6vr6

Publication Abstract from PubMed

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. Two crystal structures of ALDH9A1 are reported, including the first of the enzyme complexed with NAD(+). One of the structures reveals the active conformation of the enzyme, in which the Rossmann dinucleotide-binding domain is fully ordered and the inter-domain linker adopts the canonical beta-hairpin observed in other ALDH structures. The oligomeric structure of ALDH9A1 was investigated using analytical ultracentrifugation, small-angle X-ray scattering, and negative stain electron microscopy. These data show that ALDH9A1 forms the classic ALDH superfamily dimer-of-dimers tetramer in solution. Our results suggest that the presence of an aldehyde substrate and NAD(+) promotes isomerization of the enzyme into the active conformation.

Inhibition, crystal structures, and in-solution oligomeric structure of aldehyde dehydrogenase 9A1.,Wyatt JW, Korasick DA, Qureshi IA, Campbell AC, Gates KS, Tanner JJ Arch Biochem Biophys. 2020 Jul 24:108477. doi: 10.1016/j.abb.2020.108477. PMID:32717224^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.