Differences in susceptibility to inactivation of human aldehyde dehydrogenases by lipid peroxidation byproducts.

Aldehyde dehydrogenases (ALDHs) are involved in the detoxification of aldehydes generated as byproducts of lipid peroxidation. In this work, it was determined that, among the three most studied human ALDH isoforms, ALDH2 showed the highest catalytic efficiency for oxidation of acrolein, 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde. ALDH1A1 also exhibited significant activity with these substrates, whereas ALDH3A1 only showed activity with 4-HNE. ALDH2 was also the most sensitive isoform to irreversible inactivation by these compounds. Remarkably, ALDH3A1 was insensitive to these aldehydes even at concentrations as high as 20 mM. Formation of adducts of ALDH1A1 and ALDH2 with acrolein increased their Kd values for NAD+ by 2- and 3-fold, respectively. NADH exerted a higher protection than propionaldehyde to the inactivation by acrolein, and this protection was additive. These results suggested that both binding sites, those for aldehyde and NAD+ in ALDH2, are targets for the inactivation by lipid peroxi...