Ann Kimble Hill - Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

Document created by Ann Kimble Hill on Aug 22, 2014
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  Publication Details (including relevant citation   information): 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., Journal of Biological   Chemistry , 2011, 286 (50 ), pp   43486 -43494

  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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