Taxonomic group: bacteria / Proteobacteria (Phylum: Proteobacteria)
Associated disease: infection due to Escherichia coli [ICD11: XN6P4 ]
 
NCBI PubMed ID: 21171638
Publication DOI: 10.1021/bi101622a
Journal NLM ID: 0370623
Publisher: American Chemical Society
Correspondence: chrissas.upenn.edu
Institutions: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States, Departments of Chemistry and Biological Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States

The first committed step of lipid A biosynthesis is catalyzed by UDP-(3-O-((R)-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase, a metal-dependent deacetylase also known as LpxC. Because lipid A is essential for bacterial viability, the inhibition of LpxC is an appealing therapeutic strategy for the treatment of Gram-negative bacterial infections. Here we report the 1.79 A resolution X-ray crystal structure of LpxC from Yersinia enterocolitica (YeLpxC) complexed with the potent hydroxamate inhibitor CHIR-090. This enzyme is a nearly identical orthologue of LpxC from Yersinia pestis (99.7% sequence identity), the pathogen that causes bubonic plague. Similar to the inhibition of LpxC from Escherichia coli, CHIR-090 inhibits YeLpxC via a two-step slow, tight-binding mechanism with an apparent K(i) of 0.54 +/- 0.14 nM followed by conversion of the E.I to E.I* species with a rate constant of 0.11 +/- 0.01 min(-1). The structure of the LpxC complex with CHIR-090 shows that the inhibitor hydroxamate group chelates the active site zinc ion, and the 'tail' of the inhibitor binds in the hydrophobic tunnel in the active site. This hydrophobic tunnel is framed by a betaalphabeta subdomain that exhibits significant conformational flexibility as it accommodates inhibitor binding. CHIR-090 displays a 27 mm zone of inhibition against Y. enterocolitica in a Kirby-Bauer antibiotic assay, which is comparable to its reported activity against other Gram-negative species including E. coli and Pseudomonas aeruginosa. This study demonstrates that the inhibition of LpxC should be explored as a potential therapeutic and/or prophylatic response to infection by weaponized Yersinia species.

biosynthesis, X-ray, lipid A, crystal structure, enzyme, Yersinia, Yersinia enterocolitica, Yersinia pestis, deacetylase LpxC

Structure type: oligomer
Location inside paper: p259, fig.1
Compound class: lipid A
Contained glycoepitopes: IEDB_130650,IEDB_130659,IEDB_141806,IEDB_142488,IEDB_144998,IEDB_145002,IEDB_146664,IEDB_176772,IEDB_534864,IEDB_983931,SB_192
 
Methods: PCR, X-ray, DNA techniques, kinetics assays, inhibition studies
 
NCBI Taxonomy refs (TaxIDs): 562
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