Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

作者：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 D^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286(50): 43486-43494.

DOI：10.1074/jbc.M111.293597

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.

• 出版日期2011-12-16