Alcohol Metabolic Inefficiency: Structural Characterization of Polymorphism-Induced ALDH2 Dysfunctionality and Allosteric Site Identification for Design of Potential Wildtype Reactivators
- 93 Downloads
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.
KeywordsAlcohol Aldehyde dehydrogenase Polymorphism Carcinogenesis Metabolism dysfunctionality
I want to express my appreciation to the research colleagues in the Laboratory. My profound gratitude goes to my supervisor for his relentless support during this work.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Zakhari S (2006) Overview: how is alcohol metabolized by the body?. Alcohol Res Health 29(4):245–254Google Scholar
- 7.Johansson K, El-Ahmad M, Ramaswamy S, Hjelmqvist L, Jörnvall H, Eklund H (1998) Structure of betaine aldehyde dehydrogenase at 2.1 A resolution. Protein Sci. 7(10):2106–2117. Available https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.5560071007
- 8.Case D, Cheatham TE, Darden TOM, Luo R, Merz Y, Onufriev KM et al (2009) The Amber biomolecular simulation programs the amber biomolecular simulation programs. J Comput Chem 26(16):1–31Google Scholar
- 9.Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926–935. Available https://aip.scitation.org/doi/abs/10.1063/1.445869
- 13.Neal KB, Mahmoud ES (2017) Can we rely on computational predictions to correctly identify ligand binding sites on novel protein drug targets? Assessment of binding site prediction methods and a protocol for validation of predicted binding sites. Cell Biochem Biophys 75(1):15–23CrossRefGoogle Scholar
- 19.Bös F, Pleiss J (2009) Multiple molecular dynamics simulations of TEM beta-lactamase: dynamics and water binding of the omega-loop. Biophys J 97(9):2550–2558. Available http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2770601&tool=pmcentrez&rendertype=abstract
- 26.Jaume FS, Xinping W, Kojiro T, Suzanne J, Cunningham TTW (1994) Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase: a model to study human (Oriental type) class 2 aldehyde dehydrogenase. J Biol Chem 19:13854–13860Google Scholar