Lloyd, M. D., Yevglevskis, M., Nathubhai, A., James, T. D., Threadgill, M. D. and Woodman, T. J. (2021) Racemases and epimerases operating through a 1,1-proton transfer mechanism : reactivity, mechanism and inhibition. Chemical Society Reviews. 50(10), pp. 5952-5984. 0306-0012.
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Abstract:
Racemases and epimerases catalyse changes in the stereochemical configurations of chiral centres and are of interest as model enzymes and as biotechnological tools. They also occupy pivotal positions within metabolic pathways and, hence, many of them are important drug targets. This review summarises the catalytic mechanisms of PLP-dependent, enolase family and cofactor-independent racemases and epimerases operating by a deprotonation/reprotonation (1,1-proton transfer) mechanism and methods for measuring their catalytic activity. Strategies for inhibiting these enzymes are reviewed, as are specific examples of inhibitors. Rational design of inhibitors based on substrates has been extensively explored but there is considerable scope for development of transition-state mimics and covalent inhibitors and for the identification of inhibitors by high-throughput, fragment and virtual screening approaches. The increasing availability of enzyme structures obtained using X-ray crystallography will facilitate development of inhibitors by rational design and fragment screening, whilst protein models will facilitate development of transition-state mimics.
Uncontrolled Keywords:
Allosteric Regulation, Biocatalysis, Catalytic Domain, Coenzymes/metabolism, Drug Design, Enzyme Inhibitors/chemistry, Molecular Dynamics Simulation, Protons, Racemases and Epimerases/antagonists & inhibitors, Substrate Specificity
Creators:
Lloyd, M. D., Yevglevskis, M., Nathubhai, A., James, T. D., Threadgill, M. D. and Woodman, T. J.
Faculties, Divisions and Institutes:
?? ASSCI ??
Date:
12 April 2021
Date Type:
Publication
Page Range:
pp. 5952-5984
Journal or Publication Title:
Chemical Society Reviews
Volume:
50
Number:
10
Number of Pages:
6687499
Language:
English
ISSN:
0306-0012
Status:
Published / Disseminated
Refereed:
Yes
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