Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfDHFR-TS)

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfDHFR-TS) is a bifunctional enzyme combining dihydrofolate reductase and thymidylate synthase activities on a single polypeptide chain. It is essential for folate metabolism and DNA synthesis in P. falciparum, the parasite responsible for the most lethal form of human malaria. Both domains are crucial for nucleotide biosynthesis, with DHFR reducing dihydrofolate to tetrahydrofolate and TS methylating dUMP to dTMP. Unlike mammals, where these functions are encoded by separate genes, P. falciparum DHFR-TS functions as a dimer of bifunctional monomers, and its inhibition is lethal to the parasite. It is a validated and intensively pursued therapeutic target for antimalarial drugs such as pyrimethamine, cycloguanil, and newer candidates like P218. Drug resistance arises from point mutations in the DHFR domain. The unique structure and essential metabolic role of pfDHFR-TS make it a paradigm target for selective inhibition in malaria therapy[1][2][3][4][5][6][7].

Other names

DHFR-TS (when referring specifically to the bifunctional enzyme in Plasmodium falciparum)Plasmodium falciparum DHFR-TSP. falciparum dihydrofolate reductase-thymidylate synthase

Competitive inhibition of the DHFR or TS active sites, leading to blockage of folate metabolism and ultimately interfering with DNA synthesis and cell replication[1][2][6][4]. Some drugs bind tightly to the active site (slow-on/slow-off kinetics, e.g., P218[4]). Emergence of resistance is typically associated with point mutations in the DHFR domain, reducing drug binding affinity[4].