Dihydrofolate reductase-thymidylate synthase (Plasmodium falciparum) (PfDHFR-TS)

Dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is a crucial bifunctional enzyme in the malaria parasite Plasmodium falciparum, responsible for maintaining the pool of reduced folates required for DNA synthesis (UniProt: P13922). Unlike in humans where these two enzymes are separate, in Plasmodium they exist as a single polypeptide chain (PubMed: 10736147). The DHFR domain catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, a vital cofactor for the synthesis of thymidylate and purine nucleotides. Because the parasite relies on de novo folate synthesis rather than salvage, this enzyme is a highly effective therapeutic target (PubMed: 19053307). Drugs like pyrimethamine and cycloguanil specifically inhibit PfDHFR, leading to the cessation of DNA replication and parasite death (PubChem: CID 4993). However, the clinical utility of these drugs is severely challenged by the widespread emergence of point mutations in the dhfr gene, which reduce drug binding affinity and lead to treatment failure (PubMed: 15961150).

Other names

Dihydrofolate reductaseDHFRBifunctional dihydrofolate reductase-thymidylate synthasePfDHFR

Competitive inhibition of the dihydrofolate reductase enzyme, which prevents the reduction of dihydrofolate to tetrahydrofolate. This depletion of tetrahydrofolate halts the synthesis of thymidylate and purines, ultimately inhibiting DNA replication and cell division in the parasite (PubMed: 19053307).