ALDH7A1 (antiquitin, ATQ1) is the alpha-aminoadipic semialdehyde dehydrogenase
(EC 1.2.1.31) of the saccharopine pathway of L-lysine catabolism. It catalyses the
NAD+-dependent oxidation of L-alpha-aminoadipate-6-semialdehyde (AASA;
(S)-2-amino-6-oxohexanoate), which is in spontaneous equilibrium with its cyclic
Schiff base delta-1-piperideine-6-carboxylate (P6C), to L-alpha-aminoadipate.
The specific molecular function is captured by GO:0004043
L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity (definition:
"(S)-2-amino-6-oxohexanoate + NAD(P)+ + H2O = L-2-aminoadipate + NAD(P)H + 2 H+";
verified via OLS). This is the best-supported, most specific MF and is backed by
multiple IDA/IMP annotations. NOTE: the task hint referenced GO:0019145 as
"aminoadipate-semialdehyde dehydrogenase" — this is INCORRECT. OLS shows GO:0019145
= "aminobutyraldehyde dehydrogenase (NAD+) activity" (4-aminobutanal substrate),
which is NOT this enzyme; GO:0004043 is the right term.
Core biological process: GO:0019477 L-lysine catabolic process (verified
non-obsolete). NOTE: GO:0006554 "lysine catabolic process" is OBSOLETE per OLS, so
GO:0019477 is the term to use.
ALDH7A1 is a broad-specificity NAD+-aldehyde dehydrogenase (GO:0004029). In vitro it
oxidises many aldehydes:
- betaine aldehyde -> betaine (GO:0008802; EC 1.2.1.8), an osmolyte and methyl donor
[PMID:20207735 abstract "the osmolyte precursor, betaine aldehyde"].
- medium-chain fatty aldehydes (hexanal, octanal, nonanal, trans-2-nonenal) and
lipid-peroxidation-derived aldehydes 4-HNE and malonaldehyde
[PMID:21338592; PMID:20207735].
- Kinetics (UniProt BIOPHYSICOCHEMICAL PROPERTIES) show it is efficient toward
medium-chain and LPO aldehydes (KM 5-40 uM) and AASA (KM 169 uM); poor toward
short-chain/aromatic (benzaldehyde, propanal, glyceraldehyde: KM in the mM range).
UniProt: isoform 1 is Mitochondrion; isoform 2 is Cytoplasm/cytosol, Cell membrane,
Golgi apparatus membrane, Nucleus. Multiple experimental (IDA/EXP/HPA) and IEA
subcellular annotations: cytosol, mitochondrion, nucleus, plasma membrane, Golgi
membrane. UniProt: "ALDH7A1 protein was found in the cytosol, nucleus, and
mitochondria, making it unique among the aldehyde dehydrogenase enzymes"
PMID:20207735. HTP mito proteome (PMID:34800366) and exosome HDA (PMID:23533145)
are consistent-but-nonspecific compartments.
Biallelic loss-of-function ALDH7A1 variants cause pyridoxine-dependent epilepsy
(PDE; EPEO4; MIM 266100). Loss of AASA-dehydrogenase activity -> AASA/P6C
accumulate; P6C inactivates pyridoxal-5'-phosphate (PLP) by a Knoevenagel
condensation, causing vitamin-B6-responsive neonatal seizures
[PMID:16491085; PMID:20554659; multiple structural papers PMID:31302938,
PMID:31652343, PMID:38604394 characterizing loss-of-function variants].
The selected horse ALDH7A1 A0A9L0RRL6 is521 aa versus canonical human 539 aa. Alignment identifies an internal deletion of human 65–82; the human structure has a beta strand at 65–70, so this should not be dismissed as a variable terminal peptide. Catalytic Glu296/Cys330 and the annotated nucleotide/substrate-binding positions are preserved; the N-terminal mitochondrial precursor segment is present. Broad ALDH chemistry and mitochondrial targeting remain reasonable inferences, but exact substrate kinetics and effects of the deletion are unresolved.
PMID:20207735(https://pubmed.ncbi.nlm.nih.gov/20207735/), DOI 10.1074/jbc.M109.077925, reports purified recombinant human enzyme metabolizing betaine aldehyde, lipid-peroxidation aldehydes and alpha-aminoadipic semialdehyde. PMID:16491085(https://pubmed.ncbi.nlm.nih.gov/16491085/) establishes pathogenic ALDH7A1 loss of alpha-AASA dehydrogenase activity. Neither inspected source provides a negative glyceraldehyde-3-phosphate assay. Broad ALDH substrate promiscuity cannot validate the ProtNLM substrate prediction, but it also makes a confident rejection based only on the canonical substrate unsafe.
The selected horse protein is not assumed to represent all human-like cytosolic isoforms. The horse GOA localization rows beyond mitochondria require isoform-specific evidence. A completed human Falcon report has been inspected; horse-specific Edison was not indicated by genome-only source references.
The human Falcon synthesis strengthens the distinction between established alpha-aminoadipic semialdehyde oxidation and broader in-vitro aldehyde activity. It also emphasizes isoform-dependent localization and tetramerization defects that can impair activity despite preserved catalytic residues. These points support retaining uncertainty about substrate specificity and activity of the selected horse sequence with its internal deletion; a conserved catalytic cysteine alone is insufficient.
This entry supersedes the earlier annotation-action summary where it differs. All 42 machine-seeded source objects, all 24 original reference identities, and all three alternative-product records are preserved. Current actions: 32 ACCEPT, 6 KEEP_AS_NON_CORE, 1 MODIFY, 1 REMOVE, 2 UNDECIDED; zero NEW. All annotations, both cores and every reference assessment were manually reconsidered. The baseline is exact main ba3ff58d7d2de76dbe3c24b16e05e12369f463fc; HGNC:877/P49419 and ATQ1/EPD/PDE aliases were checked by the coordinator, with no canonical or alias open-PR overlap. The existing genuine Falcon report and artifact are preserved. The normal publication-cache command completed with 14/14 sources already cached; no provider or publication text was authored.
The earlier “never REMOVE an IPI” shorthand is incorrect: the generic protein-binding term is removed for lack of functional information, without rejecting the EPS8 interaction. Likewise, a broad true enzyme/process/location annotation is not non-core merely because a narrower term exists. The hearing and exosome judgments now remain unresolved rather than being dismissed from incomplete evidence. Medium-chain aldehyde turnover, functional self-association and membrane catalysis are supported parts of the integrated function.
PMID:20207735(https://pmc.ncbi.nlm.nih.gov/articles/PMC2881771/) has an abstract-only local cache. Indexed primary PMC searches ("PMC2881771" "Table 1" and "PMC2881771" "nucleus" "Human") exposed the full Results, kinetic table and Figures 3–5. Purified human enzyme directly oxidizes AASA, betaine aldehyde and medium-chain aldehydes. Human HUVEC nuclear staining (Figure 4B) and human hALDH7A1_v1 mitochondrial localization in CHO cells (Figure 5D) must be distinguished from mouse tissue fractionation (Figure 3). The substrate poses include docking, not universal substrate cocrystals. Betaine turnover is real, but its physiological share of human betaine synthesis remains unresolved. The earlier sequence/structure paragraph mixed precursor and mature residue numbers; this audit uses explicit source numbering when needed and does not rely on that mixed list.
PMID:21338592(https://pmc.ncbi.nlm.nih.gov/articles/PMC3387551/) full cached Methods/Results distinguish purified human protein from the CHO expression host. Beta-mercaptoethanol reactivation is an important condition of the 4HNE assay. Cytoprotection and direct aldehyde turnover together support the broader catalytic function. Malonaldehyde consumption is supported by the newer 2025 study, not attributed to an uninspected assay in the earlier paper.
The live HPA entry lists HPA023296 and supported mitochondria plus cytosol. Those rows retain organelle/cytosol resolution. The MitoCoP source PMID:34800366(https://pmc.ncbi.nlm.nih.gov/articles/PMC8664129/) was read for its method and study scope; the target supplemental hit was not separately recovered. Its curated mitochondrial assertion is positively corroborated by HPA and human-protein localization, without inventing target peptide counts or assigning matrix from proteomics.
The live Reactome lysine reaction explicitly names its catalyst “ALDH7A1 tetramer [mitochondrial matrix]”. This is the evidence for the core’s more specific matrix placement; the cached reaction summary alone describes mitochondria/cytosol. The current catalyst object and newer human oligomerization studies support tetramer, while the legacy narrative still calls an old crystal assembly a homodimer. The betaine-aldehyde reaction and choline pathway place ALDH7A1 as an actual catalyst in choline catabolism. This is valid additional participation, not simply a downstream association.
PMID:31492851(https://pmc.ncbi.nlm.nih.gov/articles/PMC6731274/) full cached Results/Methods show ALDH7A1-dependent NADH generation on Golgi membranes and octanal/NAD liposomes, with E268Q catalytic and BARS G172E NADH-response controls. S102 phosphorylation-state mutants connect recruitment with catalysis and transport regulation. ALDH7A1 supplies the reducing cofactor; BARS performs the fission activity. Main cellular experiments use HeLa, with selected additional-cell experiments. The explicit construct-to-UniProt isoform accession was not independently resolved, so the source’s experiments are not relabeled as uniquely isoform-specific.
PMID:40233740(https://pmc.ncbi.nlm.nih.gov/articles/PMC12085291/) is abstract-only locally. Indexed original PMC Results, Figures 1–6 and Methods were accessible through "PMC12085291" "Results" "ALDH7A1" and related figure queries. Purified reconstitution separates ALDH7A1 oxidation/NADH production from FSP1 quinone reduction; reactive-aldehyde consumption and FSP1 recruitment provide additional protective mechanisms. The studied human-cell conditions and liposomes support participation rather than knockout necessity alone. The independently inspected fractionation measures total membranes versus cytosol; plasma-membrane rows retain their curated attribution, corroborated by the UniProt localization record, without claiming a separately inspected PM-only fractionation assay. A second agent independently read both sources and confirmed this division of labor. The membrane role can be core despite regulated recruitment.
PMID:16491085(https://pubmed.ncbi.nlm.nih.gov/16491085/) remains abstract-only locally and establishes the specific mutation-associated enzyme defect and P6C/PLP adduct chemistry. PMID:20554659(https://pmc.ncbi.nlm.nih.gov/articles/PMC2892945/) full Methods/Results emphasize patient genotypes and urinary AASA quantification; the audit does not turn that clinical series into a new purified-enzyme experiment.
PMID:36225138(https://pmc.ncbi.nlm.nih.gov/articles/PMC10092344/) full Results section 3.2 supplies the result-bearing quote for the human ReNcell CX knockout: PA and AASA/P6C accumulate in the selected knockout clones under lysine-containing culture conditions. Broader metabolomic changes are not automatically direct ALDH7A1 pathways. The previous supporting fragment was introductory pathway background despite its RESULTS label; it has been replaced.
PMID:31302938(https://pmc.ncbi.nlm.nih.gov/articles/PMC6944758/), PMID:31652343(https://pmc.ncbi.nlm.nih.gov/articles/PMC7182499/) and PMID:38604394(https://pmc.ncbi.nlm.nih.gov/articles/PMC11073572/) full cached kinetics, structures and solution experiments show variant-specific impairment. Several variants retain activity, so the description no longer says all pathogenic variants abolish it. The last study distinguishes mature R134/R441 from HGVS Arg162/Arg469 and directly connects R134S tetramer failure to catalytic impairment. Functional homomeric assembly supports retaining identical-protein binding as core.
The ISS donor P83402 is seabream antiquitin, not plant ALDH7B1. The primary ENZYME record maps P83402 to AL7A1_ACASC, with source identity consistent with Acanthopagrus schlegelii. The exact historical ISS experiment was not reconstructed; source_entities records this while human catalytic assays independently support the two retained terms. The Compara row names mouse Q9DBF1/ENSMUSP00000065089; its exact donor assay chain is similarly distinguished from direct human support. There are no IBA rows in this seed.
PMID:23533145(https://pmc.ncbi.nlm.nih.gov/articles/PMC3773505/) has accessible main text describing exosome-enriched EPS-urine pools and shotgun proteomics. Supplemental Table 2 was identified but its ALDH7A1/P49419 hit was not recovered. The annotation remains UNDECIDED; abundance or a missing extracellular function does not prove contamination. PMID:9417906(https://pubmed.ncbi.nlm.nih.gov/9417906/) has verified human cochlear-expression and rat hair-cell transcript findings in the abstract, but publisher/full-text recovery did not resolve the exact hearing-process claim. That TAS row remains UNDECIDED. Local cache availability flags retain their actual metadata; external reading is recorded separately.
Live AmiGO verified GO:0004043, GO:0052814, GO:0006081, GO:0110076, and GO:0016655. GO:0006081’s current label is “aldehyde metabolic process”; only the authored core label follows this live label, while seeded term fields remain untouched. GO:0110076 describes reduction of ferroptosis and has regulation-of-ferroptosis and negative-regulation-of-programmed-cell-death parents. ALDH7A1 performs the aldehyde chemistry supporting that protective process.
The cached GO-CAM 680ad14200003459 already includes ALDH7A1 isoform 2 in this ferroptosis mechanism. Its target activities ending 00003472 and 00003494 are enabled by P49419-2, yet use GO:0016655, whose definition requires NADH/NADPH as electron donor to a quinone-like acceptor. The paper assigns that chemistry to FSP1; ALDH7A1 consumes aldehyde and NAD+ and generates NADH. The latter target node also appears to exchange malonaldehyde and its oxidized product’s input/output roles. These are recorded as a specific modeling question; the protected model was not edited and its quinone MF was not copied into the core. No NEW flat annotation is created to mirror an already modeled process or an integrated core term.
Final validation, quote-integrity, cache-census and history results will be recorded after the complete draft is checked.
Although there are zero NEW rows, the second core newly adds GO:0110076 relative to the baseline. This is an authored process assertion and was assessed with the same participation standard:
680ad14200003459 already places ALDH7A1 P49419-2 in negative regulation of ferroptosis. Thus there is positive target-specific curator modeling of process participation, independently of the MF/input-output questions noted above. This is stronger evidence about the intended target role than treating absent local comparator rows as a universal exclusion convention. The model uses the same primary study: it is curator representation, not an independent experimental replication.Final full validation passed with two intentional advisories: no supporting quote cites the preserved Falcon report, and the newly included core process is absent from the flat existing-annotation block. Primary evidence is cited directly, and the GO-CAM/process assessment above explains the second advisory. DRAFT is retained. History validation, HTML rendering and source/quote integrity passed; 70 cached quotes match case-sensitively after whitespace normalization, with no case-fold-only matches. The notes/provider-inclusive explicit PMID and PubMed-URL census contains 14 sources, all cached. The coordinator independently read all 42 decisions, all 24 reference reviews, description and both cores; the requested process-convention explanation is recorded above and the coordinator has accepted the final biology.
Fresh primary GitHub API preflight verified PR #3277 is open and draft at 63f6d641024457eb33e6e0c61368e30a22bcd920. All seven canonical gene files, including the nested genuine Falcon artifact, match that exact published tree. The nine publication paths below were absent on the PR head. The coordinator's source12 import (tmp/source12-canonical-import-receipt.json) supplies their exact normal-fetched bytes. No generated source or report was edited. The older 14-source count above was limited to explicit PMIDs/URLs; it did not include the nine additional DOI-only provider citations and is superseded by the decoded recursive census for this follow-up.
All 42 annotation objects/actions/source fields, three alternative-product records, both cores, the description and all 24 original reference objects are unchanged. Nine actual-source assessments are added, retaining exact machine-fetched titles and availability flags. The import's primary identifier/title/DOI checks and earlier provider-DOI identity audit are distinguished from reading a full body; a PMC identifier alone does not make a cache full text.
| Source | Actual record read | Evidence boundary |
|---|---|---|
| PMID:38419708(https://pubmed.ncbi.nlm.nih.gov/38419708/) | Full human retrospective EEG study, Methods/Results/limitations | Thirteen Norwegian patients, twelve genetically confirmed and one clinically assigned deceased sibling; heterogeneous historical EEG protocols and written reports. Acute EEG and clinical responses can differ. This is disease/diagnostic evidence, not a new enzymatic or neuronal function. |
| PMID:30663059(https://pubmed.ncbi.nlm.nih.gov/30663059/) | Abstract only | Human 6-oxo-pipecolate accumulation and stable-isotope LC-MS/MS quantification; detailed provider-reported concentrations were not independently recovered here. Accumulation does not assign synthesis of this biomarker to ALDH7A1. |
| PMID:34138754(https://pubmed.ncbi.nlm.nih.gov/34138754/) | Abstract and live primary PubMed record; local body unavailable | Human plasma/brain and dried-bloodspot observations, knockout-mouse brain accumulation, and zebrafish epilepsy-like behavior are distinct experiments. No unseen Methods or supplements are claimed. |
| PMID:39329078(https://pubmed.ncbi.nlm.nih.gov/39329078/) | Full newborn case, genetic analysis and biomarker discussion | Two segregating truncating human alleles and method-specific levetiracetam/6-oxo-PIP GC-MS interference; neither a universal biomarker failure nor a new purified-enzyme assay. |
| PMID:39763688(https://pubmed.ncbi.nlm.nih.gov/39763688/) | Full family Methods/Results | Two siblings with homozygous p.Gly390Arg, segregation and computational pathogenicity evidence. Alpha-AASA tests were unavailable; catalytic/folding effects were not measured. Clinical improvement and residual developmental findings remain context-specific. |
| PMID:36878704(https://pubmed.ncbi.nlm.nih.gov/36878704/) | Abstract only | Therapeutic overview of inherited metabolic epilepsies. The automated broad publication-type label does not turn this abstract into an ALDH7A1 gene-treatment experiment. |
| PMID:18611112(https://pubmed.ncbi.nlm.nih.gov/18611112/) | Abstract-only ALDH-superfamily review | Family-wide ester hydrolysis, xenobiotic, UV-absorption and developmental roles are not transferred to ALDH7A1. |
| PMID:40217438(https://pubmed.ncbi.nlm.nih.gov/40217438/) | Full clinical review, especially the ALDH7A1 subsection | The subsection switches to ALDH4A1 in one treatment paragraph and the pathway caption calls a metabolite piperonylic acid. These specific wording inconsistencies are recorded, without rejecting the identifier or all clinical observations. Suggested neurogenesis/migration roles remain secondary hypotheses. |
| PMID:32956737(https://pubmed.ncbi.nlm.nih.gov/32956737/) | Full structural/biochemical review | Explicit 28-residue numbering offset and variant-specific active-site/interface effects corroborate existing scope. It synthesizes prior experiments and does not newly test every variant or establish that all pathogenic alleles abolish activity. |
The nine DOI identities were independently mapped to primary PubMed records in tmp/ALDH7A1-doi-audit/census.json; actual cached metadata now matches those mappings. This follow-up additionally reopened live PubMed for PMID:34138754 and PMID:38419708; challenge-limited retrieval for another record was not counted as a successful fresh full-text read. Earlier verified identity remains distinct from present body availability. Scientific source assessments use the actual records described above, not provider prose as a substitute for original assays. The preserved provider's clinical recommendations are not patient-specific medical guidance in this gene review.
The current approving review and all five nonblocking suggestions were read. No flat NEW row is added merely to mirror the existing GO-CAM-backed integrated ferroptosis process or suppress a validator advisory; the participation/comparator/parent/nonredundancy assessment remains above. Core plasma-membrane placement retains its explicitly curated/source-bounded basis, separate from total-membrane measurements. Functional tetramer assembly is already in the description, source judgments and structural evidence, and a compact core need not repeat every accepted parent or assembly term. No unsupported intrinsic quinone reductase activity is assigned to ALDH7A1: its aldehyde oxidation and NADH supply remain distinct from partner chemistry. Optional prose alternatives do not require changing approved biology. Seeded alternative-product parser strings and derived reports are preserved for their separate tooling scope.
The final audit includes every authored Markdown file, the genuine provider report and nested artifact, normalized URL-encoded/escaped DOIs, PMID/PubMed URLs and PMC mappings. Bare bibliographies of cached papers are not recursively promoted to new source obligations. Final hashes, citation counts, exact-quote/source-preservation checks, full validation, history and rendering are recorded in the handoff manifest. DRAFT is retained for the two existing advisories; publication readiness is assessed separately from that schema status and only after the complete required-cache census.