Plasmodium dihydrofolate reductase-thymidylate synthase (DHFR-TS (PfDHFR-TS for Plasmodium falciparum))

Plasmodium dihydrofolate reductase-thymidylate synthase is a bifunctional enzyme found in malaria parasites, such as Plasmodium falciparum, that catalyzes two sequential reactions in folate and thymidylate metabolism. The enzyme's dihydrofolate reductase (DHFR) domain reduces dihydrofolate to tetrahydrofolate, while the thymidylate synthase (TS) domain catalyzes the conversion of dUMP to dTMP, both functions essential for DNA synthesis in the parasite. Unlike higher eukaryotes, where DHFR and TS are encoded by separate genes, Plasmodium species have a single polypeptide with both activities. DHFR-TS is a validated molecular target for antimalarial drugs such as pyrimethamine and cycloguanil, with resistance commonly developing through point mutations within the DHFR domain. This enzyme is essential for parasite survival, and inhibition leads to impaired DNA replication and cell death.

Other names

Plasmodium DHFR-TSbifunctional dihydrofolate reductase-thymidylate synthaseTS-DHFRPfDHFR-TS (specifically for Plasmodium falciparum)PFD0830w (gene, Plasmodium falciparum)PF3D7_0417200 (PlasmoDB reference)

Competitive inhibition of the DHFR domain (by pyrimethamine, cycloguanil, proguanil, P218): blocks reduction of dihydrofolate to tetrahydrofolate, inhibiting DNA synthesis. Some inhibitors also bind to the thymidylate synthase domain, affecting dTMP synthesis.