Format

Send to

Choose Destination
See comment in PubMed Commons below
Chem Biol Drug Des. 2012 Jan;79(1):128-36. doi: 10.1111/j.1747-0285.2011.01267.x. Epub 2011 Nov 28.

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

Author information

  • 1Department of Chemistry, University of Toledo, Toledo, OH 43606, USA.

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.

PMID:
22039970
PMCID:
PMC3383612
DOI:
10.1111/j.1747-0285.2011.01267.x
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Support Center