== Introduction ==
Some kind of intro, where it’s located, coding gene is located on chromosome 12 (12q24.2), 44kpbs in lenght with 13 exons<ref>DOI:10.1074/jbc.M606477200</ref>…
== Structure ==
<StructureSection load='3N80' size='350' side='right' caption='Human mitochondrial aldehyde dehydrogenase, apo form (PDB entry [http://doi.org/10.2210/pdb3N80/pdb 3N80])' scene=''>
Homotetramer functioning as dimer of dimers. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref>
</StructureSection>

== Function ==
<StructureSection load='1CW3' size='250' side='right' caption='active site of A-chain of human mitochondrial ALDH2 complexed with NAD+ (PDB entry [http://doi.org/10.2210/pdb1CW3/pdb 1CW3])' scene='76/763091/Aldh2_active_site_a-chain/2'>
Detoxifying of toxic aldehydes, involved in many pathways such as ethanol breakdown, lipid metabolization, role in oxidative stress of cell. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref>
</StructureSection>

== Mutations ==
<StructureSection load='3INL' size='350' side='right' caption='Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with agonist Alda-1 (PDB entry [http://doi.org/10.2210/pdb3INL/pdb 3INL])' scene=''>
There are seven mutations observed in different ethnicities with higher relative prevalence, there is more cancer issued mutations<ref>''ALDH''2 Gene - Somatic Mutations in Cancer https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=ALDH2</ref>. Most studied of them is East Asian mutation (''ALDH''2*2) connected with alcohol flushing syndrome and other diseases<ref name="nov2020"/>.
{| class="wikitable"
|-
! ''ALDH''2 designation
! Mutation
! Location
! AA change
! Major ethnicity
! Allele frequency
! Relative activity
|-
| '''WT (''ALDH''2*1)'''
|
|
|
|
|
|-
| '''''ALDH''2*2'''
| E504K<ref>Mutation overview page ALDH2 - p.E504K (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451499</ref>
| 504
| Glu → Lys 
| East Asian
| 26.6%
| 0%
|-
| '''''ALDH''2*3'''
| I41V
| colspan="2" | single-carbon change in the AA side chain <ref name="nov2020"/>
| African
| 0.6%
| 60%
|-
| '''''ALDH''2*4'''
| P92T<ref>Mutation overview page ALDH2 - p.P92T (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99454838</ref>
| 92
| Pro → Thr
| Latino
| 2.5%
| 32%
|-
| '''''ALDH''2*5'''
| T244M<ref>Mutation overview page ALDH2 - p.T244M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99452531</ref>
| 244
| Thr → Met
| South Asian
| 0.7%
| 38%
|-
| '''''ALDH''2*6'''
| V304M<ref>Mutation overview page ALDH2 - p.V304M (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99451318</ref>
| 304
| Val → Met
| Latino
| 2.4%
| 11% 
|-
| '''''ALDH''2*7'''
| R338W<ref>Mutation overview page ALDH2 - p.R338W (Substitution - Missense) https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=99455550</ref>
| 338
| Arg → Trp
| Finnish
| 1.2%
| 23%
|}

== Alcohol liver disease ==

''ALDH''2*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 ''ALDH''2*1/2*1<ref>DOI:10.1111/j.1530-0277.1992.tb01907.x</ref>. There are fewer people with at least one copy of ''ALDH''2*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<ref name="HP">DOI:10.14218/jcth.2020.00104</ref>. Generally, individuals with the ''ALDH''2 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 <ref>DOI:10.1073/ pnas.1908137116</ref>.
</StructureSection>

== 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 ''ALDH''2*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<ref name="HP"/>. .

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 ''ALDH''2*2 patients has increased probability of developing liver cirrhosis<ref name="HP"/>.

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 ''ALDH''2 enzyme in mitochondria, is cocluded a correlation between low ALDH2 activity and liver cancer<ref name="HP"/>.

== 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 -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<ref>DOI: 10.1021/jm800488j</ref>.

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<ref>DOI: 10.1038/nsmb.1737</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/>