Dihydrofolate reductase–thymidylate synthase (DHFR-TS)

Dihydrofolate reductase–thymidylate synthase (DHFR-TS) is a bifunctional enzyme in many protozoa, plants, and some bacteria, and consists of two domains: the N-terminal DHFR, which reduces dihydrofolate (DHF) to tetrahydrofolate (THF), regenerating the cofactor required for one-carbon metabolism and DNA synthesis; and the C-terminal thymidylate synthase (TS or TYMS), which methylates dUMP to dTMP, a critical reaction for de novo synthesis of thymidine nucleotides for DNA replication. In mammals, DHFR and TS are separate, essential enzymes and important therapeutic targets in oncology and antimicrobial therapy, as their inhibition depletes DNA precursors and halts cell proliferation. Inhibitors such as methotrexate, pemetrexed, raltitrexed, and trimethoprim exploit species-specific differences in enzyme structure for selective activity and are widely used in the treatment of cancer and infectious diseases.

Other names

Dihydrofolate reductase–thymidylate synthase (DHFR-TS)Thymidylate synthase (TS, TYMS)Dihydrofolate reductase (DHFR)Bifunctional DHFR-TS (in protozoa, plants)

Enzyme inhibition (blockade of folate cycle) Inhibition of thymidine/dTMP synthesis (TS inhibitors) Inhibition of dihydrofolate reduction (DHFR inhibitors) Disruption of DNA, RNA, and protein synthesis