Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

Chem Soc Rev. 2021 May 24;50(10):5952-5984. doi: 10.1039/d0cs00540a.

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.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation
  • Biocatalysis
  • Catalytic Domain
  • Coenzymes / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Molecular Dynamics Simulation
  • Protons
  • Racemases and Epimerases / antagonists & inhibitors
  • Racemases and Epimerases / metabolism*
  • Substrate Specificity

Substances

  • Coenzymes
  • Enzyme Inhibitors
  • Protons
  • Racemases and Epimerases