Glutamate racemase as a target for drug discovery

Abstract

SummaryThe 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.

A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

“…It has been suggested that subtle structural differences in GR active sites among the different bacterial species weaken the binding of inhibitors in some species resulting in the narrow antibacterial spectrum of the D-Glu-analogue inhibitors (Fisher, 2008). This could be the reason limiting the antibacterial spectrum of the K compounds as well.…”

“…Therefore, we hypothesized that the charged groups on these inhibitors adversely affect their permeability properties leading to their narrow antibacterial spectrum. Other factors such as structural differences among GRs from different bacterial species, however, remain possible as has been suggested (Fisher, 2008).…”

Resistance Mechanism to an Uncompetitive Inhibitor of a Single-Substrate, Single-Product Enzyme: A Study of Helicobacter Pylori Glutamate Racemase

“…The enzyme MurI is a glutamate racemase [18], producing d-Glu from the cellular pool of l-Glu for incorporation into growing peptidoglycan [19,20]. MurI operates via a two-base mechanism, wherein conserved cysteine residues in the enzyme active site alternately abstract and donate a proton to opposite faces of the glutamate a-carbon in order to effect racemization [21][22][23].…”

Evaluation of new antimicrobial agents on Bacillus spp. strains: docking affinity and in vitro inhibition of glutamate-racemase

“…Antimicrobial agents, which represent an important advance in modern medicine for the treatment of infectious diseases, currently interfere with one of four cellular processes: cell wall biosynthesis, protein synthesis, DNA replication and repair, or folic acid coenzyme biosynthesis inhibition (this coenzyme is necessary for the biosynthesis of timine 1 ). Although heralded in the 1940's as the beginning of the end of infectious diseases, during the last 20 years, more of these agents have lost their efficiency due to their abuse in medicine and agriculture.…”