Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases.
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.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
May
M
Khanna
Che-Hong
CH
Chen
Ann
A
Kimble-Hill
Bibek
B
Parajuli
Samantha
S
Perez-Miller
Sulochanadevi
S
Baskaran
Jeewon
J
Kim
Karl
K
Dria
Vasilis
V
Vasiliou
Daria
D
Mochly-Rosen
Thomas D
TD
Hurley
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D050697:Retinal Dehydrogenase
D000447:Aldehydes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C048341:mafosfamide; D003520:Cyclophosphamide; D000080924:Aldehyde Dehydrogenase 1 Family; C096127:ALDH2 protein, human; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase