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Glutamate racemase as a target for drug discovery.

Fisher SL - Microb Biotechnol (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stewart.Fisher@astrazeneca.com

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Allosteric inhibitors of Gram‐positive glutamate racemase enzymes. Selected data are shown; refer to the citations for experimental details and additional data. See Fig. 4 for definition of terms.
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f7: Allosteric inhibitors of Gram‐positive glutamate racemase enzymes. Selected data are shown; refer to the citations for experimental details and additional data. See Fig. 4 for definition of terms.

Mentions: Recently, two series of allosteric inhibitors have been reported that have activity against Gram‐positive organisms. The first series features a purine scaffold (Fig. 7, analogues 16–18, Geng et al., 2007) and was identified using a high‐throughput screen of E. faecalis MurI enzyme activity. Early analogues in this series exhibited good potency against the enzymes from Enterococcus spp. and crystallographic studies with the E. faecalis enzyme revealed that the compounds bind to a site that partially overlaps with the region corresponding to the H. pylori pyrazolopyrimidinedione binding site. Importantly, both series of inhibitors utilize a displacement of the C‐terminal tryptophan (W252 in H. pylori; W254, E. faecalis) for binding; however, the movement of this residue, and the C‐terminal helix as a whole, is less extensive in formation of the purine binding pocket relative to that observed for the pyrazolopyrimidinedione binding site. Analysis of the in vitro inhibition structure activity relationships suggests that hydrophobic substitutions at the 2‐ and 9‐positions of the purine ring are required for binding, whereas the 6‐position is positioned near the solvent front and hydrophilic substitutions are tolerated. Despite efforts to improve the analogues through iterative structure‐based drug design strategies, only modest improvements in potency was observed for the Enterococcus spp and no activity was observed against the S. aureus enzyme. Further, analogues in the series exhibited relatively poor solubility and only moderate antibacterial activity (MIC = 16–64 µg ml−1).


Glutamate racemase as a target for drug discovery.

Fisher SL - Microb Biotechnol (2008)

Allosteric inhibitors of Gram‐positive glutamate racemase enzymes. Selected data are shown; refer to the citations for experimental details and additional data. See Fig. 4 for definition of terms.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815242&req=5

f7: Allosteric inhibitors of Gram‐positive glutamate racemase enzymes. Selected data are shown; refer to the citations for experimental details and additional data. See Fig. 4 for definition of terms.
Mentions: Recently, two series of allosteric inhibitors have been reported that have activity against Gram‐positive organisms. The first series features a purine scaffold (Fig. 7, analogues 16–18, Geng et al., 2007) and was identified using a high‐throughput screen of E. faecalis MurI enzyme activity. Early analogues in this series exhibited good potency against the enzymes from Enterococcus spp. and crystallographic studies with the E. faecalis enzyme revealed that the compounds bind to a site that partially overlaps with the region corresponding to the H. pylori pyrazolopyrimidinedione binding site. Importantly, both series of inhibitors utilize a displacement of the C‐terminal tryptophan (W252 in H. pylori; W254, E. faecalis) for binding; however, the movement of this residue, and the C‐terminal helix as a whole, is less extensive in formation of the purine binding pocket relative to that observed for the pyrazolopyrimidinedione binding site. Analysis of the in vitro inhibition structure activity relationships suggests that hydrophobic substitutions at the 2‐ and 9‐positions of the purine ring are required for binding, whereas the 6‐position is positioned near the solvent front and hydrophilic substitutions are tolerated. Despite efforts to improve the analogues through iterative structure‐based drug design strategies, only modest improvements in potency was observed for the Enterococcus spp and no activity was observed against the S. aureus enzyme. Further, analogues in the series exhibited relatively poor solubility and only moderate antibacterial activity (MIC = 16–64 µg ml−1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Stewart.Fisher@astrazeneca.com

Show MeSH