Thymidylate synthase and Dihydrofolate reductase (TS, DHFR)

Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes of folate-dependent one-carbon metabolism, playing pivotal roles in the synthesis of thymidine and regeneration of tetrahydrofolate, respectively. TS catalyzes the methylation of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), which is necessary for DNA synthesis and repair, while DHFR regenerates tetrahydrofolate from dihydrofolate following the TS reaction, enabling sustained one-carbon transfer for nucleotide and amino acid metabolism. Both are targets for chemotherapeutic agents used in cancer and infectious diseases. In some protozoa and lower organisms, DHFR and TS are present as a bifunctional polypeptide, while in mammals, they are distinct enzymes. Disruption of these enzymes leads to inhibition of DNA synthesis and cell proliferation, underpinning their roles as therapeutic targets. However, clinical use of antifolate drugs is limited by toxicity and the development of drug resistance.

Other names

TSDHFRDHFR-TSFolate-dependent enzymes

DHFR inhibitors: competitively block the reduction of dihydrofolate to tetrahydrofolate, depleting reduced folates and blocking nucleotide synthesis. TS inhibitors: block methylation of deoxyuridylate to thymidylate, inhibiting DNA synthesis. Antimetabolite analogs: act as substrate mimics, directly blocking enzyme activity.