Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Oct 25

PMID 22021038

Citations 42

Authors

May Khanna

Che-Hong Chen

Ann Kimble-Hill

Bibek Parajuli

Samantha Perez-Miller

Sulochanadevi Baskaran

Jeewon Kim

Karl Dria

Vasilis Vasiliou

Daria Mochly-Rosen

Thomas D Hurley

Affiliations

Soon will be listed here.

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.

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