Arabinose 5-phosphate isomerase as a target for antibacterial design: Studies with substrate analogues and inhibitors

• Published in: Bioorganic & medicinal chemistry 2014-04, Vol.22 (8), p.2576-2583
• Main Authors: Gabrielli, Luca, Merlo, Silvia, Airoldi, Cristina, Sperandeo, Paola, Gianera, Serena, Polissi, Alessandra, Nicotra, Francesco, Holler, Tod P., Woodard, Ronald W., Cipolla, Laura
• Format: Article
• Language: English
• Subjects: Aldose-Ketose Isomerases - antagonists & inhibitors; Aldose-Ketose Isomerases - genetics; Aldose-Ketose Isomerases - metabolism; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; d-Arabinose 5-phosphate isomerase; Drug Design; Enzyme inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli - drug effects; Isomerism; Microbial Sensitivity Tests; Molecular recognition; NMR binding studies; Protein Binding; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Substrate Specificity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.08.012

Structural requirements of d-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Pseudomonas aeruginosa were analysed in detail using advanced NMR techniques. We performed epitope mapping studies of the binding between the enzyme and the most potent KdsD inhibitors found to date, together with studies of a set of newly synthesised arabinose 5-phosphate (A5P) mimetics. We report here the first experimental evidence that KdsD may bind the furanose form of A5P, suggesting that catalysis of ring opening may be an important part of KdsD catalysis.