Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Abstract

Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD + coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer's, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.

An integrative bioinformatics pipeline to demonstrate the alteration of the interaction between the ALDH2*2 allele with NAD+ and Disulfiram

“…39 In addition, they have also reported that the binding efficiency of NAD + to be lower with the E504K variant. 39 For this purpose, we have analyzed the effect of the mutation on the protein and the role of the mutant (E504K/E487K) in NAD + interaction and Disulfiram interaction using the extensive computational pipeline to underpin the molecular nature of such interaction. Several earlier studies have shown the success of implementing the computational analysis in predicting the pathogenicity of disease-causing mutations using the power of combing in silico tools, simulation modeling, and molecular docking.…”

“…39 In addition, they have also reported that the binding efficiency of NAD + to be lower with the E504K variant. 39 For this purpose, we have analyzed the effect of the mutation on the protein and the role of the mutant (E504K/E487K) in NAD + interaction and Disulfiram interaction using the extensive computational pipeline to underpin the molecular nature of such interaction.…”

“…The Drug Gene Interaction database (DGIdb; http://dgidb.genome.wustl.edu/) revealed that the probable targets for the Disulfiram are ALDH2, DBH, and ABCB1 proteins, whereas a recent study by Gueldner et al 39 predicted that Disulfiram induces the same undesirable physiological effects as the mutant by inhibiting the normal function of the ALDH2 enzyme. 39 In addition, they have also reported that the binding efficiency of NAD + to be lower with the E504K variant. 39 For this purpose, we have analyzed the effect of the mutation on the protein and the role of the mutant (E504K/E487K) in NAD + interaction and Disulfiram interaction using the extensive computational pipeline to underpin the molecular nature of such interaction.…”

Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle

“…Approximately 40% of people from East Asia have an inactivating mutation in the ALDH2 gene (15). Epidemiological studies have demonstrated that this mutant ALDH2 is associated with several diseases, such as alcoholism, cancer, metabolic disorder, cardiovascular diseases, neurogenerative diseases, and osteoporosis (16). However, there is little biological evidence to support the findings of the epidemiological studies.…”

“…The ALDH2*2 phenotype includes facial flushing and higher heart rate when alcohol is consumed. Beyond the response to alcohol, a growing body of epidemiological studies suggests that ALDH2*2 can increase the risk of several diseases, such as cancer, metabolic disorders, cardiac diseases, neurodegenerative diseases, and osteoporosis (16,47). However, there is little biological evidence to support these epidemiological findings.…”