Mycobacterium tuberculosis dihydropteroate synthase (DHPS)

Mycobacterium tuberculosis dihydropteroate synthase (DHPS), encoded by the folP1 gene, is a key enzyme in the de novo folate biosynthesis pathway of the tuberculosis-causing bacterium [1, 4]. It catalyzes the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate to produce 7,8-dihydropteroate, a precursor to essential folate cofactors required for DNA, RNA, and amino acid synthesis [1, 8]. Because humans lack the DHPS enzyme and must obtain folate through their diet, this protein represents a highly attractive target for selective antimicrobial therapy [2, 8]. Historically, DHPS has been the target of sulfonamides and dapsone, which act as competitive inhibitors of pABA [2, 4]. Additionally, the antitubercular drug para-aminosalicylic acid (PAS) is bioactivated by DHPS into a toxic folate analog that disrupts downstream metabolic processes [1, 4]. However, the emergence of drug-resistant strains, often characterized by specific mutations in the folP1 gene, remains a significant challenge in treating tuberculosis [12, 13].

Other names

FolP17,8-dihydropteroate synthaseDihydropteroate pyrophosphorylaseRv3608cMtDHPS

Competitive inhibition of para-aminobenzoic acid (pABA) binding; bioactivation of para-aminosalicylic acid (PAS) into inhibitory folate analogs.