Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR)

The Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is a critical metabolic enzyme that catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in the parasite’s folate metabolism and DNA synthesis[1][4][5]. It forms part of a bifunctional protein with thymidylate synthase (TS-DHFR) unique to Plasmodium and other protozoa, enabling efficient de novo nucleotide production. As a validated and essential antimalarial drug target, inhibition of PfDHFR halts parasite proliferation but is challenged by rapid emergence of resistance, primarily due to well-characterized mutations in the dhfr gene[3][6]. Common antifolate drugs (e.g., pyrimethamine, cycloguanil, proguanil) selectively inhibit parasite DHFR over the human enzyme, but widespread resistance has necessitated next-generation inhibitors like P218 and hybrid molecules that better forestall resistance[2][6]. PfDHFR mutation status is commonly used as a molecular marker for monitoring antifolate resistance in malaria control programs. The enzyme’s essential role and unique structural properties continue to make it a focal point for antimalarial drug development[1][5][6].

Other names

Plasmodium falciparum DHFRTS-DHFR (when referring to the bifunctional thymidylate synthase–dihydrofolate reductase enzyme)malarial DHFR

Competitive inhibition of the DHFR active site, blocking the reduction of dihydrofolate to tetrahydrofolate, thereby impairing DNA synthesis and parasite replication[3][5][6].