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

Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) of Plasmodium species is a single polypeptide enzyme that catalyzes two essential consecutive reactions in folate metabolism: reduction of dihydrofolate to tetrahydrofolate (DHFR activity) and conversion of deoxyuridylate (dUMP) to thymidylate (dTMP) (TS activity), which are critical for DNA synthesis and cell proliferation in the malaria parasite[1][5][9]. Unlike humans, where DHFR and TS are encoded by separate genes and expressed as distinct proteins, Plasmodium expresses a bifunctional enzyme that forms a homodimer, with each monomer containing both DHFR and TS domains[5][1]. DHFR-TS is a validated antimalarial drug target; antifolate drugs like pyrimethamine and cycloguanil act by inhibiting its DHFR activity, leading to parasite death[4][7][8]. Drug resistance is a major clinical concern due to mutations in the DHFR domain, prompting development of next-generation inhibitors such as P218 that retain activity against resistant variants[8][4]. This target's similarity to human DHFR and TS raises safety concerns about off-target toxicity, making selectivity a key requirement in drug development[2][4][8].

Other names

Plasmodium DHFR-TSDihydrofolate reductase-thymidylate synthase (Plasmodium falciparum)PfDHFR-TSPlasmodium dihydrofolate reductase-thymidylate synthase

Inhibition of dihydrofolate reductase activity, preventing tetrahydrofolate formation Blockade of thymidylate synthase activity, disrupting thymidylate (dTMP) production Disruption of DNA synthesis and replication in Plasmodium parasites