ALDH2: Difference between revisions
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== Inhibitors and activators == | == Inhibitors and activators == | ||
''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>. | ''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>. | ||
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<ref name="nov2020"/>. | |||
== References == | == References == | ||
<references/> | <references/> | ||
