dTMPsyntasen

dTMPsyntasen, more commonly known as thymidylate synthase (TS), is an enzyme that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to form deoxythymidine monophosphate (dTMP), a crucial precursor for DNA synthesis and repair.

The reaction uses 5,10-methylene-tetrahydrofolate (5,10-m THF) as the methyl donor, converting dUMP to dTMP and generating dihydrofolate (DHF). The DHF is subsequently reduced back to tetrahydrofolate (THF) by dihydrofolate reductase, regenerating the folate cofactor required for ongoing nucleotide synthesis.

In most organisms, thymidylate synthase is encoded by thyA (bacteria) or TYMS (eukaryotes) and typically functions as a homodimer in the cytosol. Some bacteria also possess an alternative thymidylate synthase, ThyX, which is flavin-dependent and mechanistically distinct from ThyA.

TS activity is tightly linked to DNA replication and cell cycle progression in proliferating cells. Its expression and activity are influenced by folate availability and other metabolic signals, reflecting its central role in nucleotide metabolism.

Thymidylate synthase is a major drug target in medicine. In cancer therapy, inhibitors such as 5-fluorouracil and raltitrexed block thymidylate synthesis, reducing dTMP pools and impairing DNA replication. Methotrexate and other antifolates indirectly suppress TS activity by depleting cellular THF cofactors. Bacterial TS has also been explored as a target for antimicrobial therapy.

Because of its essential role in DNA synthesis, dTMPsyntasen is a focus of structural, biochemical, and pharmacological research, with numerous studies detailing its mechanism, regulation, and inhibitors.