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

Luca Gabrielli; Silvia Merlo; Cristina Airoldi; Paola Sperandeo; Serena Gianera; Alessandra Polissi; Francesco Nicotra; Tod P Holler; Ronald W Woodard; Laura Cipolla

doi:10.1016/j.bmc.2013.08.012

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

Bioorg Med Chem. 2014 Apr 15;22(8):2576-83. doi: 10.1016/j.bmc.2013.08.012. Epub 2013 Aug 11.

Affiliations

¹ Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
² Department of Medicinal Chemistry, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
³ Department of Medicinal Chemistry, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA. Electronic address: rww@umich.edu.
⁴ Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy. Electronic address: laura.cipolla@unimib.itUSA.

PMID: 24680056
DOI: 10.1016/j.bmc.2013.08.012

Abstract

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.

Keywords: Enzyme inhibitors; Escherichia coli; Molecular recognition; NMR binding studies; Pseudomonas aeruginosa; d-Arabinose 5-phosphate isomerase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Isomerism
Microbial Sensitivity Tests
Protein Binding
Pseudomonas aeruginosa / drug effects
Pseudomonas aeruginosa / enzymology
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Substrate Specificity

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Recombinant Proteins
Aldose-Ketose Isomerases
arabinose-5-phosphate isomerase