Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases

J Biol Chem. 2011 Dec 16;286(50):43486-94. doi: 10.1074/jbc.M111.293597. Epub 2011 Oct 21.

Abstract

Human aldehyde dehydrogenases (ALDHs) comprise a family of 17 homologous enzymes that metabolize different biogenic and exogenic aldehydes. To date, there are relatively few general ALDH inhibitors that can be used to probe the contribution of this class of enzymes to particular metabolic pathways. Here, we report the discovery of a general class of ALDH inhibitors with a common mechanism of action. The combined data from kinetic studies, mass spectrometric measurements, and crystallographic analyses demonstrate that these inhibitors undergo an enzyme-mediated β-elimination reaction generating a vinyl ketone intermediate that covalently modifies the active site cysteine residue present in these enzymes. The studies described here can provide the basis for rational approach to design ALDH isoenzyme-specific inhibitors as research tools and perhaps as drugs, to address diseases such as cancer where increased ALDH activity is associated with a cellular phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldehyde Dehydrogenase / antagonists & inhibitors*
  • Aldehyde Dehydrogenase / chemistry*
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase, Mitochondrial
  • Aldehydes / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclophosphamide / analogs & derivatives
  • Cyclophosphamide / pharmacology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Mass Spectrometry
  • Molecular Structure
  • Protein Structure, Secondary
  • Retinal Dehydrogenase

Substances

  • Aldehydes
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • mafosfamide
  • Cyclophosphamide
  • Aldehyde Dehydrogenase 1 Family
  • ALDH2 protein, human
  • ALDH3A1 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase

Associated data

  • PDB/3SZ9
  • PDB/3SZA
  • PDB/3SZB