Bacterial dihydropteroate synthase (DHPS)

Bacterial dihydropteroate synthase (DHPS) is an enzyme crucial for folate biosynthesis in bacteria. It catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate with para-aminobenzoic acid (pABA) to form 7,8-dihydropteroate, which is the second step in the pathway leading to 7,8-dihydrofolate. Folate synthesis is essential for bacterial survival as most microorganisms must synthesize it de novo. DHPS is a protein of approximately 275-315 residues, encoded by sul or folP genes, and functions as a dimer. It belongs to the TIM-barrel protein group. Its active site includes a pterin binding site, a pABA binding pocket, and flexible loops important for catalysis. DHPS is an important therapeutic target for antibacterial treatments, notably targeted by sulfonamide antibacterials (sulfa drugs) which compete with pABA. However, resistance to sulfonamides has developed due to mutations in the DHPS gene, leading to reduced clinical use. Research is ongoing to develop new inhibitors, particularly those targeting the pterin binding site, to overcome sulfonamide resistance. Structure-based drug design utilizing crystal structures of DHPS has provided valuable insights for developing next-generation inhibitors.

Other names

sulfolP

Sulfonamide antibacterials act as substrate analogues that compete with para-aminobenzoic acid (pABA) for binding at the active site; New inhibitors can target the pterin binding site.