Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase (PfPPPK-DHPS) (PfPPPK-DHPS)

Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase (PfPPPK-DHPS) is a critical bifunctional enzyme in the de novo folate biosynthesis pathway of the malaria parasite [2, 14]. Unlike humans, who salvage folate from their diet, Plasmodium parasites must synthesize folates to produce essential precursors for DNA synthesis, such as deoxythymidine triphosphate (dTTP) [1, 7]. The DHPS domain of this enzyme catalyzes the condensation of p-aminobenzoic acid (pABA) with 6-hydroxymethyldihydropterin pyrophosphate to form 7,8-dihydropteroate [1, 11]. This enzyme is the primary target of sulfonamide and sulfone drugs, such as sulfadoxine and dapsone, which act as competitive inhibitors of the pABA binding site [1, 6]. However, the clinical utility of these drugs is severely compromised by the widespread emergence of point mutations in the dhps gene, such as A437G and K540E, which reduce drug binding affinity and lead to treatment failure [5, 18, 19]. Consequently, PfPPPK-DHPS remains a focal point for monitoring antimalarial resistance and developing next-generation antifolate therapies [17, 18].

Other names

Dihydropteroate synthaseDihydropteroate synthetasedhpsPPPK-DHPS6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthaseH2Pte synthasePlasmodium dihydropteroate synthase

Competitive inhibition of the p-aminobenzoic acid (pABA) binding site within the dihydropteroate synthase domain, which prevents the condensation of pABA with 6-hydroxymethyldihydropterin pyrophosphate, thereby blocking the synthesis of 7,8-dihydropteroate and subsequent folate precursors essential for DNA synthesis [1, 6, 10].