9j7s
From Proteopedia
Crystal structure of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHP synthase) from Providencia alcalifaciens complexed with Phe
Structural highlights
FunctionB6XIT1_9GAMM Stereospecific condensation of phosphoenolpyruvate (PEP) and D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP).[ARBA:ARBA00003726][PIRNR:PIRNR001361] Publication Abstract from PubMedThe shikimate pathway, essential for aromatic amino acid biosynthesis, is absent in animals, making its enzymes promising targets for developing antimicrobials. 3-Deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS) catalyzes the first committed step, which serves as the primary checkpoint for regulating the flow within the pathway, regulated by its end products (Phe, Tyr and Trp). Previously, we identified chlorogenic acid (CGA), an ester of caffeic and quinic acid, as an inhibitor of DAHPS from Bacillus subtilis, prompting us to investigate quinic acid as a potential inhibitor of Providencia alcalifaciens DAHPS (PaDAHPS). Here, we report the crystal structures of phenylalanine-sensitive DAHPS from Providenciaalcalifaciens in complex with phenylalanine (Phe) and quinic acid (QA) at resolutions of 2.5 A and 2.68 A, respectively. Structural analysis reveals that QA binds to the same site as Phe, with biophysical assays showing a similar binding affinity (K(D) = 42 muM for QA and K(D) = 32 muM for Phe). In vitro inhibition studies demonstrated that QA and Phe inhibit PaDAHPS activity, with (app)K(i) values of 382 muM and 132 muM, respectively. Additionally, QA inhibited the growth of several bacterial species, including Pseudomonas aeruginosa, Moraxella catarrhalis, Providencia alcalifaciens, Staphylococcus aureus, Escherichia coli with minimum inhibitory concentrations (MICs) ranging from 2.5 to 5 mg/ml. These findings identify quinic acid as a promising scaffold for developing novel antimicrobial agents targeting the shikimate pathway, providing potential therapeutic strategies for bacterial infections. Structural and biochemical analyses reveal quinic acid inhibits DAHP synthase a key player in shikimate pathway.,Jangid K, Mahto JK, Kumar KA, Dhaka P, Sharma A, Tariq A, Sharma AK, Kumar P Arch Biochem Biophys. 2025 Jan;763:110219. doi: 10.1016/j.abb.2024.110219. Epub , 2024 Nov 19. PMID:39566672[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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