Structural characterization of inhibitors with selectivity against members of a homologous enzyme family

Pavlovsky, A. G., Liu, X., Faehnle, C. R., Potente, N., Viola, R. E. (January 2012) Structural characterization of inhibitors with selectivity against members of a homologous enzyme family. Chemical Biology and Drug Design, 79 (1). pp. 128-136. ISSN 17470277 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22039970
DOI: 10.1111/j.1747-0285.2011.01267.x

Abstract

The aspartate biosynthetic pathway provides essential metabolites for many important biological functions, including the production of four essential amino acids. As this critical pathway is only present in plants and microbes, any disruptions will be fatal to these organisms. An early pathway enzyme, l-aspartate-β-semialdehyde dehydrogenase, produces a key intermediate at the first branch point of this pathway. Developing potent and selective inhibitors against several orthologs in the l-aspartate-β-semialdehyde dehydrogenase family can serve as lead compounds for antibiotic development. Kinetic studies of two small molecule fragment libraries have identified inhibitors that show good selectivity against l-aspartate-β-semialdehyde dehydrogenases from two different bacterial species, Streptococcus pneumoniae and Vibrio cholerae, despite the presence of an identical constellation of active site amino acids in this homologous enzyme family. Structural characterization of enzyme-inhibitor complexes have elucidated different modes of binding between these structurally related enzymes. This information provides the basis for a structure-guided approach to the development of more potent and more selective inhibitors. Disruptions of the aspartate biosynthetic pathway are fatal to microorganisms, and provide key enzyme targets for antibiotic development. Comparison of different enzyme-inhibitor structures against an early pathway enzyme have identified different binding modes that will serve as the basis for the development of more potent and selective inhibitors. © 2011 John Wiley & Sons A/S.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein structure rendering
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Joshua-Tor lab
CSHL Post Doctoral Fellows
Depositing User: Matt Covey
Date: January 2012
Date Deposited: 29 Jan 2013 17:01
Last Modified: 02 May 2013 14:08
PMCID: PMC3383612
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27021

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