ALDH2

From Proteopedia

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Contents 1 Introduction 2 Structure 3 Function 4 Mutations 5 Non-alcoholic liver diseases 6 Inhibitors and activators 7 References

Introduction

Some kind of intro, where it’s located, coding gene is located on chromosome 12 (12q24.2), 44kpbs in lenght with 13 exons^[1]…

Structure

spinqualitylabelsall models Human mitochondrial aldehyde dehydrogenase, apo form (PDB entry 3N80) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Homotetramer functioning as dimer of dimers. [2]

Function

Detoxifying of toxic aldehydes, involved in many pathways such as ethanol breakdown, lipid metabolization, role in oxidative stress of cell.

Mutations

spinqualitylabelsall models Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with agonist Alda-1 (PDB entry 3INL) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image There are seven mutations observed in different ethnicities with higher relative prevalence, there is more cancer issued mutations[3]. Most studied of them is East Asian mutation (ALDH2*2) connected with alcohol flushing syndrome and other diseases[2]. ALDH2 designation Mutation Location AA change Major ethnicity Allele frequency Relative activity WT (ALDH2*1) ALDH2*2 E504K[4] 504 Glu → Lys East Asian 26.6% 0% ALDH2*3 I41V single-carbon change in the AA side chain [2] African 0.6% 60% ALDH2*4 P92T[5] 92 Pro → Thr Latino 2.5% 32% ALDH2*5 T244M[6] 244 Thr → Met South Asian 0.7% 38% ALDH2*6 V304M[7] 304 Val → Met Latino 2.4% 11% ALDH2*7 R338W[8] 338 Arg → Trp Finnish 1.2% 23% Alcohol liver disease ALDH2*2 alcohol flushing response is semidominant, thus heterozygotic individuals show lesser phenotype. After moderate consumption of alcohol, individuals affected by alcohol suffer from heavier hangover symptoms, homozygotes, even extreme one such as tachycardia, hypotension, nausea, and vomiting. Heterozygotes have reported subjectively more intense and more pleasant rection to alcohol than individuals with ALDH2*1/2*1[9]. There are fewer people with at least one copy of ALDH2*2 who suffer from liver cirrhosis. Therefore, is concluded that this mutation can serve as protection against alcohol abuse. This fact depends on cultural differences and relationship with alcohol as the protective effect is somehow weaker in African or European populations, as there can be social pressure to drink more alcohol in social activities, even in Eastern cultures people with flushing cannot escape or reject such alcoholism[10]. Generally, individuals with the ALDH2 polymorphism experience less hepatic oxidative stress due to lesser alcohol consumption, by cumulating unprocessed acetaldehyde. Consequently, artificial regulation of ALH2 may be used as potential therapeutic intervention for alcoholism [11].

Non-alcoholic liver diseases

Although ALHD2 misfunction can play a protective role against, on the other hand, it can increase the number of non-alcoholic fatty liver disease (NAFLD) among carriers of ALDH2*2. This can be the result of the missing ALDH2 enzyme for preserving mitochondrial respiratory function or for the cleavage of aldehydes, which can be byproducts of fat metabolism^[10]. .

There are concerns about metabolic interaction between retinol and ethanol metabolism. As I can result in inhibition of immunological feedback to some viral infections such as viral hepatitis. Among ALDH2*2 patients has increased probability of developing liver cirrhosis^[10].

Hepatocellular carcinoma is suspected of connection with ALHD2 deficiency as it could be result of habitual alcohol drinking, non-alcoholic fatty liver disease or HBV. Due to the oxidative base of ethanol metabolism and the occurrence of the ALDH2 enzyme in mitochondria, is cocluded a correlation between low ALDH2 activity and liver cancer^[10].

Inhibitors and activators

ALDH2 can be selectively inhibited by Daidzin, as ALDH1 by Antabuse (disulfiram, DS, tetraethylthiuram disulfide), an early alcoholic treatment, as it causes accumulation of acetaldehyde resulting in heavier hangover symptoms. Daidzin is more specific to ALDH2 than to ALDH1, this could be due to a smaller substrate-binding cleft than of ALDH1. The daidzin binding sites are spread over all four subunits. The fully bound daidzin is buried from 90%. The isoflavon ring structure conducts extensive Van der Waals contacts with the surrounding residues, including long contact with Cys302. Cys302 was identified as an important catalyst group. The separation of Daidzin O4′-hydroxyl oxygen from Cys302 sulfur atoms is 3.7 Å, and there is no covalent interaction. Despite the general similarity of the ALDH2 apo and daidzin structures, the conformation has been locally altered. The lateral chain of Cys302 moves 2.5 Å from the site to avoid close contact with the O4′-phenoxy ring of Daidzin. Other isoflavonoid derivatives show some inhibitory impact on ALDH2, although prunetin does not result in structural changes as it binds only one subunit per tetramer. Studies of structural activity indicate that the 7-O position can be replaced by several straight chain alkyls with terminal polar functions such as -OH, -COOH, or -NH₂. It was observed that longer ethyl group has better hydrophobic interactions resulting in better binding, longer chains can result in lesser affinity due to more complex formation of both polar and nonpolar interactions at the same time^[12].

References

1. ↑ Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, Ho KK, Weiner H, Bachschmid M, Munzel T, Daiber A. Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem. 2007 Jan 5;282(1):792-9. doi: 10.1074/jbc.M606477200. Epub 2006 Nov , 13. PMID:17102135 doi:http://dx.doi.org/10.1074/jbc.M606477200
2. ↑ ^{2.0 2.1 2.2} Chen CH, Ferreira JCB, Joshi AU, Stevens MC, Li SJ, Hsu JH, Maclean R, Ferreira ND, Cervantes PR, Martinez DD, Barrientos FL, Quintanares GHR, Mochly-Rosen D. Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity. EBioMedicine. 2020 May;55:102753. doi: 10.1016/j.ebiom.2020.102753. Epub 2020 May, 8. PMID:32403082 doi:http://dx.doi.org/10.1016/j.ebiom.2020.102753
3. ↑ ALDH2 Gene - Somatic Mutations in Cancer https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ALDH2
4. ↑ Mutation overview page ALDH2 - p.E504K (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451499
5. ↑ Mutation overview page ALDH2 - p.P92T (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99454838
6. ↑ Mutation overview page ALDH2 - p.T244M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99452531
7. ↑ Mutation overview page ALDH2 - p.V304M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451318
8. ↑ Mutation overview page ALDH2 - p.R338W (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99455550
9. ↑ Wall TL, Thomasson HR, Schuckit MA, Ehlers CL. Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles. Alcohol Clin Exp Res. 1992 Oct;16(5):991-5. doi:, 10.1111/j.1530-0277.1992.tb01907.x. PMID:1443441 doi:http://dx.doi.org/10.1111/j.1530-0277.1992.tb01907.x
10. ↑ ^{10.0 10.1 10.2 10.3} Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. J Clin Transl Hepatol. 2021 Feb 28;9(1):90-98. doi: 10.14218/JCTH.2020.00104., Epub 2021 Jan 4. PMID:33604259 doi:http://dx.doi.org/10.14218/JCTH.2020.00104
11. ↑ Guillot A, Ren T, Jourdan T, Pawlosky RJ, Han E, Kim SJ, Zhang L, Koob GF, Gao B. Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking. Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25974-25981. doi:, 10.1073/pnas.1908137116. Epub 2019 Dec 2. PMID:31792171 doi:http://dx.doi.org/10.1073/pnas.1908137116
12. ↑ Lowe ED, Gao GY, Johnson LN, Keung WM. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. J Med Chem. 2008 Aug 14;51(15):4482-7. Epub 2008 Jul 10. PMID:18613661 doi:10.1021/jm800488j