymidylate synthase (TS) and other folate-dependent one-carbon transferases represent a cluster of enzymes essential for the biosynthesis of nucleotides required for DNA replication and repair. Thymidylate synthase specifically catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), a rate-limiting step in the production of thymidine (Source: UniProt P04818). Other enzymes in this metabolic network, including dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), manage the pool of reduced folates and the de novo synthesis of purines (Source: PubMed: 11714470). These enzymes are highly expressed in proliferating cells, making them classic targets for antineoplastic agents known as antifolates. Therapeutic inhibition of these enzymes, by drugs such as 5-fluorouracil or pemetrexed, leads to the depletion of nucleotide pools, resulting in DNA damage and 'thymineless' cell death (Source: StatPearls). Despite their efficacy in treating various cancers, targeting these enzymes is associated with systemic toxicities due to their fundamental role in the maintenance of normal hematopoietic and mucosal tissues (Source: NIH).

Other names

TYMSFolate-dependent enzymesOne-carbon metabolism enzymesAntifolate targetsThymidylate synthetaseDihydrofolate reductaseGlycinamide ribonucleotide formyltransferase

Drugs targeting this group primarily act as antimetabolites that mimic natural folates or nucleotides. They bind to the active sites of enzymes like thymidylate synthase (TS), dihydrofolate reductase (DHFR), or glycinamide ribonucleotide formyltransferase (GARFT), thereby blocking the transfer of one-carbon units necessary for the synthesis of thymidylate and purines (Source: PubMed: 15501967, StatPearls).