Bifunctional dihydrofolate reductase-thymidylate synthase of Plasmodium falciparum (PfDHFR-TS)

Bifunctional dihydrofolate reductase-thymidylate synthase of Plasmodium falciparum (PfDHFR-TS) is a dual-function enzyme that catalyzes key reactions in the folate pathway, enabling synthesis of DNA precursors and purines essential for parasite replication. Unlike humans, where dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are separate, Plasmodium falciparum encodes both activities on a single polypeptide. PfDHFR-TS is the primary target of antifolate drugs, including pyrimethamine, cycloguanil, and others; inhibition disrupts nucleotide synthesis and is lethal to the malaria parasite. The enzyme is notable for the rapid emergence of clinical resistance, mediated by specific point mutations in the DHFR domain that decrease drug binding affinity. Therapeutic interventions are challenged by resistance and drug-related toxicity.

Other names

Bifunctional dihydrofolate reductase-thymidylate synthaseDHFR-TSPfDHFR-TSPFD0830w (gene)PF3D7_0417200 (gene)

Competitive inhibition at the active site, blocking folate utilization and DNA synthesis, arresting parasite survival. Resistance mechanism: mutations in DHFR domain reduce drug affinity