ALDH2

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Contents

Introduction

Mitochondrial aldehyde dehydrogenase (ALDH2) is a single member of ALDH2 family and one of 19 members of ALDH superfamily. It is responsible for metabolism of acetaldehyde, typical metabolite from alcohol consumption, and other aldehydes. It is expressed in variety of tissues with highest level found in liver. Its’ cytosolic isoform has 70% sequence identity. Chromosomal location of ALDH2 is on 12q24.2. Polymorphism in the ALDH2 gene is related to development of alcohol-induced cancer and decreased risk of alcoholism.[1] ALDH2 gene is 44kpbs long with 13 exons.[2]


Structure

Human mitochondrial aldehyde dehydrogenase, apo form (PDB entry 3N80)

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Function

active site of A-chain of human mitochondrial ALDH2 complexed with NAD+ (PDB entry 1CW3)

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Mutations

Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with agonist Alda-1 (PDB entry 3INL)

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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[18]. .

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[18].

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[18].

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[20].

Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide) is considered as chemical chaperone for ALDH2. Even though it shares overlapping binding sites with daidzin, binding results in activation of structurally distorted ALDH2. Structural complex of ALDH2 and Alda-1 shows that Alda-1 binds at the entrance to the active site and does not interfere with catalytic residues. As Alda-1 block part of substrate site it is suggested dependence on substrate size. Concentration dependence of Alda-1 activation at saturating concentrations of acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, phenylacetaldehyde and DACA were observed. Smaller linear aldehydes were activated by Alda-1, activation decreases with increasing length of aldehydes. Presence of Alda-1 with ALDH2*2 shows greater activity increase than with WT, this suggests that Alda-1 promotes structural and functional rescue than only increasing effective concentration within active site. Distortions starting with 246 residues through the catalyst site, especially Glu268, ending with Glu478. The site of coenzyme binding is reliant on the coenzyme binding, the active site remains even less ordered. Alda-1 has no direct contact with residues from the active site, but forms close interactions with Phe459 and Trp177 near Phe465 and Glu268. This hypothesizes that the binding of Alda-1 could reorient abnormal dynamics in both regions to improve enzyme efficiency[21].

After additional screening another most potent activator was identified as Alda-64 (2-(azepane-1-carbonyl)-N-(2chlorobenzyl)-2,3-dihydrobenzo (b) <1,4> dioxine-6-sulfonamide) as Alda-1 it is more specific in favor of ALDH2. Different mutations react differently to each activator. Alda-64 increased activity of ALDH2*3 and ALDH2*5 to WT levels, greater effect than with Alda-1. On the other hand, ALDH2*4 and ALDH2*5 were activated better by Alda-1. This suggests fundamentally different structural changes in each mutation[3].

References

  1. ↑ Vasiliou V, Nebert DW. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics. 2005 Jun;2(2):138-43. doi: 10.1186/1479-7364-2-2-138. PMID:16004729 doi:http://dx.doi.org/10.1186/1479-7364-2-2-138
  2. ↑ 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
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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
  4. ↑ Gonzalez-Segura L, Ho KK, Perez-Miller S, Weiner H, Hurley TD. Catalytic contribution of threonine 244 in human ALDH2. Chem Biol Interact. 2013 Feb 25;202(1-3):32-40. doi: 10.1016/j.cbi.2012.12.009., Epub 2013 Jan 4. PMID:23295226 doi:http://dx.doi.org/10.1016/j.cbi.2012.12.009
  5. ↑ doi: https://dx.doi.org/10.1016/j.cbi.2012.12.009.Epub2013Jan4.PMID
  6. ↑ Gonzalez-Segura L, Ho KK, Perez-Miller S, Weiner H, Hurley TD. Catalytic contribution of threonine 244 in human ALDH2. Chem Biol Interact. 2013 Feb 25;202(1-3):32-40. doi: 10.1016/j.cbi.2012.12.009., Epub 2013 Jan 4. PMID:23295226 doi:http://dx.doi.org/10.1016/j.cbi.2012.12.009
  7. ↑ doi: https://dx.doi.org/10.1074/jbc.272.30.18817.PMID
  8. ↑ Sladek NE. Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol. 2003;17(1):7-23. doi: 10.1002/jbt.10057. PMID:12616643 doi:http://dx.doi.org/10.1002/jbt.10057
  9. ↑ doi.org/10.1016/S0021-9258(18)98796-X
  10. ↑ doi: https://dx.doi.org/10.1172/JCI19267.PMID
  11. ↑ ALDH2 Gene - Somatic Mutations in Cancer https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ALDH2
  12. ↑ Mutation overview page ALDH2 - p.E504K (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451499
  13. ↑ Mutation overview page ALDH2 - p.P92T (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99454838
  14. ↑ Mutation overview page ALDH2 - p.T244M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99452531
  15. ↑ Mutation overview page ALDH2 - p.V304M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451318
  16. ↑ Mutation overview page ALDH2 - p.R338W (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99455550
  17. ↑ 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
  18. ↑ 18.0 18.1 18.2 18.3 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ Perez-Miller S, Younus H, Vanam R, Chen CH, Mochly-Rosen D, Hurley TD. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. Nat Struct Mol Biol. 2010 Feb;17(2):159-64. Epub 2010 Jan 10. PMID:20062057 doi:10.1038/nsmb.1737

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