Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) (DHFR-TS)

Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a critical enzyme in the protozoan parasite Toxoplasma gondii, where it exists as a single polypeptide chain containing two catalytic domains [6, 9]. This enzyme plays a central role in the folate metabolic pathway by reducing dihydrofolate to tetrahydrofolate and subsequently facilitating the synthesis of deoxythymidine monophosphate (dTMP), which is indispensable for DNA replication and cellular proliferation [1, 11]. Because humans express these two enzymes as separate proteins with distinct structural features, the parasite's bifunctional form serves as a key therapeutic target for treating toxoplasmosis [4, 8]. Classical antifolate drugs, most notably pyrimethamine, act by competitively inhibiting the DHFR domain, thereby depleting the parasite's pool of reduced folates and leading to thymineless death [1, 8]. However, the effectiveness of these treatments can be compromised by the emergence of point mutations in the DHFR gene that confer drug resistance, as well as by mechanism-based toxicities in the human host, such as bone marrow suppression [1, 5, 7]. To mitigate these side effects, leucovorin is often co-administered to provide a source of folate for human cells while the parasite remains inhibited [1]. Recent research focuses on developing more selective inhibitors that exploit structural differences between the parasite and human enzymes to improve safety and efficacy [1, 8].

Other names

Dihydrofolate reductaseThymidylate synthaseTgDHFR-TSDHFRTSBifunctional DHFR-TS

Inhibition of dihydrofolate reductase activity, which prevents the conversion of dihydrofolate to tetrahydrofolate, thereby disrupting the synthesis of thymidylate and DNA [1, 8, 11].