ALDH2: Difference between revisions
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== Structure == | == 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=''> | <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=''> | ||
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> | 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</ | 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</ref> | ||
</StructureSection> | |||
== Function == | == Function == | ||
<StructureSection load='1CW3' size=' | <StructureSection load='1CW3' size='200' 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'> | ||
ALDH2 plays crucial role in metabolism of ethanol and lipid breakdown, in responce to oxidative stress of cell and Together with other ALDHs, takes part in breakdown of vast number of diverse aldehydes which might otherwise cause damage to the organism. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref> | ALDH2 plays crucial role in metabolism of ethanol and lipid breakdown, in responce to oxidative stress of cell and Together with other ALDHs, takes part in breakdown of vast number of diverse aldehydes which might otherwise cause damage to the organism. <ref name="nov2020">DOI: 10.1016/j.ebiom.2020.102753</ref> | ||
Important function of ALDH2 is NAD+ -dependent oxidation of acetaldehyde, however it can also catalyse ester hydrolysis, which is similar in mechanism to acyl-sulfur bond hydrolysis. Efficiency of ester hydrolysis depends on length of chain of substrate, as longer chains tend to decrease rate of conversion. In case of aldehydes, no such drastic trend has been observed. <ref>doi: 10.1002/jbt.10057</ref> In addition to acetaldehyde, for which ALDH2 shows highest affinity among ALDHs, this enzyme also participates in metabolism of biogenic amines, corticosteroids and histamine<ref>doi.org/10.1016/S0021-9258(18)98796-X</ref> or in metabolism of nitroglycerin in mitochondria and nitrates as general.<ref>doi: 10.1172/JCI19267. PMID: 14755345; PMCID: PMC324536</ref> | Important function of ALDH2 is NAD+ -dependent oxidation of acetaldehyde, however it can also catalyse ester hydrolysis, which is similar in mechanism to acyl-sulfur bond hydrolysis. Efficiency of ester hydrolysis depends on length of chain of substrate, as longer chains tend to decrease rate of conversion. In case of aldehydes, no such drastic trend has been observed. <ref>doi: 10.1002/jbt.10057</ref> In addition to acetaldehyde, for which ALDH2 shows highest affinity among ALDHs, this enzyme also participates in metabolism of biogenic amines, corticosteroids and histamine<ref>doi.org/10.1016/S0021-9258(18)98796-X</ref> or in metabolism of nitroglycerin in mitochondria and nitrates as general.<ref>doi: 10.1172/JCI19267. PMID: 14755345; PMCID: PMC324536</ref> | ||
