Dihydrofolate reductase from Plasmodium (DHFR)

Dihydrofolate reductase from Plasmodium (DHFR, particularly from *Plasmodium falciparum*) is an essential enzyme that catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, a key reaction in the folate pathway necessary for DNA synthesis and cell proliferation. In Plasmodium species, DHFR is often part of a bifunctional protein (DHFR-thymidylate synthase), distinct from the separate enzymes found in humans. DHFR is a validated molecular drug target for malaria therapy, notably for antifolate drugs such as pyrimethamine and cycloguanil. The effectiveness of these drugs has been limited by rapid evolution of drug resistance due to point mutations in the dhfr gene. Newer inhibitors, including P218, have been developed with improved efficacy against resistant strains and greater selectivity for the parasite enzyme over the human homolog. The structural differences between plasmodial and human DHFR underpin both drug action and resistance mechanisms.

Other names

Plasmodium DHFRMalaria DHFRPlasmodium dihydrofolate reductase-thymidylate synthase (when referring to the bifunctional protein in Plasmodium)PfDHFR (for plasmodial enzyme, mostly for *P. falciparum*)

Competitive inhibition of the DHFR active site, preventing reduction of dihydrofolate to tetrahydrofolate, thus blocking thymidylate and purine synthesis and inhibiting parasite DNA replication.