ALDH2: Difference between revisions

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== 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.<ref>DOI:10.1186/1479-7364-2-2-138</ref> ALDH2 gene is 44kpbs long with 13 exons.<ref>DOI:10.1074/jbc.M606477200</ref>

== Structure ==

~~Homotetramer functioning~~ as ~~dimer~~ of ~~dimers~~. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref>

ALDH2 enzyme functions as homotetramer where each monomer consists of two Rossmann fold domains and an oligomerization tail. NAD+ binds to one of the Rossmann folds in the gap between αF and αG helices while leaving pyrophosphate exposed to the solvent. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref> <ref>DOI:10.1016/j.cbi.2012.12.009</ref>

Active site consists of highly conserved Cys-302, Asn-169 and Glu-268 catalytic triad. Cys-302 acting as nucleophile and covalently binding the metabolized aldehyde. Formed thiohemiacetal is stabilized by Asn-169 and hydride is transferred to substrate NAD+. It is agreed upon, that role of Glu-268 is to mediate attack of water molecule on the acyl-sulfur bond.<ref>doi: 10.1016/s0969-2126(97)00224-4. PMID: 9195888.</ref> Thr-244 is also highly conserved residue, as it plays role in hydride transfer between substrates. Substitution of this amino acid results in decrease of catalytic efficiency.<ref>doi: 10.1016/j.cbi.2012.12.009</ref> Another conserved residues are Arg84, Lys192, Thr384, Glu399, Ser471, Glu398 and Lys489, all of them negatively effecting catalysis when substituted.<ref>doi: 10.1074/jbc.272.30.18817. PMID: 9228056</re>

</StructureSection>

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 == 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.<ref>DOI:10.1186/1479-7364-2-2-138</ref> ALDH2 gene is 44kpbs long 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>
+ALDH2 enzyme functions as homotetramer where each monomer consists of two Rossmann fold domains and an oligomerization tail. NAD+ binds to one of the Rossmann folds in the gap between αF and αG helices while leaving pyrophosphate exposed to the solvent. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref> <ref>DOI:10.1016/j.cbi.2012.12.009</ref>
+Active site consists of highly conserved Cys-302, Asn-169 and Glu-268 catalytic triad. Cys-302 acting as nucleophile and covalently binding the metabolized aldehyde. Formed thiohemiacetal is stabilized by Asn-169 and hydride is transferred to substrate NAD+. It is agreed upon, that role of Glu-268 is to mediate attack of water molecule on the acyl-sulfur bond.<ref>doi: 10.1016/s0969-2126(97)00224-4. PMID: 9195888.</ref> Thr-244 is also highly conserved residue, as it plays role in hydride transfer between substrates. Substitution of this amino acid results in decrease of catalytic efficiency.<ref>doi: 10.1016/j.cbi.2012.12.009</ref> Another conserved residues are Arg84, Lys192, Thr384, Glu399, Ser471, Glu398 and Lys489, all of them negatively effecting catalysis when substituted.<ref>doi: 10.1074/jbc.272.30.18817. PMID: 9228056</re>
 </StructureSection>