Exploitation of structural and regulatory diversity in glutamate racemases

Tomas Lundqvist, Stewart L. Fisher (), Gunther Kern, Rutger H. A. Folmer, Yafeng Xue, D. Trevor Newton, Thomas A. Keating, Richard A. Alm and Boudewijn L. M. de Jonge
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Tomas Lundqvist: AstraZeneca Global Structural Chemistry, AstraZeneca R&D Mölndal, SE-431 83, Mölndal, Sweden
Stewart L. Fisher: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA
Gunther Kern: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA
Rutger H. A. Folmer: AstraZeneca Global Structural Chemistry, AstraZeneca R&D Mölndal, SE-431 83, Mölndal, Sweden
Yafeng Xue: AstraZeneca Global Structural Chemistry, AstraZeneca R&D Mölndal, SE-431 83, Mölndal, Sweden
D. Trevor Newton: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA
Thomas A. Keating: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA
Richard A. Alm: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA
Boudewijn L. M. de Jonge: Infection Discovery, AstraZeneca R&D Boston, Waltham, 02451 Massachusetts, USA

Nature, 2007, vol. 447, issue 7146, 817-822

Abstract: Abstract Glutamate racemase is an enzyme essential to the bacterial cell wall biosynthesis pathway, and has therefore been considered as a target for antibacterial drug discovery. We characterized the glutamate racemases of several pathogenic bacteria using structural and biochemical approaches. Here we describe three distinct mechanisms of regulation for the family of glutamate racemases: allosteric activation by metabolic precursors, kinetic regulation through substrate inhibition, and d-glutamate recycling using a d-amino acid transaminase. In a search for selective inhibitors, we identified a series of uncompetitive inhibitors specifically targeting Helicobacter pylori glutamate racemase that bind to a cryptic allosteric site, and used these inhibitors to probe the mechanistic and dynamic features of the enzyme. These structural, kinetic and mutational studies provide insight into the physiological regulation of these essential enzymes and provide a basis for designing narrow-spectrum antimicrobial agents.

Date: 2007
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DOI: 10.1038/nature05689

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