Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (50), p.43486-43494
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Aldehyde Dehydrogenase - antagonists & inhibitors; Aldehyde Dehydrogenase - chemistry; Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase 1 Family; Aldehyde Dehydrogenase, Mitochondrial; ALDEHYDES; Aldehydes - metabolism; Anticancer Drug; Antineoplastic Agents - pharmacology; BASIC BIOLOGICAL SCIENCES; BIOLOGICAL PATHWAYS; BIOLOGY; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemical Biology; CROSS-LINKING; CRYSTAL STRUCTURE; CRYSTALLIZATION; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacology; CYSTEINE; Cysteine-mediated Cross-linking; DESIGN; DISEASES; ENZYME INHIBITORS; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; ENZYMES; Enzymology; Humans; KETONES; KINETICS; Mass Spectrometry; Mass Spectrometry (MS); MASS SPECTROSCOPY; Molecular Structure; NEOPLASMS; OXIDOREDUCTASES; PHENOTYPE; PROBES; Protein Crystallization; Protein Structure, Secondary; PROTEINS; RESIDUES; Retinal Dehydrogenase
• ISSN: 0021-9258; 1083-351X
• 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 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. Background: ALDH enzymes metabolize aldehydes in many pathways, including the inactivation of cyclophosphamide. Results: Covalent inhibitors against ALDH were discovered, and their mechanism of action was determined. Conclusion: Covalent inhibitors against ALDH potentiate cell killing in cyclophosphamide-resistant cells. Significance: These inhibitors represent novel research tools and can serve as leads toward therapeutics where increased ALDH activity is associated with disease.