Plasmodium spp. dihydrofolate reductase (DHFR) (DHFR)

Plasmodium spp. dihydrofolate reductase (DHFR) is a vital enzyme in the folate metabolism of malaria parasites, including Plasmodium falciparum and Plasmodium vivax [1.2.1, 1.5.1]. In these organisms, DHFR exists as part of a bifunctional protein coupled with thymidylate synthase (DHFR-TS), a structural arrangement distinct from the separate enzymes found in humans [1.1.1, 1.3.1]. The enzyme's primary role is to catalyze the reduction of dihydrofolate to tetrahydrofolate, providing essential one-carbon units for the de novo synthesis of thymidylate, purines, and certain amino acids necessary for DNA replication and parasite survival [1.3.2, 1.5.1]. DHFR is a well-established target for antifolate antimalarials like pyrimethamine and cycloguanil, which competitively inhibit the enzyme to arrest parasite growth [1.2.1, 1.2.4]. However, the effectiveness of these treatments is significantly compromised by the global spread of specific point mutations in the dhfr gene that alter the active site and reduce drug affinity [1.1.3, 1.4.1]. Consequently, current drug development efforts are focused on identifying novel inhibitors that can effectively target these resistant variants while maintaining high selectivity to avoid interfering with human folate metabolism [1.2.1, 1.3.1].

Other names

DHFRDHFR-TSBifunctional dihydrofolate reductase-thymidylate synthasepfdhfrpvdhfrDihydrofolate reductase-thymidylate synthase

Inhibition of dihydrofolate reductase activity, preventing the conversion of dihydrofolate to tetrahydrofolate, which depletes the pool of folate cofactors required for dTMP and purine biosynthesis, ultimately inhibiting DNA synthesis and parasite cell division [1.2.1, 1.3.2].