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 D. Hurley

Research output: Contribution to journalArticle

46 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases'. Together they form a unique fingerprint.

  • Cite this

    Khanna, M., Chen, C. H., Kimble-Hill, A., Parajuli, B., Perez-Miller, S., Baskaran, S., Kim, J., Dria, K., Vasiliou, V., Mochly-Rosen, D., & 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