Plasmodium falciparum dihydropteroate synthase (DHPS) (DHPS)

Plasmodium falciparum dihydropteroate synthase (DHPS) is a vital enzyme in the de novo folate biosynthetic pathway of the malaria parasite, where it exists as part of a bifunctional protein alongside hydroxymethyldihydropterin pyrophosphokinase (HPPK) [1, 8]. It catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate with p-aminobenzoic acid (pABA) to form 7,8-dihydropteroate, a precursor for tetrahydrofolate cofactors essential for DNA synthesis and amino acid metabolism [2, 4]. Because humans lack the DHPS enzyme and must obtain folate through their diet, it is a highly selective and effective target for antimalarial drugs such as sulfadoxine and dapsone [4, 7]. These drugs act as structural analogs of pABA, competitively inhibiting the enzyme and leading to a depletion of the parasite's folate pool [2, 14]. However, the clinical utility of DHPS inhibitors is severely challenged by the widespread emergence of point mutations in the dhps gene, such as A437G and K540E, which significantly reduce the binding affinity of sulfonamides and confer high levels of drug resistance [3, 15, 18].

Other names

Dihydropteroate synthetase7,8-dihydropteroate synthaseHydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthasePPPK-DHPSHPPK-DHPSFolate synthesis protein 1PfDHPS

Competitive inhibition of the p-aminobenzoic acid (pABA) binding site, which prevents the condensation of pABA with 6-hydroxymethyl-7,8-dihydropterin pyrophosphate, thereby blocking the synthesis of dihydropteroate.