Hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase (HPPK-DHPS) (DHPS)

Plasmodial dihydropteroate synthase (DHPS) is a critical enzyme in the de novo folate biosynthesis pathway of malaria parasites, such as Plasmodium falciparum and Plasmodium vivax [10, 11]. In these organisms, DHPS exists as a bifunctional protein combined with hydroxymethyldihydropterin pyrophosphokinase (HPPK), often referred to as HPPK-DHPS [11, 12]. The enzyme catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate with p-aminobenzoic acid (pABA) to produce 7,8-dihydropteroate, a precursor to tetrahydrofolate [10, 16]. Since humans lack this pathway and obtain folate from their diet, DHPS is an ideal target for selective antimalarial chemotherapy [15, 16]. Drugs like sulfadoxine and dapsone act as competitive inhibitors of pABA, effectively halting DNA synthesis and parasite replication [2, 7, 10]. However, the therapeutic utility of targeting DHPS is severely challenged by the emergence of widespread point mutations in the dhps gene, which confer high levels of resistance to sulfonamides and sulfones [1, 10, 13].

Other names

7,8-dihydropteroate synthase7,8-dihydropteroate synthetaseDihydropteroate synthetasePPPK-DHPSPfdhpsPvdhps

Competitive inhibition of p-aminobenzoic acid (pABA) binding and the formation of pterin-sulfa dead-end metabolic products, which depletes the pool of 7,8-dihydropteroate and subsequently inhibits downstream folate and DNA synthesis [2, 7, 10].