There is growing interest in aldehyde dehydrogenases (ALDHs) because of their overexpression in cancer stem cells and the ability to mediate resistance to cancer drugs. Here, we report the first crystal structure of an aldehyde dehydrogenase complexed with the inhibitor 4-diethylaminobenzaldehyde (DEAB). Contrary to the widely held belief that DEAB is a reversible inhibitor of ALDHs, we show that DEAB irreversibly inactivates ALDH7A1 via formation of a stable, covalent acyl-enzyme species.
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Inhibition, crystal structures, and in-solution oligomeric structure of aldehyde dehydrogenase 9A1.
Arch Biochem Biophys
September 2020
Department of Chemistry, University of Missouri, Columbia, MO, 65211, United States; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, United States. Electronic address:
Aldehyde dehydrogenase 9A1 (ALDH9A1) is a human enzyme that catalyzes the NAD-dependent oxidation of the carnitine precursor 4-trimethylaminobutyraldehyde to 4-N-trimethylaminobutyrate. Here we show that the broad-spectrum ALDH inhibitor diethylaminobenzaldehyde (DEAB) reversibly inhibits ALDH9A1 in a time-dependent manner. Possible mechanisms of inhibition include covalent reversible inactivation involving the thiohemiacetal intermediate and slow, tight-binding inhibition.
View Article and Find Full Text PDFDiethylaminobenzaldehyde is a covalent, irreversible inactivator of ALDH7A1.
ACS Chem Biol
March 2015
†Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, United States.
There is growing interest in aldehyde dehydrogenases (ALDHs) because of their overexpression in cancer stem cells and the ability to mediate resistance to cancer drugs. Here, we report the first crystal structure of an aldehyde dehydrogenase complexed with the inhibitor 4-diethylaminobenzaldehyde (DEAB). Contrary to the widely held belief that DEAB is a reversible inhibitor of ALDHs, we show that DEAB irreversibly inactivates ALDH7A1 via formation of a stable, covalent acyl-enzyme species.
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