Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases

69Citations
Citations of this article
110Readers
Mendeley users who have this article in their library.

This article is free to access.

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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Cite

CITATION STYLE

APA

Khanna, M., Chen, C. H., Kimble-Hill, A., Parajuli, B., Perez-Miller, S., Baskaran, S., … Hurley, T. D. (2011). Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. Journal of Biological Chemistry, 286(50), 43486–43494. https://doi.org/10.1074/jbc.M111.293597

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free