Aldh2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004029 aldehyde dehydrogenase (NAD+) activity	IDA PMID:3996732 Mouse mitochondrial aldehyde dehydrogenase isozymes: purific...	ACCEPT	Summary: Direct enzymatic assay of purified mouse mitochondrial ALDH isozyme AHD-5 (=Aldh2) demonstrated aldehyde dehydrogenase activity with very low Km for acetaldehyde (0.2 µM), confirming it as the high-affinity mitochondrial acetaldehyde-oxidizing enzyme. Reason: Core enzymatic function directly demonstrated by purification and kinetic characterization. Supporting Evidence: PMID:3996732 AHD-5 exhibited a low Km value with acetaldehyde of 0.2 microM.
GO:0005759 mitochondrial matrix	IDA PMID:3996732 Mouse mitochondrial aldehyde dehydrogenase isozymes: purific...	ACCEPT	Summary: Aldh2 (AHD-5) was purified from mouse liver mitochondrial extracts, directly demonstrating mitochondrial localization. Reason: Core subcellular localization directly demonstrated by subcellular fractionation and enzyme purification. Supporting Evidence: PMID:3996732 Aldehyde dehydrogenase isozymes (AHD-1 and AHD-5) have been isolated in a highly purified state from extracts of mouse liver mitochondria.
GO:0006068 ethanol catabolic process	IMP PMID:19356968 Ethanol metabolism in ALDH2 knockout mice--blood acetate lev...	ACCEPT	Summary: ALDH2 knockout mice showed significantly higher blood ethanol and acetaldehyde levels and lower blood acetate levels after ethanol dosing, confirming Aldh2 is required for normal ethanol catabolism (acetaldehyde to acetate conversion). Reason: Core biological process directly demonstrated by knockout mouse phenotype. Supporting Evidence: PMID:19356968 We found that blood acetate levels in ALDH2 KO mice were slightly lower than those in wild type (WT), whereas EtOH and AcH levels in ALDH2 KO were significantly higher than those in WT
GO:1903179 regulation of dopamine biosynthetic process	IMP PMID:26711020 Ethanol and acetaldehyde differentially alter extracellular ...	MARK AS OVER ANNOTATED	Summary: The paper measured extracellular dopamine levels in Aldh2-KO mouse dorsal striatum by microdialysis after acetaldehyde perfusion, not dopamine biosynthesis per se. Acetaldehyde decreased extracellular DA in KO but not WT mice, but this is an indirect consequence of acetaldehyde accumulation due to Aldh2 loss, not a direct role of Aldh2 in dopamine biosynthesis regulation. Reason: The observed effect on dopamine levels is an indirect consequence of acetaldehyde accumulation in Aldh2-deficient mice, not a direct enzymatic or regulatory function of Aldh2 in dopamine biosynthesis. The paper measured extracellular levels, not biosynthetic rate.
GO:1905627 regulation of serotonin biosynthetic process	IMP PMID:26711020 Ethanol and acetaldehyde differentially alter extracellular ...	MARK AS OVER ANNOTATED	Summary: Similarly to the dopamine annotation, the paper showed acetaldehyde decreased extracellular 5-HT in Aldh2-KO but not WT mice. This reflects indirect neurotoxic effects of acetaldehyde accumulation, not a direct role of Aldh2 in serotonin biosynthesis. Reason: Indirect consequence of acetaldehyde accumulation in knockout mice, not a direct function of Aldh2 in serotonin biosynthesis regulation.
GO:0005515 protein binding	IPI PMID:21720390 SIRT3-dependent deacetylation exacerbates acetaminophen hepa...	REMOVE	Summary: The paper showed ALDH2 is a direct SIRT3 substrate whose deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. While the physical interaction with SIRT3 is real, the generic protein binding term is uninformative per curation guidelines. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative. The interaction reflects ALDH2 being a SIRT3 deacetylase substrate, which is better captured by annotations on SIRT3 itself. No specific binding activity of ALDH2 is demonstrated. Supporting Evidence: PMID:21720390 We show that mitochondrial deacetylase SIRT3(-/-) mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation
GO:0005739 mitochondrion	HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise...	ACCEPT	Summary: Aldh2 was detected in the mitochondrial proteome by mass spectrometry in the MitoCarta compendium across multiple mouse tissues. Reason: Consistent with core mitochondrial localization. More specific IDA localization to mitochondrial matrix is also available. Supporting Evidence: PMID:18614015 Mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues.
GO:0005739 mitochondrion	HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity...	ACCEPT	Summary: Aldh2 was detected in the mouse mitochondrial proteome by mass spectrometry across brain, heart, kidney, and liver. Reason: Consistent with core mitochondrial localization confirmed by multiple independent studies. Supporting Evidence: PMID:14651853 To explore its molecular composition, we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver and combined the results with existing gene annotations to produce a list of 591 mitochondrial proteins, including 163 proteins not previously associated with this organelle
GO:0004029 aldehyde dehydrogenase (NAD+) activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred aldehyde dehydrogenase activity, consistent with direct experimental evidence (IDA from PMID:3996732). Reason: Core enzymatic function confirmed by direct experimental evidence.
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred mitochondrial localization, consistent with direct evidence (IDA, HDA). Reason: Core localization confirmed by multiple experimental approaches.
GO:0006067 ethanol metabolic process	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetically inferred involvement in ethanol metabolism is directionally correct, but the supported mouse function is specifically ethanol catabolism through oxidation of acetaldehyde to acetate. Reason: Ethanol metabolic process is broader than the established catabolic role; GO:0006068 better captures the second step of ethanol degradation demonstrated in Aldh2 knockout mice. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000192855 SUPPORTS TRANSFER The aldehyde dehydrogenase node correctly places mouse Aldh2 in the ethanol-oxidation branch; the transfer is sound and only the breadth of the term is at issue. RGD:69219 · rat Aldh2 SUPPORTS TRANSFER The single rodent seed is the direct rat ortholog. A short donor list is not weak support here: the ALDH2 acetaldehyde-oxidation step is one of the best characterised reactions in the family, and the seed states the same biology as the target. Proposed replacements: ethanol catabolic process Supporting Evidence: PMID:19356968 These observations indicate that high EtOH, AcH and low acetate in the blood of ALDH2 KO are due to the deficient effect of ALDH2 enzyme activity. file:mouse/Aldh2/Aldh2-deep-research-falcon.md ALDH2 is described as the second enzyme in oxidative alcohol metabolism, converting acetaldehyde to acetic acid, and is also capable of oxidizing lipid aldehydes including acrolein (ACR), 4-HNE, and MDA.
GO:0046185 aldehyde catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in aldehyde catabolism, consistent with core ALDH2 enzymatic function. Reason: Core biological process directly related to primary enzymatic function.
GO:0110095 cellular detoxification of aldehyde	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred role in aldehyde detoxification, consistent with UniProt annotation that Aldh2 is required for clearance of cellular formaldehyde. Reason: Core detoxification function of ALDH2. Supporting Evidence: UniProtKB:P47738 Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage. file:mouse/Aldh2/Aldh2-deep-research-falcon.md 4-HNE and acrolein are explicitly cited as aldehydes metabolized/detoxified by ALDH2 in kidney and metabolic disease contexts.
GO:0004029 aldehyde dehydrogenase (NAD+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronically inferred ALDH activity from ortholog mapping, redundant with IDA evidence. Reason: Consistent with core function confirmed by direct evidence.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: Electronically inferred from UniProt subcellular location vocabulary, consistent with IDA evidence. Reason: Core localization confirmed by direct evidence.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000002	MODIFY	Summary: Generic oxidoreductase activity inferred from InterPro domain. This is a parent term of the more specific GO:0004029 (aldehyde dehydrogenase (NAD+) activity) which is already well-annotated with direct evidence. Reason: The broad oxidoreductase parent term should be replaced by the directly supported NAD+-dependent aldehyde dehydrogenase activity. Proposed replacements: aldehyde dehydrogenase (NAD+) activity Supporting Evidence: PMID:3996732 AHD-5 exhibited a low Km value with acetaldehyde of 0.2 microM. UniProtKB:P47738 Reaction=an aldehyde + NAD(+) + H2O = a carboxylate + NADH + 2 H(+)
GO:0006068 ethanol catabolic process	IEA GO_REF:0000041	ACCEPT	Summary: Electronically inferred from UniPathway, consistent with IMP evidence from ALDH2 knockout studies. Reason: Core biological process confirmed by direct evidence.
GO:0018937 nitroglycerin metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred from human ALDH2. Nitroglycerin bioactivation is a pharmacological activity of ALDH2, not a primary physiological function. Reason: Secondary pharmacological activity, not the primary physiological function of Aldh2.
GO:0046185 aldehyde catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Electronically transferred aldehyde catabolism, consistent with core function. Reason: Core biological process.
GO:0106435 carboxylesterase activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronically transferred carboxylesterase activity. This is a secondary catalytic activity of ALDH2 distinct from its primary dehydrogenase function. Reason: Secondary enzymatic activity, not the primary physiological function.
GO:0004029 aldehyde dehydrogenase (NAD+) activity	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human ALDH2, consistent with direct mouse evidence. Reason: Core function confirmed by IDA.
GO:0018937 nitroglycerin metabolic process	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human ALDH2. Pharmacological activity, not primary function. Reason: Secondary pharmacological activity.
GO:0046185 aldehyde catabolic process	ISO GO_REF:0000119	ACCEPT	Summary: ISO from human ALDH2, consistent with core function. Reason: Core biological process.
GO:0106435 carboxylesterase activity	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO from human ALDH2. Secondary catalytic activity. Reason: Secondary enzymatic activity.
GO:0004029 aldehyde dehydrogenase (NAD+) activity	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat Aldh2, consistent with direct mouse evidence. Reason: Core function confirmed by IDA.
GO:0005759 mitochondrial matrix	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat Aldh2, consistent with direct mouse evidence. Reason: Core localization confirmed by IDA.
GO:0006117 acetaldehyde metabolic process	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat Aldh2. Acetaldehyde is the primary physiological substrate of Aldh2 in the ethanol degradation pathway. Consistent with knockout data showing acetaldehyde accumulation in Aldh2-/- mice. Reason: Core biological process directly linked to primary enzymatic function.
GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. ALDH2 can protect against oxidative stress-induced apoptosis by detoxifying reactive aldehydes (e.g., 4-HNE), but apoptotic signaling is a downstream consequence rather than a core function of the enzyme. Reason: Downstream protective effect of aldehyde detoxification, not a core enzymatic function.
GO:0042802 identical protein binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. ALDH2 functions as a homotetramer, consistent with identical protein binding. Reason: Homotetramerization is supported by UniProt and ALDH-family structural evidence, but identical protein binding is a quaternary-structure annotation rather than Aldh2's core catalytic function. Supporting Evidence: UniProtKB:P47738 SUBUNIT: Homotetramer.
GO:0043066 negative regulation of apoptotic process	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. Anti-apoptotic effect is secondary to the aldehyde detoxification function. Reason: Downstream protective effect, not a core enzymatic function.
GO:0048149 behavioral response to ethanol	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. Behavioral effects of ethanol are modulated by acetaldehyde levels, which depend on ALDH2 activity. This is an organism-level phenotypic consequence rather than a molecular or cellular function. Reason: Organism-level behavioral consequence of aldehyde metabolism, not a core molecular function.
GO:0070404 NADH binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. ALDH2 uses NAD+ as cofactor and produces NADH during catalysis. While NADH binding during product release is valid, the more relevant annotation is NAD binding (GO:0051287) which captures the cofactor requirement. Reason: NADH is the product of the reaction; NAD+ binding as cofactor (GO:0051287) is more functionally informative.
GO:0110095 cellular detoxification of aldehyde	ISO GO_REF:0000096	ACCEPT	Summary: ISO from rat Aldh2, consistent with core detoxification function. Reason: Core biological process of Aldh2.
GO:2000377 regulation of reactive oxygen species metabolic process	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO from rat Aldh2. By detoxifying reactive aldehydes that can amplify oxidative stress, ALDH2 indirectly modulates ROS metabolism. This is a secondary consequence of the primary detoxification function. Reason: Indirect effect of aldehyde detoxification on oxidative stress, not a direct enzymatic function.
GO:0018937 nitroglycerin metabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from human ALDH2. Pharmacological activity. Reason: Secondary pharmacological activity.
GO:0106435 carboxylesterase activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from human ALDH2. Secondary enzymatic activity. Reason: Secondary enzymatic activity.
GO:0008957 phenylacetaldehyde dehydrogenase (NAD+) activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS-based annotation for activity toward phenylacetaldehyde. ALDH2 can oxidize various aldehyde substrates including phenylacetaldehyde, but this represents substrate promiscuity rather than a distinct core function. Reason: Reflects broad substrate specificity of the aldehyde dehydrogenase, not a distinct core function.
GO:0004029 aldehyde dehydrogenase (NAD+) activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS from human ALDH2, consistent with core function. Reason: Core enzymatic function confirmed by IDA.
GO:0046185 aldehyde catabolic process	ISS GO_REF:0000024	ACCEPT	Summary: ISS from human ALDH2, consistent with core biological process. Reason: Core biological process.
GO:0051287 NAD binding	ISS PMID:12693930 Crystal structure of eta-crystallin: adaptation of a class 1...	ACCEPT	Summary: ISS based on structural comparison with eta-crystallin (a class 1 ALDH). The crystal structure shows a well-ordered NAD binding site conserved across class 1 and 2 ALDHs. NAD+ is the essential cofactor for ALDH2 catalysis. Reason: Core cofactor binding required for enzymatic function. Supporting Evidence: PMID:12693930 It has a better-defined NAD binding site than those of related mammalian ALDH1 enzymes with the cofactor bound in the "hydride transfer" position in all four monomers with small differences about the dimer dyads

Gene Description

Existing Annotations Review

Core Functions

NAD+-dependent oxidation of aldehydes to carboxylic acids, with highest affinity for acetaldehyde among the mouse mitochondrial isozymes tested (Km 0.2 µM). This is the primary catalytic function of the enzyme.

Catalyzes the second and final step of the ethanol degradation pathway, oxidizing acetaldehyde to acetate using NAD+ as cofactor.

Detoxifies cytotoxic and reactive aldehydes including formaldehyde and lipid peroxidation-derived aldehydes, protecting cells from aldehyde-induced damage.

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