Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases

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 Hurley

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)43486-43494
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number50
DOIs
StatePublished - Dec 16 2011

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Aldehyde Dehydrogenase
Enzymes
Enzyme Inhibitors
Metabolic Networks and Pathways
Ketones
Aldehydes
Isoenzymes
Cysteine
Catalytic Domain
Phenotype
Kinetics
Research
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Khanna, M., Chen, C. H., Kimble-Hill, A., Parajuli, B., Perez-Miller, S., Baskaran, S., ... Hurley, T. (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

Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. / Khanna, May; Chen, Che Hong; Kimble-Hill, Ann; Parajuli, Bibek; Perez-Miller, Samantha; Baskaran, Sulochanadevi; Kim, Jeewon; Dria, Karl; Vasiliou, Vasilis; Mochly-Rosen, Daria; Hurley, Thomas.

In: Journal of Biological Chemistry, Vol. 286, No. 50, 16.12.2011, p. 43486-43494.

Research output: Contribution to journalArticle

Khanna, M, Chen, CH, Kimble-Hill, A, Parajuli, B, Perez-Miller, S, Baskaran, S, Kim, J, Dria, K, Vasiliou, V, Mochly-Rosen, D & Hurley, T 2011, 'Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases', Journal of Biological Chemistry, vol. 286, no. 50, pp. 43486-43494. https://doi.org/10.1074/jbc.M111.293597
Khanna M, Chen CH, Kimble-Hill A, Parajuli B, Perez-Miller S, Baskaran S et al. Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. Journal of Biological Chemistry. 2011 Dec 16;286(50):43486-43494. https://doi.org/10.1074/jbc.M111.293597
Khanna, May ; Chen, Che Hong ; Kimble-Hill, Ann ; Parajuli, Bibek ; Perez-Miller, Samantha ; Baskaran, Sulochanadevi ; Kim, Jeewon ; Dria, Karl ; Vasiliou, Vasilis ; Mochly-Rosen, Daria ; Hurley, Thomas. / Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 50. pp. 43486-43494.
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