Glutamate racemase as a target for drug discovery.
The bacterial cell wall is a highly cross-linked polymeric structure consisting of repeating peptidoglycan units, each of which contains a novel pentapeptide substitution which is cross-linked through transpeptidation. The incorporation of D-glutamate as the second residue is strictly conserved across the bacterial kingdom. Glutamate racemase, a member of the cofactor-independent, two-thiol-based family of amino acid racemases, has been implicated in the production and maintenance of sufficient d-glutamate pool levels required for growth. The subject of over four decades of research, it is now evident that the enzyme is conserved and essential for growth across the bacterial kingdom and has a conserved overall topology and active site architecture; however, several different mechanisms of regulation have been observed. These traits have recently been targeted in the discovery of both narrow and broad spectrum inhibitors. This review outlines the biological history of this enzyme, the recent biochemical and structural characterization of isozymes from a wide range of species and developments in the identification of inhibitors that target the enzyme as possible therapeutic agents.
Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stewart.Fisher@astrazeneca.com
Stewart L
SL
Fisher
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D000591:Amino Acid Isomerases; C062292:glutamate racemase
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