ALDH7A1 (antiquitin) is a homomeric NAD+-dependent aldehyde dehydrogenase. It oxidizes alpha-aminoadipic semialdehyde (AASA), which equilibrates with delta-1-piperideine-6-carboxylate (P6C), to alpha-aminoadipate in L-lysine degradation. Mitochondrial and cytosolic forms are characterized, with an additional nuclear pool. The enzyme also oxidizes medium-chain and lipid-peroxidation-derived aldehydes and can use betaine aldehyde as a substrate. Stress-regulated membrane recruitment supports local NADH production: at Golgi membranes NADH inhibits BARS-dependent carrier fission, and membrane ALDH7A1 supports AIFM2/FSP1-mediated ferroptosis protection while also consuming reactive aldehydes. ALDH7A1 supplies NADH and promotes FSP1 recruitment; FSP1 performs quinone reduction. Human enzyme structures and solution studies connect active tetramer formation to catalysis. Biallelic pathogenic variants impair AASA oxidation to varying degrees, causing substrate accumulation and pyridoxine-dependent epilepsy associated with P6C-mediated inactivation of pyridoxal phosphate.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi membrane recruitment supports local NADH generation. Reason: The SL-0134 mapping agrees with the Golgi-membrane reconstitution and recruitment experiments in PMID:31492851. At this site ALDH7A1 performs aldehyde oxidation, generating NADH that inhibits BARS-dependent carrier fission. Conditional recruitment is part of this supported catalytic role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0134 SUPPORTS TRANSFER This UniProt subcellular-location source agrees with the corresponding curated protein location and human-protein experimental evidence; the action distinguishes core catalytic locations from the additional nuclear pool. Supporting Evidence: PMID:31492851 simply incubating recombinant ALDH7A1 with Golgi membrane results in this NAD being converted to NADH |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: ALDH7A1 oxidizes several aldehydes using NAD+. Reason: The combined InterPro, Rhea and EC mapping captures the experimentally measured substrate breadth. AASA oxidation, medium-chain aldehyde turnover and reactive-aldehyde consumption support this broad catalytic assertion alongside more specific activities. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR044638 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:16185 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:67252 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. EC:1.2.1.3 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | ACCEPT | Summary: ALDH7A1 catalyzes AASA oxidation in lysine degradation. Reason: The EC 1.2.1.31/Rhea:12308 mapping matches the human enzyme reaction and patient and purified-protein studies. Experiments discussed here use NAD+; the accepted GO term includes NAD(P)+ and does not require both cofactors to be used. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:12308 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. EC:1.2.1.31 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. PMID:16491085 these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A nuclear pool is supported in human endothelial cells. Reason: The subcellular-location mapping is corroborated by endogenous staining of human HUVECs in PMID:20207735 Figure 4B. This is a genuine additional pool; a distinct nuclear catalytic process is not established by that localization assay. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER This UniProt subcellular-location source agrees with the corresponding curated protein location and human-protein experimental evidence; the action distinguishes core catalytic locations from the additional nuclear pool. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: The targeting-sequence-containing form localizes to mitochondria. Reason: The SL-0173 mapping agrees with human hALDH7A1_v1 localization in transfected CHO cells and independent human-cell localization evidence. Retain the organelle resolution of the assertion; the targeting sequence does not itself establish a particular submitochondrial membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0173 SUPPORTS TRANSFER This UniProt subcellular-location source agrees with the corresponding curated protein location and human-protein experimental evidence; the action distinguishes core catalytic locations from the additional nuclear pool. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosolic ALDH7A1 supports aldehyde metabolism and membrane recruitment. Reason: The SL-0091 mapping agrees with the human protein localization literature and supported cytosolic HPA staining. The cytosolic pool supplies the enzyme recruited to membranes during the directly characterized NADH-generating response. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0091 SUPPORTS TRANSFER This UniProt subcellular-location source agrees with the corresponding curated protein location and human-protein experimental evidence; the action distinguishes core catalytic locations from the additional nuclear pool. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria PMID:31492851 hypoxia and starvation, conditions that activate AMPK phosphorylation of ALDH7A1, enhance the membrane distribution of ALDH7A1 |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: A membrane-associated pool acts in aldehyde oxidation and redox protection. Reason: UniProt maps the experimentally curated cell-membrane location to plasma membrane. The membrane catalytic role is supported by PMID:31492851 and PMID:40233740. Retain the curated plasma-membrane assignment while distinguishing it from the total-membrane fractionation read independently in the latter study. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER This UniProt subcellular-location source agrees with the corresponding curated protein location and human-protein experimental evidence; the action distinguishes core catalytic locations from the additional nuclear pool. Supporting Evidence: PMID:31492851 hypoxia and starvation, conditions that activate AMPK phosphorylation of ALDH7A1, enhance the membrane distribution of ALDH7A1 PMID:40233740 this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Betaine aldehyde is a measured NAD+-dependent substrate. Reason: The Rhea:15305/EC 1.2.1.8 mapping matches human recombinant-enzyme kinetics in PMID:20207735. Betaine production is a supported additional activity relevant to osmolyte metabolism; those experiments do not determine its quantitative contribution to normal human tissue betaine flux. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: RHEA:15305 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. EC:1.2.1.8 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: NAD+-dependent aldehyde oxidation resolves the broad redox activity. Reason: The InterPro mappings correctly identify an oxidoreductase. Human substrate assays resolve aldehyde dehydrogenase (NAD+) activity, which retains the demonstrated substrate range rather than limiting this family-level assertion to AASA alone. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR015590 SUPPORTS TRANSFER This InterPro source maps conserved redox-enzyme architecture; measured human aldehyde/NAD+ chemistry permits a more informative catalytic term. InterPro:IPR029510 SUPPORTS TRANSFER This InterPro source maps conserved redox-enzyme architecture; measured human aldehyde/NAD+ chemistry permits a more informative catalytic term. Proposed replacements: aldehyde dehydrogenase (NAD+) activity Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates |
| GO:0052814 medium-chain fatty aldehyde dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Medium-chain aldehyde oxidation is an experimentally characterized activity. Reason: The five Rhea mappings specify measured aldehyde reactions. Human recombinant kinetics in PMID:20207735 Table 1 include hexanal, octanal and nonanal, and PMID:31492851 reconstitutes octanal-dependent NADH generation on liposomes. This chemistry is part of the integrated aldehyde-detoxification and NADH-generating function. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:44100 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:67248 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:67276 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:69759 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. RHEA:69767 SUPPORTS TRANSFER The listed reaction/family/EC source is concordant with the human substrate assays and the matching catalytic reaction in the cached UniProt record. The action reflects the supported substrate scope. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates PMID:31492851 simply incubating recombinant ALDH7A1 with Golgi membrane results in this NAD being converted to NADH |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: The generic binding term does not specify a molecular function. Reason: PMID:21988832 is a human liver interaction study and the seeded partner is EPS8. The generic protein-binding label is uninformative about what ALDH7A1 does; remove that term under the curation policy without claiming that the interaction is false or replacing it with an untested adaptor activity. |
| GO:0019477 L-lysine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: ALDH7A1 directly performs a step of L-lysine degradation. Reason: The Ensembl Compara row transfers from mouse Q9DBF1. Independent human enzyme and neural-progenitor knockout evidence establishes the same catalytic role: ALDH7A1 oxidizes AASA, and its loss blocks this part of lysine degradation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DBF1 UNRESOLVED This row names mouse Aldh7a1 Q9DBF1 and its Ensembl protein as the Compara source. Human knockout and catalytic data independently support lysine catabolism; the exact mouse experimental assertion was not independently reconstructed. ensembl:ENSMUSP00000065089 UNRESOLVED This row names mouse Aldh7a1 Q9DBF1 and its Ensembl protein as the Compara source. Human knockout and catalytic data independently support lysine catabolism; the exact mouse experimental assertion was not independently reconstructed. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. PMID:36225138 Quantitative analysis showed accumulation of PA and AASA/P6C in the antiquitin‐deficient NPC colonies but not in control cells |
| GO:0042426 choline catabolic process | TAS Reactome:R-HSA-6798163 | KEEP AS NON CORE | Summary: Betaine-aldehyde oxidation is a catalytic step in choline catabolism. Reason: Reactome places ALDH7A1 at the second oxidation step from choline to betaine. ALDH7A1 itself performs this aldehyde oxidation; this is direct pathway participation. Retain the additional pathway context, with the contribution to human physiological choline flux remaining less resolved than lysine catabolism. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | TAS Reactome:R-HSA-6797955 | KEEP AS NON CORE | Summary: Reactome records the supported betaine-aldehyde reaction. Reason: The curated event names ALDH7A1 as the catalyst converting betaine aldehyde to betaine, concordant with human purified-enzyme kinetics. Retain this additional substrate activity and the modeled mitochondrial context without treating it as a quantitative in-vivo flux measurement. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0019477 L-lysine catabolic process | IMP PMID:36225138 Metabolomics analysis of antiquitin deficiency in cultured h... | ACCEPT | Summary: Human neural-progenitor knockout cells show a lysine-degradation block. Reason: PMID:36225138 generated two selected exon-2 knockout clones of human ReNcell CX cells. Under lysine-containing culture conditions, PA and AASA/P6C accumulated; the substrate chemistry established independently identifies ALDH7A1 as the enzyme performing the blocked step. Broader metabolomic changes are not separately assigned as direct functions. Supporting Evidence: PMID:36225138 Quantitative analysis showed accumulation of PA and AASA/P6C in the antiquitin‐deficient NPC colonies but not in control cells |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA supports mitochondrial localization in human cells. Reason: The live HPA entry reports supported mitochondrial staining with HPA023296. This matches the characterized mitochondrial form and retains the microscopy assertion at organelle resolution; no matrix refinement is inferred from this assay. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA supports an additional cytosolic pool in human cells. Reason: The live HPA entry reports supported cytosolic staining with HPA023296 alongside mitochondrial staining. The cytosolic pool fits the experimentally demonstrated aldehyde chemistry and regulated membrane recruitment; the assay does not assign all staining to one isoform. |
| GO:0000139 Golgi membrane | EXP PMID:31492851 ALDH7A1 inhibits the intracellular transport pathways during... | ACCEPT | Summary: Golgi-associated ALDH7A1 generates NADH that inhibits transport. Reason: PMID:31492851 directly reconstituted NADH generation by recombinant ALDH7A1 on Golgi membranes and showed phosphorylation-dependent recruitment and transport regulation. This location is part of the enzyme’s characterized membrane catalytic function, with BARS retaining the carrier-fission role. Supporting Evidence: PMID:31492851 simply incubating recombinant ALDH7A1 with Golgi membrane results in this NAD being converted to NADH |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | EXP PMID:40233740 ALDH7A1 protects against ferroptosis by generating membrane ... | ACCEPT | Summary: Membrane ALDH7A1 oxidizes reactive aldehydes while generating NADH. Reason: PMID:40233740 separates ALDH7A1-dependent aldehyde consumption/NADH generation from FSP1-dependent quinone reduction using purified reconstitution and cell experiments. This is direct support for the aldehyde-dehydrogenase assertion, not evidence that ALDH7A1 itself is the quinone reductase. Supporting Evidence: PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. PMID:40233740 this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. |
| GO:0005634 nucleus | EXP PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | KEEP AS NON CORE | Summary: Human endothelial-cell staining supports nuclear ALDH7A1. Reason: The external full primary PMID:20207735 Figure 4B shows endogenous ALDH7A1 staining overlapping nuclei in human HUVECs. Mouse tissue fractionation is a separate experiment in the same paper. Retain the human nuclear location as an additional pool without assigning an unmeasured nuclear process. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria |
| GO:0005739 mitochondrion | EXP PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | ACCEPT | Summary: Human hALDH7A1_v1 is targeted to mitochondria. Reason: The external full primary PMID:20207735 Figure 5D examines human hALDH7A1_v1 expressed in CHO cells and its colocalization with a mitochondrial marker. Distinguish the human construct from the hamster host and the paper’s separate mouse tissue experiments. This supports the curated mitochondrial assertion. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria |
| GO:0005886 plasma membrane | EXP PMID:31492851 ALDH7A1 inhibits the intracellular transport pathways during... | ACCEPT | Summary: The curated plasma-membrane pool fits stress-regulated membrane recruitment. Reason: PMID:31492851 documents increased membrane distribution and compartmental localization under hypoxia and starvation, together with membrane-dependent catalysis. Retain the experimental plasma-membrane assignment and its connection to the membrane catalytic role. The independently read main-text fractionation is broader than plasma membrane, so it is not described as a separately resolved plasma-membrane purification. Supporting Evidence: PMID:31492851 hypoxia and starvation, conditions that activate AMPK phosphorylation of ALDH7A1, enhance the membrane distribution of ALDH7A1 |
| GO:0005886 plasma membrane | EXP PMID:40233740 ALDH7A1 protects against ferroptosis by generating membrane ... | ACCEPT | Summary: Membrane recruitment supports the ALDH7A1–FSP1 protective mechanism. Reason: PMID:40233740 establishes regulated ALDH7A1 membrane recruitment and local NADH production, and UniProt curates the plasma-membrane location from this study. Retain that location in the membrane catalytic core with experimental-curator deference; the total-membrane assays read here are not re-labeled as an independent plasma-membrane-specific assay. Supporting Evidence: PMID:40233740 this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:36225138 Metabolomics analysis of antiquitin deficiency in cultured h... | ACCEPT | Summary: Human-cell loss of ALDH7A1 blocks AASA oxidation. Reason: The two selected ALDH7A1-deficient neural-progenitor clones in PMID:36225138 accumulate substrate-related metabolites under lysine-containing conditions. Together with direct purified-enzyme AASA assays, this supports the specific molecular function while preserving the IMP source code. Supporting Evidence: PMID:36225138 Quantitative analysis showed accumulation of PA and AASA/P6C in the antiquitin‐deficient NPC colonies but not in control cells PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IDA PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | ACCEPT | Summary: Purified human ALDH7A1 oxidizes AASA. Reason: PMID:20207735 Table 1 measures AASA-dependent NAD+ reduction with recombinant human protein. This directly supports the specific dehydrogenase activity; substrate docking in the structural analysis is complementary modeling rather than the catalytic assay. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:16491085 Mutations in antiquitin in individuals with pyridoxine-depen... | ACCEPT | Summary: Patient mutations establish loss of antiquitin AASA/P6C dehydrogenase function. Reason: PMID:16491085 explicitly reports defective activity for the studied ALDH7A1 mutations and substrate accumulation. Retain the experimental assertion, corroborated by subsequent human purified-enzyme studies. The accessible local source is abstract-only, so unreported assay details are not reconstructed. Supporting Evidence: PMID:16491085 these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0019477 L-lysine catabolic process | IMP PMID:16491085 Mutations in antiquitin in individuals with pyridoxine-depen... | ACCEPT | Summary: ALDH7A1 performs the AASA oxidation step of lysine catabolism. Reason: The source’s loss of AASA/P6C dehydrogenase activity and substrate accumulation fit the independently established catalytic reaction in the lysine-degradation pathway. This is participation through chemistry, not a process inferred merely from the downstream seizure phenotype. Supporting Evidence: PMID:16491085 these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. Reactome:R-HSA-70941 Alpha-aminoadipic semialdehyde dehydrogenase (ALDH7A1) catalyzes the reaction of alpha-aminoadipic semialdehyde and NAD+ to form alpha-aminoadipate and NADH + H+ |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:20554659 Genotypic and phenotypic spectrum of pyridoxine-dependent ep... | ACCEPT | Summary: Patient biochemical phenotypes corroborate the AASA dehydrogenase role. Reason: PMID:20554659 links ALDH7A1 genotypes to elevated urinary AASA in a clinical series. Its full Methods emphasize metabolite quantification and sequencing, rather than a new purified-enzyme assay. Preserve the IMP evidence and accept the supported function in conjunction with direct human enzymology. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:31302938 Structural and biochemical consequences of pyridoxine-depend... | ACCEPT | Summary: Aldehyde-pocket substitutions impair AASA turnover by human ALDH7A1. Reason: PMID:31302938 directly compares recombinant wild-type enzyme with purified variants using AASA and NAD+. Effects vary markedly across substitutions; the retained activity in several variants is incompatible with a universal statement that every pathogenic variant abolishes catalysis. Supporting Evidence: PMID:31302938 W175G has a relatively mild kinetic defect, exhibiting a fivefold decrease in kcat with no change in Km |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:31652343 Structural analysis of pathogenic mutations targeting Glu427... | ACCEPT | Summary: Glu427 substitutions disrupt catalytic NAD+ positioning. Reason: PMID:31652343 assays purified human E427Q, E427D and E427G proteins and finds negligible activity compared with wild type. Their structures explain defective nicotinamide positioning. The source directly supports the AASA dehydrogenase function without equating every NAD+-bound structure with productive catalysis. Supporting Evidence: PMID:31652343 The recombinant enzymes displayed negligible catalytic activity compared to the wild-type enzyme. |
| GO:0004043 L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity | IMP PMID:38604394 Biochemical, structural, and computational analyses of two n... | ACCEPT | Summary: Human oligomer-interface variants impair AASA dehydrogenase activity. Reason: PMID:38604394 measures catalytic defects of recombinant R134S and R441C and distinguishes their oligomerization mechanisms. The numbering used in the paper omits the targeting sequence; the corresponding HGVS residues are Arg162 and Arg469. These experiments support the specific enzyme activity and the importance of active tetramer assembly. Supporting Evidence: PMID:38604394 R134S and R441C have 10,000- and 50-fold lower catalytic efficiency than wild-type ALDH7A1, respectively. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The mitochondrial-proteome assertion agrees with independent target localization. Reason: PMID:34800366 is the human MitoCoP proteome study underlying this HTP annotation. Although the target-level supplementary record was not independently recovered here, human HPA staining and human-protein mitochondrial localization provide positive corroboration. Retain the curated organelle-level assertion without inventing a target peptide count or matrix localization. Supporting Evidence: PMID:20207735 ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | ACCEPT | Summary: Human ALDH7A1 displays a broad NAD+-dependent aldehyde substrate spectrum. Reason: PMID:20207735 directly measures activity on AASA, betaine aldehyde and several medium-chain or lipid-peroxidation-derived aldehydes. The broad MF captures experimentally demonstrated breadth; replacing it solely with the AASA term would discard genuine catalytic coverage. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | IDA PMID:21338592 Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive ald... | ACCEPT | Summary: Human ALDH7A1 metabolizes 4-hydroxynonenal under defined reducing conditions. Reason: PMID:21338592 assays recombinant enzyme and shows that beta-mercaptoethanol reactivation permits 4HNE oxidation. Human-protein expression in CHO cells also protects against aldehyde and oxidative challenges. Retain the direct aldehyde-dehydrogenase activity while recording the redox dependence of the in-vitro assay. Supporting Evidence: PMID:21338592 after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. |
| GO:0008802 betaine-aldehyde dehydrogenase (NAD+) activity | IDA PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | KEEP AS NON CORE | Summary: Human ALDH7A1 directly oxidizes betaine aldehyde. Reason: PMID:20207735 Table 1 establishes betaine-aldehyde turnover by purified human protein. The activity is valid, while the paper’s osmoprotection experiments do not isolate the quantitative share of betaine production versus aldehyde detoxification in normal human physiology. Supporting Evidence: PMID:20207735 including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. |
| GO:0042802 identical protein binding | IDA PMID:20207735 Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme invol... | ACCEPT | Summary: Homomeric assembly is part of the active enzyme architecture. Reason: PMID:20207735 establishes human ALDH7A1 oligomeric structure; later direct solution and catalytic analyses in PMID:38604394 connect tetramer assembly to activity. Identical-protein binding here represents functional self-association, rather than the uninformative binding of an unspecified partner. Supporting Evidence: PMID:38604394 Because the tetramer is the active form of ALDH7A1, the defect in oligomerization explains the very low catalytic activity of R134S. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | UNDECIDED | Summary: The exosome proteomics assignment needs its target-level record checked. Reason: PMID:23533145 describes proteomics of exosome-enriched expressed-prostatic-secretion urine pools. The main article is accessible, but the ALDH7A1/P49419 row in Supplemental Table 2 was not recovered. Cytosolic abundance does not establish contamination and extracellular detection does not require a demonstrated extracellular catalytic role. Preserve the HDA assertion pending the exact hit and preparation context. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6797955 | ACCEPT | Summary: Reactome places the mitochondrial enzyme in the matrix. Reason: R-HSA-6797955 represents the betaine-aldehyde reaction in the mitochondrial matrix. This is a curated compartment assertion consistent with the matrix enzyme represented in the lysine-catabolic reaction, even though betaine oxidation is an additional substrate activity. Retain its TAS scope without claiming new matrix-resolving microscopy. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70941 | ACCEPT | Summary: The lysine-catabolic Reactome catalyst is a matrix ALDH7A1 tetramer. Reason: The live R-HSA-70941 event explicitly identifies ALDH7A1 tetramer in mitochondrial matrix as its catalyst. This supports the specific core compartment at the curated pathway level. Retain the seeded matrix term and distinguish it from the organelle-level resolution of HPA and MitoCoP. Supporting Evidence: Reactome:R-HSA-70941 Alpha-aminoadipic semialdehyde dehydrogenase (ALDH7A1) catalyzes the reaction of alpha-aminoadipic semialdehyde and NAD+ to form alpha-aminoadipate and NADH + H+ |
| GO:0004029 aldehyde dehydrogenase (NAD+) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Conserved aldehyde oxidation is directly confirmed in the human enzyme. Reason: The ISS donor P83402 is black seabream antiquitin, not the plant homolog described in the prior review. The exact historical donor experiment was not reconstructed, but independent human NAD+-dependent aldehyde assays establish the target function. Retain the source assertion with transparent donor-chain uncertainty. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P83402 UNRESOLVED P83402 is the seabream ALDH7A1/antiquitin donor; current primary identifier mapping was checked, but the original donor evidence chain was not recovered. Human direct assays independently support the target claim. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates |
| GO:0006081 aldehyde metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: ALDH7A1 performs aldehyde metabolism by direct oxidation. Reason: The seabream donor P83402 supports a conserved enzyme assignment, and the human protein directly consumes several aldehydes. Aldehyde metabolism is a valid core process encompassing that chemistry; breadth alone does not make this assertion non-core. The exact historical ISS donor experiment remains unresolved. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P83402 UNRESOLVED P83402 is the seabream ALDH7A1/antiquitin donor; current primary identifier mapping was checked, but the original donor evidence chain was not recovered. Human direct assays independently support the target claim. Supporting Evidence: PMID:20207735 Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates PMID:40233740 ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. |
| GO:0007605 sensory perception of sound | TAS PMID:9417906 An ancient conserved gene expressed in the human inner ear: ... | UNDECIDED | Summary: Cochlear expression motivates a hearing hypothesis but does not resolve the full TAS evidence. Reason: PMID:9417906 describes a human fetal cochlear clone, human tissue expression and rat outer-hair-cell transcripts in the accessible abstract. The original full article was not recovered, so the precise basis of the sensory-perception assertion cannot be fully assessed. Retain explicit uncertainty rather than treating expression as sufficient participation or using the abstract to disprove the curator’s claim. |
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Download this section (compressed HTML)Q: What fraction of human tissue betaine production is catalyzed by ALDH7A1 under physiological osmotic conditions, separately from its reactive-aldehyde detoxification?
Q: Can the ALDH7A1 target entry and peptide evidence in the urinary exosome study be checked, and does the original cochlear-expression article provide evidence beyond expression for the hearing annotation?
Q: In GO-CAM 680ad14200003459, should the ALDH7A1-enabled activities be represented as aldehyde oxidation producing NADH rather than the quinone-reducing MF performed by FSP1, and is the malonaldehyde input/product orientation correct?
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