Alcohol Metabolic Inefficiency: Structural Characterization of Polymorphism-Induced ALDH2 Dysfunctionality and Allosteric Site Identification for Design of Potential Wildtype Reactivators.

Abstract

Liver mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme is responsible for the rapid conversion of acetaldehyde to acetic acid. ALDH2 (E487K) polymorphism results in an inactive allele (ALDH2*2) which cause dysfunctional acetaldehyde metabolism. The 3D structure of an enzyme is crucial to its functionality and a disruption in its structural integrity could result in its metabolic inefficiency and dysfunctionality. Allosteric targeting of polymorphs could facilitate the restoration of wildtype functionalities in ALDH2 polymorphs and serve as an advancement in the treatment of associated diseases. Therefore, structural insights into ALDH2*2 polymorph could reveal the varying degree of alterations which occur at its critical domains and accounts for enzymatic dysfunctionality. In this study, we report the structural characterization of ALDH2*2 polymorph and its critical domains using computational tools. Our findings revealed that the polymorph exhibited significant alterations in stability and flexibility at the catalytic and co-enzyme-binding domain. Moreover, there was an increase in the solvent-exposed surface residues and this indicates structural perturbations. Analysis of the interaction network at ALDH2*2 catalytic domain revealed residual displacement and interaction loss when compared to the wildtype thereby providing insight into the catalytic inefficiency of the polymorph. Interestingly, perturbations induced by ALDH2 polymorphism involves the re-orientation of surface residues, which resulted in the formation of surface exposed pockets. These identified pockets could be potential sites for allosteric targeting. The findings from this study will aid the design of novel site-specific small molecule reactivators with the propensity of restoring wildtype activities for treatment of polymorphic ALDH2 related diseases.