Inhibition, crystal structures, and in-solution oligomeric structure of aldehyde dehydrogenase 9A1.

ABSTRACT: 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 β-hairpin

SUBMITTER: Wyatt JW 

PROVIDER: S-EPMC7484307 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature