LAUSR

ABSTRACT Accumulation of oxidative stress-induced lipid peroxidation products; 4-hydroxynonenal (4HNE) and 4-oxononenal (4ONE), inactivates the metabolic activity of human liver aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts acetaldehyde to carboxylic acids during alcohol metabolism. Previous reports showed that 4HNE and 4ONE covalently target the catalytic Cys302 residue and inactivate ALDH2, thereby preventing the metabolism of acetaldehyde (ACE), its primary substrate. However, the molecular basis of these reactions remains elusive. Therefore, in this study, we investigated the inactivation mechanism of 4HNE and 4ONE on ALDH2 using advanced computational tools. Interestingly, our findings revealed that both inhibitors significantly distorted ALDH2 oligomerization and co-enzyme binding domains, which are crucial to its metabolic activity. The resulting structural alterations could disrupt co-factor binding and enzymatic oligomerization mechanisms. In contrast to the acetaldehyde, 4HNE and 4ONE were bound to ALDH2 with high affinity, coupled with high energy contributions by catalytic site residues and could indicate the possible mechanism by which acetaldehyde is displaced from ALDH2 binding by 4HNE and 4ONE. These findings will be useful in the design of novel compounds that either mop up or block the binding of these endogenous compounds to ALDH2 thereby preventing the development of associated cancers and neurodegenerative diseases.