ALDH2: Difference between revisions

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== Inhibitors and activators ==
== 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 ''ALDH''2 than to ''ALDH''1, this could be due to a smaller substrate-binding cleft than of ''ALDH''1. 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 ''ALDH''2 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 ''ALDH''2, 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 -NH<sub>2</sub>. 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<ref>DOI: 10.1021/jm800488j</ref>.
''ALDH''2 can be selectively inhibited by Daidzin, as ''ALDH''1 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 ''ALDH''2 than to ''ALDH''1, this could be due to a smaller substrate-binding cleft than of ''ALDH''1. 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 ''ALDH''2 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 ''ALDH''2, 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 -NH<sub>2</sub>. 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<ref>DOI: 10.1021/jm800488j</ref>.


== References ==
== References ==
<references/>
<references/>

Revision as of 19:58, 28 April 2022

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

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

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Function

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

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[2]. .

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[2].

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[2].

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[3].

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:https://dx.doi.org/10.1074/jbc.M606477200
  2. ↑ 2.0 2.1 2.2 Cite error: Invalid <ref> tag; no text was provided for refs named HP
  3. ↑ 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

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