ALDH3A1 encodes aldehyde dehydrogenase 3A1, a homodimeric cytosolic class 3 aldehyde dehydrogenase that oxidizes aldehydes to carboxylic acids using NAD+ or NADP+. It prefers medium- and long-chain saturated and unsaturated aliphatic aldehydes, including the lipid-peroxidation product 4-hydroxy-2-nonenal, and aromatic aldehydes such as benzaldehyde, and is a poor enzyme for short-chain aldehydes. ALDH3A1 is very abundant in the stomach, the upper airways and above all the corneal epithelium, where it is a corneal crystallin. There it protects against UV-induced damage both by detoxifying peroxidic aldehydes and by directly absorbing UV light. It is also found in nasal mucus and tears, where it oxidizes aldehyde odorants, and it inactivates oxazaphosphorine anticancer drugs, contributing to chemoresistance. Expressed in yeast, human ALDH3A1 can substitute for the Hfd1 4-hydroxybenzaldehyde dehydrogenase in coenzyme Q precursor synthesis, although a role in human CoQ biosynthesis has not been shown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004028 3-chloroallyl aldehyde dehydrogenase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA 3-chloroallyl aldehyde dehydrogenase activity from the euteleostome ALDH3 node PTN002882967 (rodent Aldh3 seeds). Reason: The term names a microbial xenobiotic-degradation reaction (3-chloroallyl aldehyde to 3-chloroacrylate). No measurement of this substrate on human ALDH3A1 is in the literature reviewed; a broad-specificity aliphatic ALDH may well oxidize it in vitro, but the term describes no known physiological activity of ALDH3A1. The general aldehyde dehydrogenase rows already describe the activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002882967 SOURCE WEAK OR INFERRED Euteleostome ALDH3 node seeded by rodent Aldh3 annotations; the 3-chloroallyl aldehyde reaction is a microbial xenobiotic substrate with no measurement on human ALDH3A1, so the specific term overstates the broad aldehyde activity the clade shares. Supporting Evidence: PMID:12943535 Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal file:human/ALDH3A1/ALDH3A1-uniprot.txt Cytosolic aldehyde dehydrogenase that catalyzes the oxidation |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA aldehyde dehydrogenase (NAD+) activity from the ALDH3 node PTN008111916. Reason: Core activity of a broad-specificity aldehyde dehydrogenase; ALDH3A1 is a member and seed of the node and its own NAD+-dependent activity is measured. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt Cytosolic aldehyde dehydrogenase that catalyzes the oxidation file:human/ALDH3A1/ALDH3A1-uniprot.txt preferentially using NAD+ but also accepting NADP+ as cofactor |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:12706498 Aldh3a1 protects human corneal epithelial cells from ultravi... | ACCEPT | Summary: Pappa et al. 2003: ALDH3A1-transfected corneal cells oxidize 4-HNE and raise NAD(P)H levels. Reason: Direct activity measurement in cells; consistent with the other rows for the same term. Supporting Evidence: PMID:12706498 The Michaelis-Menten constant (K(m)) for 4-HNE was 54 microM in ALDH3A1-transfected cells |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:1737758 Human stomach aldehyde dehydrogenase cDNA and genomic clonin... | ACCEPT | Summary: Hsu et al. 1992: recombinant ALDH3 expressed in E. coli has the kinetic properties of the stomach enzyme. Reason: Direct activity of the recombinant human enzyme; core. Supporting Evidence: PMID:1737758 Expression of ALDH3 cDNA in Escherichia coli yielded a protein of 55 kDa, which exhibited kinetic properties similar to that found in ALDH3 isozyme purified from human stomach and liver |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:22339434 Differences in susceptibility to inactivation of human aldeh... | ACCEPT | Summary: Yoval-Sanchez and Rodriguez-Zavala 2012: ALDH3A1 oxidizes 4-HNE and resists inactivation by lipid-peroxidation aldehydes. Reason: Direct activity measurement with a physiological lipid-peroxidation substrate; core. Supporting Evidence: PMID:22339434 ALDH3A1 only showed activity with 4-HNE |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA (RHEA:16185, mouse ortholog). Reason: Consistent with the experimental rows for the same term. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt Cytosolic aldehyde dehydrogenase that catalyzes the oxidation |
| GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity | IDA PMID:12943535 Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical char... | ACCEPT | Summary: Pappa et al. 2003 (corneal ALDH3A1): purified recombinant enzyme oxidizes medium-chain aldehydes with NAD(P)+. Reason: Direct activity; UniProt records NADP+ use from this paper. ALDH3A1 uses both NAD+ and NADP+. Supporting Evidence: PMID:12943535 Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal file:human/ALDH3A1/ALDH3A1-uniprot.txt preferentially using NAD+ but also accepting NADP+ as cofactor |
| GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity | IDA PMID:1737758 Human stomach aldehyde dehydrogenase cDNA and genomic clonin... | ACCEPT | Summary: Hsu et al. 1992: recombinant ALDH3 activity with NAD(P)+. Reason: Direct activity; consistent with the other rows for the same term. Supporting Evidence: PMID:1737758 Expression of ALDH3 cDNA in Escherichia coli yielded a protein of 55 kDa, which exhibited kinetic properties similar to that found in ALDH3 isozyme purified from human stomach and liver file:human/ALDH3A1/ALDH3A1-uniprot.txt preferentially using NAD+ but also accepting NADP+ as cofactor |
| GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA from EC 1.2.1.5. Reason: EC 1.2.1.5 is the NAD(P)+-dependent aldehyde dehydrogenase; consistent with the experimental rows. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt preferentially using NAD+ but also accepting NADP+ as cofactor |
| GO:0004030 aldehyde dehydrogenase [NAD(P)+] activity | TAS Reactome:R-HSA-5692283 | ACCEPT | Summary: Reactome TAS: ALDH3A1 oxidises 4-hydroperoxycyclophosphamide (R-HSA-5692283). Reason: Correct activity; the drug substrate is one of many aldehydes the enzyme oxidizes. Supporting Evidence: Reactome:R-HSA-5692283 Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in cancer chemo-resistance by oxidising activated forms of oxazaphosphorine drugs |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: Genome-wide BiFC telomere interactome screen: ALDH3A1 with POT1. Reason: Bare protein binding from a fluorescence-complementation screen; uninformative under the protein-binding policy and with no known functional relevance. Supporting Evidence: PMID:21044950 Telomere Interactome, built upon the six core telomeric proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary Y2H interaction of ALDH3A1 with UniProtKB:O75344. Reason: Bare protein binding from a proteome-scale Y2H screen; uninformative under the protein-binding policy. Supporting Evidence: PMID:32296183 yeast two-hybrid (Y2H) represents the only binary PPI assay that can be operated at sufficient throughput to systematically screen the human proteome for binary PPIs |
| GO:0005576 extracellular region | HDA PMID:22664934 Comparison of tear protein levels in breast cancer patients ... | KEEP AS NON CORE | Summary: Tear-fluid proteomics detected ALDH3A in human tears. Reason: Direct detection, consistent with ALDH3A1 release into mucosal secretions (nasal mucus, tears) despite lacking a signal peptide; peripheral to its intracellular role. Supporting Evidence: PMID:22664934 different metabolic cascades (ALDH3A or TPI) PMID:36966166 AKR1B10 as ALDH1A1 and ALDH3A1 also lack the conventional signal peptide at the N terminus |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytoplasm from the ALDH3 node PTN008111916. Reason: Correct for this soluble cytosolic enzyme; ALDH3A1 is a member and seed of the node. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA cytoplasm (SubCell SL-0086, mouse ortholog). Reason: Consistent with the experimental cytosol rows. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS cytoplasm from mouse Aldh3a1 (P47739). Reason: Consistent with the experimental cytosol rows. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | MARK AS OVER ANNOTATED | Summary: HPA/UniProt localization of an expressed fusion protein to the endoplasmic reticulum (GO_REF:0000054). Reason: Direct imaging, but of an expressed fusion protein. ALDH3A1 is a soluble enzyme with no signal peptide or membrane anchor, all other evidence places endogenous ALDH3A1 in the cytosol, and no ER function is known. A location resting only on an over-expressed fusion is an over-annotation (projects/ORGANELLES.md rule 7). Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localization to the cytosol (GO_REF:0000052). Reason: Consistent with the other cytosol rows. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | IDA PMID:12706498 Aldh3a1 protects human corneal epithelial cells from ultravi... | ACCEPT | Summary: Pappa et al. 2003 (HCE cells): cytosolic ALDH3A1 activity. Reason: Consistent with the other cytosol rows. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:12706498 The Michaelis-Menten constant (K(m)) for 4-HNE was 54 microM in ALDH3A1-transfected cells |
| GO:0005829 cytosol | IDA PMID:12943535 Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical char... | ACCEPT | Summary: Pappa et al. 2003 (cornea): UniProt cites this paper for the cytosol location. Reason: Curated cytosolic location from this paper; core location. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of cytosol from mouse. Reason: Consistent with the experimental rows for the same term. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: ISS cytosol from rat Aldh3a1 (P11883). Reason: Consistent with the experimental rows for the same term. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5692283 | ACCEPT | Summary: Reactome TAS cytosol for the oxazaphosphorine oxidation reaction. Reason: Consistent with the experimental rows for the same term. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0006081 aldehyde metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA aldehyde metabolic process from PTN008111916 (ALDH3 node, including human ALDH3A1 and yeast HFD1). Reason: ALDH3A1 oxidizes a broad range of aliphatic and aromatic aldehydes, so the general process is an accurate description; the detoxification row adds the physiological context. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt Cytosolic aldehyde dehydrogenase that catalyzes the oxidation PMID:12943535 Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal |
| GO:0006081 aldehyde metabolic process | IDA PMID:1737758 Human stomach aldehyde dehydrogenase cDNA and genomic clonin... | ACCEPT | Summary: Hsu et al. 1992: ALDH3 may oxidize toxic aldehydes. Reason: Direct activity data support the broad aldehyde metabolism term; consistent with the IBA row. Supporting Evidence: PMID:1737758 may play a role in the oxidation of toxic aldehydes PMID:1737758 Expression of ALDH3 cDNA in Escherichia coli yielded a protein of 55 kDa, which exhibited kinetic properties similar to that found in ALDH3 isozyme purified from human stomach and liver |
| GO:0006081 aldehyde metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA (ARBA, InterPro IPR012394 ALDH3 family). Reason: Consistent with the experimental and IBA rows for the same term. Supporting Evidence: PMID:12943535 Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal |
| GO:0006805 xenobiotic metabolic process | TAS Reactome:R-HSA-211945 | KEEP AS NON CORE | Summary: Reactome TAS: Phase I functionalization of compounds (oxidation of activated oxazaphosphorine drugs). Reason: ALDH3A1 directly oxidizes 4-hydroperoxycyclophosphamide-derived aldophosphamide, so it does part of the work of xenobiotic metabolism, but this pharmacological role (chemoresistance) is peripheral to its role in endogenous aldehyde detoxification. Supporting Evidence: Reactome:R-HSA-5692283 Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in cancer chemo-resistance by oxidising activated forms of oxazaphosphorine drugs |
| GO:0009650 UV protection | IDA PMID:17158879 Mechanisms involved in the protection of UV-induced protein ... | ACCEPT | Summary: Estey et al. 2007: ALDH3A1 protects other proteins from UVB inactivation by directly absorbing UV energy, as a corneal crystallin. Reason: ALDH3A1 itself does the work of UV protection in the cornea, both by absorbing UV and by removing UV-generated aldehydes; a genuine, tissue-specific core role. Supporting Evidence: PMID:17158879 ALDH3A1 can reduce protein inactivation and/or aggregation not only by detoxification of reactive aldehydes but also by directly absorbing UV energy PMID:17158879 mechanistic evidence supporting the structural role of the corneal crystallin ALDH3A1 as a UV-absorbing constituent of the cornea |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA membrane from the ALDH3 node PTN008111916, whose seeds include membrane-anchored ALDH3A2 and yeast HFD1. Reason: The membrane location at this node derives from the C-terminally anchored members (ALDH3A2, HFD1). ALDH3A1 lacks that anchor and is a soluble cytosolic and secreted enzyme. The only membrane-related observation is an expressed-fusion ER call, so for this member the propagated membrane term overstates the evidence. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN008111916 SUPPORTS SOURCE BUT NOT TARGET The membrane location is right for C-terminally anchored members (ALDH3A2, yeast HFD1) but not for ALDH3A1, which lacks the anchor and is soluble and cytosolic or secreted. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol file:human/ALDH3A1/ALDH3A1-uniprot.txt Secreted {ECO:0000305|PubMed:36966166} |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of membrane from mouse Aldh3a1. Reason: Same over-statement as the IBA row: ALDH3A1 is a soluble cytosolic enzyme without a membrane anchor. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro2GO oxidoreductase activity (ALDH domain). Reason: True but entailed by the accepted aldehyde dehydrogenase (NAD+) and NAD(P)+ activities. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt Cytosolic aldehyde dehydrogenase that catalyzes the oxidation |
| GO:0016620 oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor | IEA GO_REF:0000120 | TOO GENERAL | Summary: UniProt combined IEA for oxidoreductase acting on aldehyde with NAD or NADP. Reason: True but entailed by the accepted aldehyde dehydrogenase [NAD(P)+] activity (GO:0004030). Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt preferentially using NAD+ but also accepting NADP+ as cofactor |
| GO:0018477 benzaldehyde dehydrogenase (NADP+) activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of benzaldehyde dehydrogenase (NADP+) from mouse. Reason: UniProt records the benzaldehyde + NADP+ reaction for human ALDH3A1; benzaldehyde is the classic ALDH3 substrate. Supporting Evidence: file:human/ALDH3A1/ALDH3A1-uniprot.txt Reaction=benzaldehyde + NADP(+) + H2O = benzoate + NADPH + 2 H(+) PMID:4015840 One isozyme, designated ALDH3, which is very active against benzaldehyde |
| GO:0018479 benzaldehyde dehydrogenase (NAD+) activity | IDA PMID:4015840 Biochemical genetic analysis of human and rodent aldehyde de... | ACCEPT | Summary: Hopkinson et al. 1985: the ALDH3 isozyme is very active against benzaldehyde. Reason: Direct biochemical characterization of the human isozyme; benzaldehyde is a defining ALDH3 substrate. Supporting Evidence: PMID:4015840 One isozyme, designated ALDH3, which is very active against benzaldehyde |
| GO:0052814 medium-chain fatty aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea2GO mapping of RHEA:44100 (medium-chain aldehyde oxidation with NAD+). Reason: Core: ALDH3A1 has high specificity for medium-chain (C6 and longer) aldehydes, including octanal oxidation shown structurally. Supporting Evidence: PMID:12943535 Human ALDH3A1 demonstrated high substrate specificity for medium-chain (6 carbons and more) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal PMID:36966166 ALDH3A1 catalyzes the oxidation of octanal to octanoic acid |
| GO:0070701 mucus layer | IDA PMID:36966166 Characterization of human oxidoreductases involved in aldehy... | KEEP AS NON CORE | Summary: Robert-Hazotte et al. 2023: ALDH3A1 is among the most highly expressed oxidoreductases in human nasal mucus near the olfactory cleft. Reason: Direct detection in the extracellular mucus layer, where it oxidizes aldehyde odorants; a real but peripheral location. Supporting Evidence: PMID:36966166 we characterized the most highly expressed members of these families in the human nasal mucus sampled in the olfactory vicinity PMID:36966166 Recombinant enzymes corresponding to three highly expressed human oxidoreductases (ALDH1A1, ALDH3A1, AKR1B10) were used to demonstrate the high enzymatic activity of these enzymes toward aldehyde odorants |
| GO:0110095 cellular detoxification of aldehyde | IDA PMID:12706498 Aldh3a1 protects human corneal epithelial cells from ultravi... | ACCEPT | Summary: Pappa et al. 2003: ALDH3A1 protects corneal epithelial cells from 4-HNE toxicity and prevents 4-HNE protein adducts. Reason: ALDH3A1 itself oxidizes 4-HNE, so it performs the detoxification; core process. Supporting Evidence: PMID:12706498 Cells transfected with ALDH3A1 were more resistant to UV- and 4-HNE-induced cytotoxicity than mock-transfected cells PMID:12706498 ALDH3A1 expression prevented 4-HNE-induced protein adduct formation |
| GO:0110095 cellular detoxification of aldehyde | IDA PMID:17158879 Mechanisms involved in the protection of UV-induced protein ... | ACCEPT | Summary: Estey et al. 2007: ALDH3A1 reduces 4-HNE and malondialdehyde inactivation of G6PD when NADP+ is present. Reason: Consistent with the other row for the same term; core. Supporting Evidence: PMID:17158879 ALDH3A1 can reduce protein inactivation and/or aggregation not only by detoxification of reactive aldehydes but also by directly absorbing UV energy |
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Download this section (compressed HTML)Q: ALDH3A1 is a corneal crystallin that also protects by directly absorbing UV energy (PMID:17158879). GO has no molecular-function term for a non-catalytic UV-absorbing structural role in the cornea (structural constituent of eye lens is lens-specific). Should one be created, or is UV protection as a process the right representation?
Q: Human ALDH3A1 rescues the CoQ deficiency of yeast hfd1 mutants (PMID:27693056). Does ALDH3A1, or another ALDH, supply 4-hydroxybenzoate for CoQ10 synthesis in human cells, and are ALDH3A1 variants found in patients with unexplained CoQ10 deficiency?
Experiment: Measure 4-hydroxybenzaldehyde oxidation kinetics of purified ALDH3A1 and CoQ10 synthesis from labelled tyrosine in ALDH3A1-knockout human cells (with ALDH3A2 and ALDH1 family members as comparators).
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