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

Alcohol Metabolic Inefficiency: Structural Characterization of Polymorphism-Induced ALDH2... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Protein Journal Springer Journals

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

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Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer Science+Business Media, LLC, part of Springer Nature
Subject
Chemistry; Bioorganic Chemistry; Biochemistry, general; Organic Chemistry; Animal Anatomy / Morphology / Histology
ISSN
1572-3887
eISSN
1573-4943
D.O.I.
10.1007/s10930-018-9768-8
Publisher site
See Article on Publisher Site

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.

Journal

The Protein JournalSpringer Journals

Published: Apr 12, 2018

References

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