Plasmodium falciparum dihydropteroate synthase (DHPS (also commonly written as PfDHPS))

Plasmodium falciparum dihydropteroate synthase is an enzyme essential for folate biosynthesis in the malaria parasite Plasmodium falciparum. It catalyzes the formation of dihydropteroate—a precursor in the synthesis of tetrahydrofolate—by combining 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPP) with p-aminobenzoic acid (pABA). The enzyme is the direct molecular target of sulfone and sulfonamide drugs, such as sulfadoxine, which act as competitive inhibitors by interacting with the pABA-binding site, thereby blocking the folate synthesis necessary for DNA replication and parasite survival. Resistance occurs via specific point mutations in the dhps gene, which decrease drug affinity for the enzyme and are prevalent in regions with long-standing antifolate use. The enzyme is often studied as part of a bifunctional protein (PPPK-DHPS) and features a single TIM barrel domain structure. Mutational profiling of DHPS remains vital for monitoring drug resistance and guiding the use of antifolate therapies in malaria-endemic areas.

Other names

DHPSPfDHPSPPPK-DHPS

Competitive inhibition of the enzyme's substrate-binding site, most typically by sulfadoxine and related sulfonamide drugs, thus blocking the incorporation of p-aminobenzoic acid and preventing folate pathway completion and DNA synthesis