ALDH2 encodes the mitochondrial low-Km aldehyde dehydrogenase. Its 517-residue precursor is imported into mitochondria through a cleaved N-terminal transit peptide and the mature subunits assemble into a soluble homotetramer of the mitochondrial matrix. The enzyme uses the canonical ALDH chemistry, in which an active-site cysteine (Cys319 in precursor numbering, Cys302 in the mature numbering used in the enzymology literature) adds to the aldehyde carbon, hydride passes to NAD+, and the thioacyl intermediate is hydrolysed by water activated by a glutamate general base (Glu285 precursor, Glu268 mature). Affinity for short-chain aldehydes is very high (KM for acetaldehyde about 0.02 uM), and oxidation of ethanol-derived acetaldehyde to acetate is the second and final step of ethanol degradation. The same active site handles reactive endogenous aldehydes: ALDH2 is the most catalytically efficient human isoform for the lipid-peroxidation products acrolein, 4-hydroxy-2-nonenal and malondialdehyde, it oxidises the dopamine-derived neurotoxin DOPAL to DOPAC, and it has weak but physiologically consequential activity on formaldehyde that acts as a second line of defence behind ADH5. Independently of aldehyde oxidation, the catalytic cysteine denitrates the vasodilator nitroglycerin to 1,2-glyceryl dinitrate plus nitrite and reduces it to nitric oxide, which is how the drug works. The common East Asian E504K substitution (ALDH2*2) nearly abolishes activity, causing acetaldehyde accumulation with alcohol-induced flushing and loss of nitroglycerin efficacy, and together with biallelic ADH5 loss of function it causes AMeD syndrome through failed formaldehyde clearance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001758 retinal dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Automated Rhea/EC mapping of the all-trans-retinal reaction (RHEA:42080, EC 1.2.1.36) onto human ALDH2, routed through the mouse ortholog P47738. Reason: UniProt records this reaction on the human entry only as a by-similarity statement (ECO:0000250 from mouse ALDH2 P47738), not as a measurement on this protein, and human retinaldehyde oxidation is carried by the dedicated ALDH1A subfamily. The PTHR11699 family review scopes GO:0001758 to the ALDH1A subfamilies only (SUBFAMILY_ONLY), and ALDH2 sits in PTHR11699:SF233. A broad-specificity matrix ALDH may well turn retinal over in vitro, so the claim is not called false, but it is not grounded on ALDH2 and is not part of its function. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Reaction=all-trans-retinal + NAD(+) + H2O = all-trans-retinoate + NADH file:human/ALDH2/ALDH2-uniprot.txt Mitochondrial aldehyde dehydrogenase with broad substrate specificity which participates in the detoxification of ethanol-derived acetaldehyde and endogenous aldehydes, including those arising from lipid peroxidation |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD of generic NAD+-dependent aldehyde dehydrogenase activity at PTN000192666, the deep ALDH node of PTHR11699, inherited by ALDH2. Reason: The node asserts the family's common denominator and it is correct for ALDH2, which is itself one of the descendant evidences the PAINT curator used (P05091 appears in the with-list, which is expected and not circular). The PTHR11699 family review flags this node for pruning only on the NADP+-dependent ALDH1L/FDH branch (SF120, SF131); ALDH2 is in SF233, is NAD+-dependent, and has its own direct kinetics on this reaction. Core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000192666 SUPPORTS TRANSFER Deep ALDH node of PTHR11699. The only activity shared across its bacterial, fungal, plant and animal descendants is generic NAD+-dependent aldehyde oxidation, which is what the node asserts, and ALDH2's own experimental annotation is among the seeds. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Reaction=an aldehyde + NAD(+) + H2O = a carboxylate + NADH + 2 H(+); file:human/ALDH2/ALDH2-uniprot.txt KM=0.5 uM for propanal |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:16956664 Inhibition of the oxidative metabolism of 3,4-dihydroxypheny... | ACCEPT | Summary: Recombinant human ALDH2 oxidises the dopamine-derived aldehyde DOPAL to DOPAC, and the activity is inhibited by 4-HNE. Reason: Direct assay of NAD+-dependent aldehyde oxidation by purified human ALDH2 on a physiological substrate. This is the gene's central activity. Core function. Supporting Evidence: PMID:16956664 Incubation of human recombinant ALDH2 with 4HNE (1.5-30 microM) yielded inhibition of activity toward DOPAL. PMID:16956664 DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:20062057 Alda-1 is an agonist and chemical chaperone for the common h... | ACCEPT | Summary: Dehydrogenase activity of purified ALDH2 and of the E504K (ALDH2*2) variant measured across a panel of aldehyde substrates in the Alda-1 structural study. Reason: Purified enzyme assayed directly for NAD+-dependent aldehyde oxidation on propionaldehyde and a substrate panel; the same work reports the ALDH2 and ALDH2*2 crystal structures. Core function. Supporting Evidence: PMID:20062057 We assayed for ALDH2 activity in a standard reaction mixture comprised of 25 mM BES, pH 7.5, with 100 ΞΌM propionaldehyde and either 0.5 mM (ALDH2*1) or 10 mM NAD+ (ALDH2*2). PMID:20062057 This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin. |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:22339434 Differences in susceptibility to inactivation of human aldeh... | ACCEPT | Summary: Side-by-side kinetics of the three best-studied human ALDH isoforms on lipid-peroxidation aldehydes, in which ALDH2 had the highest catalytic efficiency. Reason: Direct kinetic measurement of NAD+-dependent aldehyde oxidation by ALDH2 on acrolein, 4-HNE and malondialdehyde; the KM values of 1.1, 0.9 and 26 uM carried on the UniProt record come from this paper. Core function. Supporting Evidence: PMID:22339434 among the three most studied human ALDH isoforms, ALDH2 showed the highest catalytic efficiency for oxidation of acrolein, 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde file:human/ALDH2/ALDH2-uniprot.txt KM=0.9 uM for (E)-4-hydroxynon-2-enal (at pH 7.4) |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:27521998 Alda-1 modulates the kinetic properties of mitochondrial ald... | ACCEPT | Summary: Full steady-state kinetic characterisation of ALDH2, covering kinetic parameters, the rate-limiting step and catalytic-cysteine reactivity, with and without Alda-1. Reason: The paper's entire subject is the NAD+-dependent dehydrogenase reaction of purified ALDH2, including the order of substrate binding and product release. Core function. Supporting Evidence: PMID:27521998 kinetic experiments were performed to characterize the effect of Alda-1 on the properties of ALDH2 (kinetic parameters, determination of the rate-limiting step, reactivity of the catalytic cysteine) PMID:27521998 the Km for NAD+ decreased by 2.4-fold, and the catalytic efficiency increased 4.4-fold |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:4015840 Biochemical genetic analysis of human and rodent aldehyde de... | ACCEPT | Summary: Classical isozyme survey that characterised the human ALDH isozymes, including the mitochondrial ALDH2, by substrate and coenzyme specificity. Reason: An early biochemical characterisation of the mitochondrial isozyme's substrate and coenzyme specificity. The cached record is abstract-only, so the detailed assays are not visible here, but the curator read the full text and the activity assignment is independently established by several later direct measurements in this review. Core function. Supporting Evidence: PMID:4015840 ALDH isozymes have been characterized in terms of substrate and coenzyme specificity, heat stability, tissue distribution and electrophoretic properties. file:human/ALDH2/ALDH2-uniprot.txt Reaction=an aldehyde + NAD(+) + H2O = a carboxylate + NADH + 2 H(+); |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping of the generic aldehyde plus NAD+ reaction (RHEA:16185, EC 1.2.1.3) and of several specific ALDH2 reactions onto this entry. Reason: Unlike the retinal and succinate-semialdehyde mappings, this one rests on reactions that UniProt records with experimental evidence on this protein (ECO:0000269 for the generic aldehyde reaction, malondialdehyde, propanal, DOPAL and acrolein), and it agrees with the IDA and IBA rows above. Core function. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Reaction=an aldehyde + NAD(+) + H2O = a carboxylate + NADH + 2 H(+); file:human/ALDH2/ALDH2-uniprot.txt In vitro, ALDH2 catalyzes the oxidation of acrolein, malondialdehyde, and 4-hydroxynonenal (4-HNE) |
| GO:0004777 succinate-semialdehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Automated Rhea/EC mapping of the succinate-semialdehyde reaction (RHEA:13217, EC 1.2.1.24) onto human ALDH2. Reason: UniProt records this reaction on the human entry only by similarity to rodent ALDH2 (ECO:0000250 from P20000); there is no measurement on the human protein. The dedicated human enzyme for this step of GABA catabolism is ALDH5A1, which belongs to a different PANTHER family. The activity is plausible for a broad-specificity matrix ALDH but is not an established function of ALDH2. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Reaction=succinate semialdehyde + NAD(+) + H2O = succinate + NADH + 2 file:human/ALDH2/ALDH2-uniprot.txt Mitochondrial aldehyde dehydrogenase with broad substrate specificity which participates in the detoxification of ethanol-derived acetaldehyde and endogenous aldehydes, including those arising from lipid peroxidation |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: ALDH2 is a member of MitoCoP, the stringently filtered high-confidence human mitochondrial proteome. Reason: Whole-organelle proteomics cannot resolve a sub-compartment, so the root organelle term is the right granularity for this evidence and is kept as such under the root-organelle policy. The claim itself is not in doubt, since ALDH2 has a cleaved mitochondrial transit peptide and direct localisation evidence elsewhere in this review. Supporting Evidence: PMID:34800366 The datasets were analyzed by stringent filtering and complemented by a detailed literature/database curation as well as single-protein studies, leading to the definition of the high-confidence mitochondrial proteome MitoCoP |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD of mitochondrion at PTN008977985, the node of the mitochondrial classical ALDHs, seeded by ALDH2 itself, its rodent orthologs and ALDH1B1. Reason: This is the compartment node for the mitochondrial classical-ALDH branch rather than a family-wide compartment assertion, and the PTHR11699 family review leaves it explicitly undisputed, its mitochondrion complaint being about PTN008524390 on the ALDH1L branch. The organelle claim holds on direct evidence for the target. The row stops at the organelle because the ortholog annotations it was seeded from do, which is a granularity limit rather than a soundness problem, and the matrix sub-compartment is carried by separate rows in this review. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008977985 SUPPORTS TRANSFER Node of the mitochondrial classical ALDHs. Seeds are ALDH2 itself (P05091, expected and not circular), rat Aldh2, two mouse genes and human ALDH1B1 (P30837), all mitochondrial matrix enzymes. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16440063, |
| GO:0005739 mitochondrion | IDA PMID:16440063 Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys pol... | ACCEPT | Summary: The GTN-bioactivation study, cited by UniProt as one of the two experimental sources for the mitochondrial location of ALDH2. Reason: Direct localisation evidence from an assay that does not resolve the sub-compartment, which under the root-organelle policy is accepted at the organelle term, with the matrix added by separate rows rather than substituted here. The cached record is abstract-only, so the localisation experiment itself is not visible, but UniProt's curated subcellular location cites this paper with ECO:0000269. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16440063, PMID:16440063 Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. |
| GO:0005739 mitochondrion | IDA PMID:4065146 Mitochondrial aldehyde dehydrogenase from human liver. Prima... | ACCEPT | Summary: Primary structure of the enzyme purified from human liver mitochondria, which identified the cleaved N-terminal mitochondrial targeting region. Reason: The protein was purified from liver mitochondria and its N-terminal processing heterogeneity, read as transit-peptide cleavage, is the origin of UniProt's transit peptide feature covering residues 1 to 17. Direct evidence at organelle granularity, accepted as such. Supporting Evidence: PMID:4065146 The 500-residue amino acid sequence of the subunit of mitochondrial human liver aldehyde dehydrogenase is reported. PMID:4065146 Near-total lack of conservation of the N-terminal segments may reflect a role of the N-terminal region in signaling the transport of the mitochondrial protein chains. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Automated mapping of the UniProt subcellular-location vocabulary term Mitochondrion (SL-0173) onto GO. Reason: The UniProt location it maps from is itself curated with experimental evidence (ECO:0000269, PubMed:16440063 and PubMed:4065146), so the electronic row reproduces a sound claim at organelle granularity. Kept rather than modified, under the root-organelle policy. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16440063, |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of the mitochondrial location from an ALDH2 ortholog (A0A286XPF7). Reason: Consistent with, though redundant beside, the direct evidence on the human protein. The mitochondrial location of ALDH2 orthologs is the rule across vertebrates, and this review keeps the organelle term on the target's own direct support. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A0A286XPF7 SUPPORTS TRANSFER ALDH2 ortholog used as the similarity donor. The target already has direct experimental localisation, so this row adds breadth rather than new support. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16440063, |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara transfer of the mitochondrial matrix location from mouse Aldh2 (P47738). Reason: The sub-compartment claim is right for the human protein and is independently supported, since the transit peptide is cleaved, the mature protein is a soluble homotetramer with no transmembrane segment, and Reactome places the acetaldehyde-oxidising reaction in the matrix. This is the sub-compartment row that complements, rather than replaces, the organelle rows above. Supporting Evidence: Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ file:human/ALDH2/ALDH2-uniprot.txt SUBUNIT: Homotetramer. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-380608 | ACCEPT | Summary: Reactome reaction placing the oxidation of 5-hydroxyindole acetaldehyde, a serotonin-catabolism intermediate, by an aldehyde dehydrogenase in the matrix. Reason: The GO row asserts only the location, and the matrix location of ALDH2 is correct and independently supported. Attribution of serotonin-derived aldehyde oxidation to ALDH2 is Reactome's inference rather than an ALDH2-specific measurement, which is why no process term is taken from it in this review. Supporting Evidence: Reactome:R-HSA-380608 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71723 | ACCEPT | Summary: Reactome's mitochondrial acetaldehyde-to-acetate reaction, assigned explicitly to ALDH2 in the mitochondrial matrix. Reason: The curated statement names the gene, the reaction and the compartment together, and it matches the experimental picture of a cleaved transit peptide, a soluble tetramer and the matrix NAD+ pool. This is the strongest of the six TAS rows for the matrix location. Supporting Evidence: Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ (Greenfield and Pietruszko 1977; Hempel et al. 1985). The active form of the enzyme is a tetramer (Ni et al. 1999). |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Reactome's CLPXP substrate-binding reaction, in which ALDH2 is one of the matrix proteins bound by the protease. Reason: ALDH2's part in this reaction is as a substrate of mitochondrial protein quality control rather than as a catalyst, but the GO row asserts only the location, and the matrix compartment the reaction places it in is correct and independently supported. No process term is taken from this row. Supporting Evidence: Reactome:R-HSA-9838035 The CLPXP complex is an ATP-dependent protease located in the mitochondrial matrix that binds, unfolds, and degrades a specific set of protein substrates. Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome's LONP1 degradation reaction, in which ALDH2 is among the matrix proteins degraded. Reason: As for the other quality-control rows, the location claim is right and independently supported while the substrate role carries no functional annotation for ALDH2. Supporting Evidence: Reactome:R-HSA-9838081 LONP1 degrades several mitochondrial matrix proteins (Lee et al. 2021) Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Reactome's LONP1 substrate-binding reaction, in which ALDH2 is among the matrix proteins bound. Reason: The same judgement as the companion LONP1 and CLPXP rows, namely that the matrix location is correct while the substrate role is not a function of ALDH2. Supporting Evidence: Reactome:R-HSA-9838093 Human LONP1 binds, unfolds, and degrades several mitochondrial matrix proteins (Lee et al. 2021) Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome's CLPXP degradation reaction, in which ALDH2 is among the matrix proteins degraded. Reason: The same judgement as the companion quality-control rows, namely that the asserted location is right and independently supported while the substrate role yields no functional annotation. Supporting Evidence: Reactome:R-HSA-9838289 The CLPXP complex binds and degrades several mitochondrial matrix proteins (Lee et al. 2021, Key et al. 2021) Reactome:R-HSA-71723 ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ |
| GO:0006068 ethanol catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated UniPathway mapping (UPA00780, ethanol degradation) onto this entry. Reason: ALDH2 performs the second and final step of ethanol degradation, oxidising ADH-derived acetaldehyde to acetate, and UniProt records that pathway step with experimental evidence on the human protein. Core function. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt PATHWAY: Alcohol metabolism; ethanol degradation; acetate from ethanol: step 2/2. PMID:39075523 Reactive oxygen species (ROS) are generated when ADH converts alcohol to acetaldehyde and when ALDH2 converts acetaldehyde to acetic acid. |
| GO:0006068 ethanol catabolic process | IMP PMID:39075523 Uncovering newly identified aldehyde dehydrogenase 2 genetic... | ACCEPT | Summary: Carriers of newly identified loss-of-function ALDH2 variants (R101G, R114W) accumulate acetaldehyde and flush after an alcohol challenge. Reason: The variant carriers show the pathway failing in vivo and the recombinant variant enzymes show reduced acetaldehyde turnover, so ALDH2 is not merely required for ethanol degradation but catalyses the step. Core function. Supporting Evidence: PMID:39075523 We identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. PMID:39075523 In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. |
| GO:0008957 phenylacetaldehyde dehydrogenase (NAD+) activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of phenylacetaldehyde dehydrogenase activity from an ALDH2 ortholog. Reason: Phenylacetaldehyde is a genuine ALDH2 substrate, being one of the aldehydes used to probe the substrate-length dependence of the human enzyme's dehydrogenase reaction. That is real activity of a broad-specificity detoxifying enzyme rather than a dedicated specificity, and no physiological phenylacetaldehyde-clearance role is documented for ALDH2, so the term is kept as a non-core substrate preference rather than accepted as a core function. Supporting Evidence: PMID:20062057 we examined the concentration dependence of Alda-1 activation at saturating concentrations of acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, phenylacetaldehyde, and 4-trans-(N,N-dimethylamino)-cinnamaldehyde (DACA). file:human/ALDH2/ALDH2-uniprot.txt Mitochondrial aldehyde dehydrogenase with broad substrate specificity which participates in the detoxification of ethanol-derived acetaldehyde and endogenous aldehydes, including those arising from lipid peroxidation |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro2GO mapping from the aldehyde dehydrogenase domain and active-site signatures. Reason: True but uninformative, because GO:0004029, accepted elsewhere in this review on direct kinetics, is a descendant of this term and entails it. The signature match itself is correct and the claim is not disputed. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Pfam; PF00171; Aldedh; 1. file:human/ALDH2/ALDH2-uniprot.txt Reaction=an aldehyde + NAD(+) + H2O = a carboxylate + NADH + 2 H(+); |
| GO:0018467 formaldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated Rhea/EC mapping of the formaldehyde reaction (RHEA:16425, EC 1.2.1.46), which UniProt records with experimental evidence from the AMeD syndrome study. Reason: Unlike the retinal and succinate-semialdehyde mappings this one is experimentally grounded on the human protein (ECO:0000269, PubMed:33355142) and is physiologically consequential, since ALDH2 E504K combined with biallelic ADH5 loss causes AMeD syndrome and wild-type ALDH2 cDNA rescues formaldehyde-induced DNA damage in patient cells. The activity is nonetheless weak and secondary to the dedicated glutathione-dependent route through ADH5, so it is kept as a non-core activity. Supporting Evidence: PMID:33355142 We focused on the ALDH2 gene and rs671 because ALDH2 retains a weak catabolic activity for formaldehyde (32) PMID:33355142 Ectopic expression of either of the wild-type ADH5 or ALDH2 complementary DNA (cDNA) in the AMeDS cells completely eliminated the induction of formaldehyde-induced DNA damage |
| GO:0018937 nitroglycerin metabolic process | IDA PMID:19506075 Role of the general base Glu-268 in nitroglycerin bioactivat... | ACCEPT | Summary: Purified ALDH2 denitrates nitroglycerin to 1,2-glyceryl dinitrate and nitrite and also reduces it to NO, with active-site mutants separating the two reactions. Reason: ALDH2 itself performs the chemistry on nitroglycerin, the thionitrate intermediate sitting on its catalytic cysteine (PMID:22988236), so the participation requirement is met directly rather than through a necessity argument. The substrate is a xenobiotic, but this is a well-documented and clinically central activity. Supporting Evidence: PMID:19506075 ALDH2 denitrates GTN to 1,2-glyceryl dinitrate and nitrite but also catalyzes reduction of GTN to NO. PMID:22988236 The structure of the GTN-soaked wild-type protein revealed a thionitrate adduct to Cys-302 as the first reaction intermediate, which was also found by mass spectrometry (MS) experiments. |
| GO:0018937 nitroglycerin metabolic process | IMP PMID:16440063 Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys pol... | ACCEPT | Summary: Carriers of the E504K (ALDH2*2) variant lack a clinical response to sublingual nitroglycerin, and the Lys504 enzyme metabolises GTN about tenfold less efficiently. Reason: Human genetic evidence paired with a catalytic-efficiency measurement on the two allelic enzymes. It establishes both that ALDH2 is required for nitroglycerin bioactivation and that the enzyme catalyses the conversion. Consistent with the IDA row on the same term. Supporting Evidence: PMID:16440063 We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. PMID:16440063 we show that the common G-to-A polymorphism in exon 12 of ALDH2--resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes--is associated with a lack of efficacy of sublingual GTN in Chinese subjects |
| GO:0019145 aminobutyraldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Automated Rhea/EC mapping of the 4-aminobutanal reaction (RHEA:19105, EC 1.2.1.19) onto human ALDH2. Reason: UniProt states this activity only as a possibility transferred by similarity from rodent ALDH2 (ECO:0000250 from P20000), and the dedicated human enzyme for 4-aminobutanal oxidation in the polyamine-to-GABA route is ALDH9A1. Plausible for a broad-specificity ALDH, but not an established function of this protein. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt representing an alternative route for GABA biosynthesis from polyamine catabolism (By similarity) file:human/ALDH2/ALDH2-uniprot.txt Reaction=4-aminobutanal + NAD(+) + H2O = 4-aminobutanoate + NADH + 2 |
| GO:0042420 dopamine catabolic process | IDA PMID:16956664 Inhibition of the oxidative metabolism of 3,4-dihydroxypheny... | ACCEPT | Summary: ALDH2 oxidises DOPAL, the monoamine-oxidase product of dopamine, to DOPAC, with the rate measured in recombinant enzyme, brain mitochondrial lysate and isolated brain mitochondria. Reason: ALDH2 catalyses a step of the pathway rather than merely being required for it: the DOPAL-to-DOPAC conversion is the committed oxidative step after deamination, and the rate was measured directly in three systems. That pathway role is also the basis of the link between oxidative stress, 4-HNE-mediated ALDH2 inhibition and DOPAL accumulation. Supporting Evidence: PMID:16956664 DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. PMID:16956664 ALDH2 in rat brain mitochondrial lysate as well as isolated rat brain mitochondria was also sensitive to the lipid peroxidation product at low micromolar, as evident by a decrease in the rate of DOPAL to DOPAC conversion measured using HPLC. |
| GO:0046185 aldehyde catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD of aldehyde catabolic process at PTN002619055, placed at Eumetazoa and seeded by ALDH2 itself. Reason: The PTHR11699 family review assesses this node as sound: its descendants mix retinaldehyde-specific and non-retinoid members, so a generic aldehyde-catabolism term is the right level there, and for ALDH2 the generic process is exactly what the enzyme does across acetaldehyde, DOPAL and the lipid aldehydes. P05091's own experimental annotation being the seed is expected, not circular. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002619055 SUPPORTS TRANSFER Eumetazoan node seeded by ALDH2 itself, assessed as sound in the PTHR11699 family review. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Mitochondrial aldehyde dehydrogenase with broad substrate specificity which participates in the detoxification of ethanol-derived acetaldehyde and endogenous aldehydes, including those arising from lipid peroxidation |
| GO:0046185 aldehyde catabolic process | IDA PMID:20062057 Alda-1 is an agonist and chemical chaperone for the common h... | ACCEPT | Summary: Direct assay of ALDH2-mediated consumption of a panel of aldehydes, including the toxic endogenous aldehydes 4-HNE and acrolein. Reason: Aldehyde catabolism by ALDH2 was measured on purified enzyme across several substrates, so the gene product performs the oxidation step itself. Consistent with the IBA and the other IDA row on this term. Supporting Evidence: PMID:20062057 This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin. |
| GO:0046185 aldehyde catabolic process | IDA PMID:27521998 Alda-1 modulates the kinetic properties of mitochondrial ald... | ACCEPT | Summary: Kinetic dissection of aldehyde consumption by ALDH2, including the rate-limiting step and the order of substrate binding and product release. Reason: The paper measures the enzyme turning aldehydes over, so the process annotation rests on catalysis by this gene product. Consistent with the other rows on this term. Supporting Evidence: PMID:27521998 the Km for the aldehyde increased 8.6-fold, thus, diminishing the catalytic efficiency PMID:27521998 kinetic experiments were performed to characterize the effect of Alda-1 on the properties of ALDH2 (kinetic parameters, determination of the rate-limiting step, reactivity of the catalytic cysteine) |
| GO:0046857 oxidoreductase activity, acting on other nitrogenous compounds as donors, with NAD or NADP as acceptor | IDA PMID:16440063 Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys pol... | ACCEPT | Summary: GTN denitration activity of the Glu504 and Lys504 ALDH2 proteins, measured as the catalytic efficiency of GTN metabolism. Reason: This EC 1.7.1.- parent is the available GO class for ALDH2's nitrate-ester reductase chemistry. The specific term GO:0018547 nitroglycerin reductase activity is obsolete, so no more precise replacement can be proposed, while UniProt records the reaction on this protein with experimental evidence (RHEA:80159, RHEA:80155). Accepted at the correct available granularity; the missing specific term is raised in suggested_questions rather than as a new term, because GO obsoleted the specific class deliberately. Supporting Evidence: PMID:16440063 We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. file:human/ALDH2/ALDH2-uniprot.txt Reaction=nitroglycerin + NADH = 1,2-dinitroglycerol + nitrite + NAD(+); |
| GO:0046857 oxidoreductase activity, acting on other nitrogenous compounds as donors, with NAD or NADP as acceptor | IDA PMID:19506075 Role of the general base Glu-268 in nitroglycerin bioactivat... | ACCEPT | Summary: Rates of GTN denitration and of GTN-derived NO formation by wild-type ALDH2 and by the C302S and E268Q active-site mutants. Reason: Direct measurement of the nitrate-ester reduction reaction on purified enzyme, with mutants showing that the catalytic cysteine is required while the general base is not. The same judgement as the other rows on this term. Supporting Evidence: PMID:19506075 ALDH2 denitrates GTN to 1,2-glyceryl dinitrate and nitrite but also catalyzes reduction of GTN to NO. PMID:19506075 Although the C302S mutation led to >90% loss of all enzyme activities, the E268Q mutant exhibited virtually unaffected rates of GTN denitration despite low dehydrogenase and esterase activities. |
| GO:0046857 oxidoreductase activity, acting on other nitrogenous compounds as donors, with NAD or NADP as acceptor | IDA PMID:25413692 Human ALDH1B1 polymorphisms may affect the metabolism of ace... | ACCEPT | Summary: ALDH2 assayed as the positive control for nitroglycerin metabolism in a comparison with ALDH1B1, the source of the Vmax values for 1,2- and 1,3-dinitroglycerol formation on the UniProt entry. Reason: A control measurement is still a direct measurement of ALDH2's nitrate-ester reductase activity, and it is where UniProt's ECO:0000269 Vmax values for both dinitroglycerol products come from. Consistent with the other two rows on this term. Supporting Evidence: PMID:25413692 ALDH1A1 and ALDH2 were included in experiments as positive controls since they are established metabolizers of all-trans retinaldehyde (ALDH1A1), acetaldehyde (ALDH2), 4-HNE (ALDH2) and nitroglycerin (ALDH2). file:human/ALDH2/ALDH2-uniprot.txt Vmax=0.2 nmol/min/ug enzyme for the formation of 1,2-dinitroglycerol |
| GO:0051287 NAD binding | ISS PMID:12693930 Crystal structure of eta-crystallin: adaptation of a class 1... | ACCEPT | Summary: Transfer of NAD binding from the eta-crystallin (class 1 ALDH) structure, which resolves the ALDH NAD-binding site. Reason: NAD+ binding is not in doubt for ALDH2. The enzyme is NAD+-dependent, UniProt records a KM of 26 uM for NAD(+) measured on the human protein, and the Alda-1 work solved ALDH2 structures and measured the ligand's effect on the NAD+ Km. The similarity-based route is redundant but correct. Supporting Evidence: PMID:12693930 but also provides a well-ordered NAD binding site structure for this class of enzymes with important roles in development and health file:human/ALDH2/ALDH2-uniprot.txt KM=26 uM for NAD(+) |
| GO:0052814 medium-chain fatty aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea mapping of the 4-hydroxynon-2-enal reaction (RHEA:67248) onto this entry. Reason: Unlike the other by-similarity Rhea rows, this mapping is grounded on direct measurement of the human protein: 4-HNE oxidation was measured with a KM of 0.9 uM at pH 7.4 and ALDH2 is the most efficient human isoform for it. 4-HNE is a nine-carbon hydroxyalkenal and so falls within the term's medium-chain fatty aldehyde scope. Lipid-aldehyde detoxification is a core part of this gene's function. Supporting Evidence: PMID:22339434 among the three most studied human ALDH isoforms, ALDH2 showed the highest catalytic efficiency for oxidation of acrolein, 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde file:human/ALDH2/ALDH2-uniprot.txt KM=0.9 uM for (E)-4-hydroxynon-2-enal (at pH 7.4) |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: ALDH2 was among the 1132 proteins identified by LC-MS/MS in a proteomic survey of human urinary exosomes. Reason: A matrix enzyme of a double-membrane organelle, imported through a cleaved transit peptide, has no established route to or function in secreted vesicles, and detection in a 1132-protein exosome preparation is expected for an abundant cellular protein without establishing a location in which ALDH2 acts. The detection itself is not disputed, which is why the row is flagged rather than removed. Supporting Evidence: PMID:19056867 Overall, the analysis identified 1132 proteins unambiguously, including 177 that are represented on the Online Mendelian Inheritance in Man database of disease-related genes file:human/ALDH2/ALDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16440063, |
| GO:0106435 carboxylesterase activity | IDA PMID:19506075 Role of the general base Glu-268 in nitroglycerin bioactivat... | MARK AS OVER ANNOTATED | Summary: Esterase activity of ALDH2 measured as p-nitrophenolate release from p-nitrophenyl acetate, for wild type and the C302S and E268Q mutants. Reason: The activity is real and mechanistically understood, running through the same catalytic cysteine thioester that the general base hydrolyses, but it was measured on an artificial chromogenic ester and UniProt itself states that its physiological relevance is unclear. Under the promiscuous-activity tiers this is in vitro activity of unknown biological relevance, so the row is flagged rather than accepted as a function or removed. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt It also exhibits esterase activity that is enhanced by NAD+ but does not require it, although the physiological relevance of this activity remains unclear PMID:19506075 The esterase activity is stimulated by NAD, but the co-factor is not essential for the reaction, which is initiated by nucleophilic attack of the substrate by Cys-302, resulting in formation of a thioester and release of the corresponding alcohol by hydrolysis of the intermediate through activation of water by Glu-268 |
| GO:0110095 cellular detoxification of aldehyde | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD of cellular aldehyde detoxification at PTN000192855, seeded by human ALDH2 and rat Aldh2. Reason: The node is tightly scoped to the mitochondrial classical-ALDH branch and seeded by ALDH2 itself together with its rat ortholog, both of which have direct evidence of detoxifying acetaldehyde and lipid-derived aldehydes. The target is inside the clade the function was placed on, and the paint-losses report for this gene lists no IRD or IKR on its lineage. Core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000192855 SUPPORTS TRANSFER Node of the mitochondrial classical ALDHs, seeded by human ALDH2 (expected, not circular) and rat Aldh2. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Mitochondrial aldehyde dehydrogenase with broad substrate specificity which participates in the detoxification of ethanol-derived acetaldehyde and endogenous aldehydes, including those arising from lipid peroxidation PMID:22339434 Aldehyde dehydrogenases (ALDHs) are involved in the detoxification of aldehydes generated as byproducts of lipid peroxidation. |
| GO:0110095 cellular detoxification of aldehyde | IMP PMID:39075523 Uncovering newly identified aldehyde dehydrogenase 2 genetic... | ACCEPT | Summary: Loss-of-function ALDH2 variants cause acetaldehyde accumulation and a two- to threefold rise in reactive oxygen species after alcohol exposure in cells. Reason: The variants reduce the enzyme's own acetaldehyde turnover and the cellular consequence is accumulation of the toxic aldehyde, so ALDH2 carries out the detoxifying step rather than merely being required for it. Core function, consistent with the IBA row on this term. Supporting Evidence: PMID:39075523 Transiently transfected NIH-3T3 cells with R101G and R114W also had a reduced enzymatic activity by ~ 50% relative to transfected wild-type ALDH2 and when subjected to alcohol, the R101G and R114W variants had a 2-3-fold increase in reactive oxygen species formation with respect to wild type ALDH2. PMID:39075523 Accumulation of acetaldehyde, which occurs with inactive ALDH2 variants, results in damage to the electron transport complexes leading to overproduction of ROS |
| GO:0140087 acetaldehyde dehydrogenase (NAD+) activity | IDA PMID:19506075 Role of the general base Glu-268 in nitroglycerin bioactivat... | ACCEPT | Summary: Dehydrogenase activity of purified ALDH2 measured with acetaldehyde as substrate, for wild type and active-site mutants. Reason: The substrate-specific term matching the enzyme's defining activity, measured directly; UniProt carries the acetaldehyde KM of 0.02 uM from this work. Core function. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt KM=0.02 uM for acetaldehyde (at both pH 7.5 and pH 9.5) PMID:19506075 The mitochondrial isoform (ALDH2), a homotetrameric protein with subunits of βΌ54 kDa, appears to be essential for detoxification of ethanol-derived acetaldehyde, as indicated by significantly lowered alcohol tolerance of individuals expressing a low activity mutant of the protein (2, 3). |
| GO:0140087 acetaldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping of the acetaldehyde reaction (RHEA:25294) onto this entry. Reason: The Rhea reaction this maps from is recorded on the human entry with experimental evidence (ECO:0000269, PubMed:19506075 and PubMed:39075523), so the electronic row reproduces a directly measured activity. The ARBA component of the same row adds nothing and is not cited here. Core function, consistent with the IDA and IMP rows on this term. Supporting Evidence: file:human/ALDH2/ALDH2-uniprot.txt Reaction=acetaldehyde + NAD(+) + H2O = acetate + NADH + 2 H(+); file:human/ALDH2/ALDH2-uniprot.txt KM=0.02 uM for acetaldehyde (at both pH 7.5 and pH 9.5) |
| GO:0140087 acetaldehyde dehydrogenase (NAD+) activity | IMP PMID:39075523 Uncovering newly identified aldehyde dehydrogenase 2 genetic... | ACCEPT | Summary: Recombinant R101G and R114W ALDH2 enzymes show reduced acetaldehyde metabolism, through loss of dimer/tetramer formation for R101G and lower Vmax for both, and carriers accumulate acetaldehyde. Reason: Variant enzymology together with the human phenotype establishes the acetaldehyde-specific activity on this protein. Core function, consistent with the other rows on this term. Supporting Evidence: PMID:39075523 In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. PMID:39075523 The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased Vmax for both R101G and R114W. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: GO obsoleted GO:0018547 nitroglycerin reductase activity on the grounds that there was no evidence the specific reaction exists, yet UniProt records two nitroglycerin reactions on ALDH2 with experimental evidence (RHEA:80159, RHEA:80155) and the thionitrate intermediate has been seen crystallographically. Should a nitrate-ester reductase term be created, and if not, is GO:0046857 the intended home for this chemistry?
Suggested experts: GO molecular function ontology editors, ALDH2 nitroglycerin pharmacology groups
Q: Is the NAD+-stimulated esterase activity of ALDH2 physiologically relevant, that is, is there a biological carboxylic ester that ALDH2 hydrolyses in the mitochondrial matrix, or is it only a consequence of the thioester mechanism probed with p-nitrophenyl acetate?
Suggested experts: ALDH enzymology groups
Q: Does human ALDH2 contribute measurably in vivo to the reactions currently annotated only by similarity to rodent ALDH2, namely succinate-semialdehyde and 4-aminobutanal oxidation, given that ALDH5A1 and ALDH9A1 are the dedicated human enzymes?
Suggested experts: GABA and polyamine metabolism groups
Experiment: Measure formaldehyde-derived formate production and DNA-damage markers in isogenic ADH5-null cells carrying wild-type, E504K or catalytically dead (C319A) ALDH2, with and without mitochondrially targeted formaldehyde generation, and determine formaldehyde kinetic constants on the purified enzyme.
Hypothesis: The weak formaldehyde dehydrogenase activity of ALDH2 is a genuine second line of formaldehyde defence rather than incidental turnover, and its contribution scales with matrix formaldehyde load.
Type: Genetic complementation plus enzyme kinetics
Experiment: Determine kcat/KM of purified human ALDH2 for all-trans-retinal, succinate semialdehyde and 4-aminobutanal side by side with ALDH1A1, ALDH5A1 and ALDH9A1 under matched conditions, and report the ratios.
Hypothesis: The substrate-specific activities currently assigned to human ALDH2 only by similarity to rodent ALDH2, namely retinal, succinate semialdehyde and 4-aminobutanal oxidation, are negligible relative to the dedicated human enzymes.
Type: Comparative steady-state enzymology
Experiment: Compare ALDH2 half-life and turnover in cells after 4-HNE or acrolein exposure in wild-type versus LONP1- and CLPP-depleted backgrounds, using pulse-chase and degradation assays on the mature matrix form.
Hypothesis: ALDH2 is a physiological substrate of mitochondrial matrix quality control (LONP1 and CLPXP) once inactivated by its own aldehyde substrates, which would make the Reactome substrate rows a real regulatory mechanism rather than a bystander observation.
Type: Protein turnover and degradation assay
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)