Hydroxymethyldihydropterin pyrophosphokinase–dihydropteroate synthase (PfHPPK-DHPS) (PfHPPK-DHPS)

Hydroxymethyldihydropterin pyrophosphokinase–dihydropteroate synthase (PfHPPK-DHPS) is a bifunctional enzyme in Plasmodium falciparum that catalyzes two sequential steps in the de novo folate biosynthesis pathway (UniProt: P22101). The HPPK domain converts 6-hydroxymethyl-7,8-dihydropterin to its pyrophosphate derivative, while the DHPS domain subsequently catalyzes the condensation of this product with p-aminobenzoic acid (PABA) to form dihydropteroate (PubMed: 11553332). Because Plasmodium parasites must synthesize folates de novo and cannot salvage them from the host, this enzyme is a critical therapeutic target for antimalarial drugs (PubMed: 16150146). Sulfonamide drugs, such as sulfadoxine, act as structural analogs of PABA and competitively inhibit the DHPS domain, leading to a depletion of the folate pool required for DNA synthesis and cell division (PubChem: CID 5307). Resistance to these drugs is a major global health challenge, primarily driven by point mutations within the DHPS active site that reduce drug binding affinity (WHO: Malaria). Despite resistance, PfHPPK-DHPS remains a focal point for drug development, with research into new inhibitors that can bypass existing resistance mechanisms (PubMed: 30254078).

Other names

Bifunctional hydroxymethyldihydropterin pyrophosphokinase/dihydropteroate synthase6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthaseHPPK-DHPSDihydropteroate synthaseDHPS

Competitive inhibition of the dihydropteroate synthase domain by mimicking p-aminobenzoic acid (PABA), thereby blocking the synthesis of dihydropteroate and subsequent folate production.