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Title: Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases

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 {beta}-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.

Authors:
; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (Indiana-Med)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1049551
Resource Type:
Journal Article
Journal Name:
J. Biol. Chem.
Additional Journal Information:
Journal Volume: 286; Journal Issue: (50) ; 12, 2011; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ALDEHYDES; BIOLOGICAL PATHWAYS; BIOLOGY; CROSS-LINKING; CRYSTAL STRUCTURE; CRYSTALLIZATION; CYSTEINE; DESIGN; DISEASES; ENZYME INHIBITORS; ENZYMES; KETONES; KINETICS; MASS SPECTROSCOPY; NEOPLASMS; OXIDOREDUCTASES; PHENOTYPE; PROBES; PROTEINS; RESIDUES

Citation Formats

Khanna, Mary, Chen, Che-Hong, Kimble-Hill, Ann, Parajuli, Bibek, Perez-Miller, Samantha, Baskaran, Sulochanadevi, Kim, Jeewon, Dria, Karl, Vasiliou, Vasilis, Mochly-Rosen, Daria, Hurley, Thomas D., Stanford-MED), Purdue), and UCHSC). Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. United States: N. p., 2012. Web. doi:10.1074/jbc.M111.293597.
Khanna, Mary, Chen, Che-Hong, Kimble-Hill, Ann, Parajuli, Bibek, Perez-Miller, Samantha, Baskaran, Sulochanadevi, Kim, Jeewon, Dria, Karl, Vasiliou, Vasilis, Mochly-Rosen, Daria, Hurley, Thomas D., Stanford-MED), Purdue), & UCHSC). Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. United States. doi:10.1074/jbc.M111.293597.
Khanna, Mary, Chen, Che-Hong, Kimble-Hill, Ann, Parajuli, Bibek, Perez-Miller, Samantha, Baskaran, Sulochanadevi, Kim, Jeewon, Dria, Karl, Vasiliou, Vasilis, Mochly-Rosen, Daria, Hurley, Thomas D., Stanford-MED), Purdue), and UCHSC). Tue . "Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases". United States. doi:10.1074/jbc.M111.293597.
@article{osti_1049551,
title = {Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases},
author = {Khanna, Mary and Chen, Che-Hong and Kimble-Hill, Ann and Parajuli, Bibek and Perez-Miller, Samantha and Baskaran, Sulochanadevi and Kim, Jeewon and Dria, Karl and Vasiliou, Vasilis and Mochly-Rosen, Daria and Hurley, Thomas D. and Stanford-MED) and Purdue) and UCHSC)},
abstractNote = {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 {beta}-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.},
doi = {10.1074/jbc.M111.293597},
journal = {J. Biol. Chem.},
issn = {0021-9258},
number = (50) ; 12, 2011,
volume = 286,
place = {United States},
year = {2012},
month = {10}
}