Aga encodes lysosomal glycosylasparaginase (aspartylglucosaminidase, AGA; EC 3.5.1.26), a member of the N-terminal nucleophile (Ntn) hydrolase family. It hydrolyses the amide bond joining N-acetylglucosamine to the asparagine side chain (the GlcNAc-Asn linkage) of glycoasparagines, catalysing a terminal step in the ordered lysosomal catabolism of N-linked glycoproteins; it acts after upstream exoglycosidases have trimmed the glycan, and does not efficiently hydrolyse fucosylated complex-type N-glycans. Its physiological substrate class is glycosylated L-asparagine, requiring free alpha-amino and alpha-carboxyl groups on the asparagine moiety, and it also shows secondary beta-aspartyl peptidase and L-asparaginase activities without the glutaminase activity of bacterial asparaginases. The enzyme is synthesised as an inactive single-chain precursor: two precursor molecules dimerise and cleave autocatalytically into an N-terminal alpha and a C-terminal beta subunit, exposing the catalytic N-terminal threonine of the beta subunit that is the hallmark of Ntn-hydrolases; the mature rat liver enzyme is an approximately 49 kDa alpha/beta assembly. As a soluble, N-glycosylated lysosomal hydrolase it is delivered to the lysosome by the mannose 6-phosphate pathway, and secreted enzyme can be recaptured by M6P receptor-mediated endocytosis. Loss of this activity causes accumulation of glycoasparagines, notably aspartylglucosamine (GlcNAc-Asn), the biochemical hallmark of aspartylglucosaminuria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: cytoplasm is a broad subsuming compartment for the lysosomal enzyme Aga; it is imprecise but not wrong (lysosome is part_of cytoplasm in GO), so it is kept as non-core rather than removed (IBA, GO_REF:0000033). Reason: Aga is a soluble lysosomal hydrolase, and the specific lysosome IBA (GO:0005764, node PTN000809985) is the informative localization. However, GO:0005737 cytoplasm subsumes the lysosome (lysosome is part_of cytoplasm), so the broad term is defensible for an organellar protein and does not meet the bar for a localization REMOVE, which requires a mutually exclusive compartment (nucleus, plasma membrane, extracellular). A previous REMOVE call here was an over-reach of exactly the kind catalogued as the Pattern 13 Tier B anti-pattern in the IBA review project; downgraded to KEEP_AS_NON_CORE. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000022481 ยท PANTHER:PTN000022481 SUPPORTS TRANSFER Cytoplasm IBD sits at family node PTN000022481 (current PTHR10188 PAINT slice), seeded by mouse Aga, human AGA (P20933), a rat member, and the genuinely cytosolic paralog ASRGL1 (Q7L266). For lysosomal Aga the term is generic rather than wrong, since the lysosome is part_of the cytoplasm; the lysosome IBD at PTN000809985 carries the informative localization. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. file:rat/Aga/Aga-deep-research-falcon.md AGA is a **soluble lysosomal hydrolase**. |
| GO:0005764 lysosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: lysosome is retained as contextual support for Aga, but it is not the core function (IBA, GO_REF:0000033). Reason: lysosome records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Aga. Falcon deep research confirms Aga is a soluble lysosomal hydrolase trafficked via the mannose-6-phosphate pathway. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. file:rat/Aga/Aga-deep-research-falcon.md trafficked to lysosomes through the **mannose-6-phosphate (M6P) pathway**, and secreted AGA can be **recaptured by M6P receptorโmediated endocytosis** |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IBA GO_REF:0000033 | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (IBA, GO_REF:0000033). Reason: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Falcon deep research confirms the Asn-GlcNAc amide-bond hydrolysis (EC 3.5.1.26) as the core enzymatic activity. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. file:rat/Aga/Aga-deep-research-falcon.md it cleaves the **amide bond between N-acetylglucosamine (GlcNAc) in the glycan and the asparagine (Asn) side chain** (i.e., the AsnโGlcNAc linkage) in glycoasparagine degradation intermediates. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IEA GO_REF:0000120 | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (IEA, GO_REF:0000120). Reason: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: lysosome is retained as contextual support for Aga, but it is not the core function (IEA, GO_REF:0000044). Reason: lysosome records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Aga. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: hydrolase activity captures part of Aga biology, but more specific replacement term(s) better represent the supported function (IEA, GO_REF:0000002). Reason: hydrolase activity is too broad or imprecise for Aga; replace with the more specific supported term(s): GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity. Proposed replacements: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | ISO GO_REF:0000121 | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (ISO, GO_REF:0000121). Reason: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | EXP PMID:1554372 Comparison of liver glycosylasparaginases from six vertebrat... | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (EXP, PMID:1554372). Reason: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Supporting Evidence: PMID:1554372 Structural and physical properties of glycosylasparaginase (EC 3.5.1.26) from the livers of human, pig, cow, rat, mouse and chicken were compared. PMID:1554372 The pH maximum was between 5.5 and 6 except for the rat and mouse enzymes which had a broad maximum between pH 7 and 8. |
| GO:0005764 lysosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: lysosome is retained as contextual support for Aga, but it is not the core function (ISO, GO_REF:0000121). Reason: lysosome records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Aga. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: extracellular region is retained as contextual support for Aga, but it is not the core function (ISO, GO_REF:0000121). Reason: extracellular region records localization rather than the defining molecular activity of Aga. Falcon deep research notes that a fraction of Aga is secreted and can be recaptured by neighboring cells via mannose-6-phosphate receptor-mediated endocytosis, consistent with a non-core extracellular presence. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. file:rat/Aga/Aga-deep-research-falcon.md trafficked to lysosomes through the **mannose-6-phosphate (M6P) pathway**, and secreted AGA can be **recaptured by M6P receptorโmediated endocytosis** |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Endoplasmic reticulum is a biosynthetic-transit location for Aga, an N-glycosylated, signal-peptide-bearing lysosomal hydrolase; retained as non-core because the enzyme acts in the lysosome (ISO from human AGA, UniProtKB:P20933). Reason: Aga carries an N-terminal signal peptide and is N-glycosylated, so the precursor is co-translationally translocated into the ER, where it folds, is glycosylated and (in AGA) dimerises and begins autocatalytic activation before mannose 6-phosphate-dependent sorting to the lysosome. ER residence is therefore real but transient, part of the route to the site of action rather than where the GlcNAc-Asn amidase functions. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. UniProtKB:P30919 PTM: N-glycosylated. |
| GO:0006517 protein deglycosylation | ISO GO_REF:0000121 | ACCEPT | Summary: protein deglycosylation is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (ISO, GO_REF:0000121). Reason: protein deglycosylation is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Falcon deep research places Aga at a terminal step of the lysosomal N-linked glycoprotein degradation pathway. GOA no longer carries this rat ISO row (re-review 2026-10-04); the human ortholog retains experimental protein deglycosylation annotations. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. file:rat/Aga/Aga-deep-research-falcon.md AGA functions in the **lysosomal N-linked glycoprotein degradation pathway**, acting at a terminal step in which glycoasparagine intermediates are converted into products that can be fully catabolized. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IDA PMID:2775174 Purification and characterization of rat liver glycosylaspar... | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is retained for Aga because it matches the documented core enzymatic role or its direct pathway consequence (IDA, PMID:2775174). Reason: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity is directly supported by the curated function of Aga and is not merely a downstream phenotype or expression response. Supporting Evidence: PMID:2775174 Rat liver glycosylasparaginase [N4-(beta-N-acetylglucosaminyl)-L-asparaginase, EC 3.5.1.26] was purified to homogeneity. PMID:2775174 The purified enzyme had a specific activity of 3.8 mumol of N-acetylglucosamine/min per mg with N4-(beta-N-acetylglucosaminyl)-L-asparagine as substrate. |
| GO:0008150 biological_process | ND GO_REF:0000015 | REMOVE | Summary: biological_process should not be retained for Aga based on the combined gene function and cited/source evidence (ND, GO_REF:0000015). Reason: An ND (no biological data) root-term annotation is no longer accurate for Aga. The rat enzyme has been purified from liver and assayed directly on its glycoasparagine substrate (PMID:2775174), and it catalyses the terminal amide-bond cleavage step of lysosomal N-glycoprotein catabolism, so a biological process is known (the human ortholog carries experimental protein deglycosylation annotations). The placeholder therefore adds nothing and should be dropped in favour of the process captured in core_functions. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. PMID:2775174 The purified enzyme had a specific activity of 3.8 mumol of N-acetylglucosamine/min per mg with N4-(beta-N-acetylglucosaminyl)-L-asparagine as substrate. |
| GO:0042802 identical protein binding | IDA PMID:2775174 Purification and characterization of rat liver glycosylaspar... | KEEP AS NON CORE | Summary: Identical protein binding is biologically sound for the Aga gene product, because two identical single-chain precursors dimerise before autocatalytic cleavage and the mature enzyme is a dimer of identical alpha/beta units; the cited rat abstract itself shows only the 49 kDa alpha/beta assembly, so the row is kept as non-core oligomeric-state information (IDA, PMID:2775174). Reason: The cached abstract of PMID:2775174 reports that purified native rat liver Aga is a 49 kDa assembly of two non-identical subunits (24 kDa alpha and 20 kDa beta), and PMID:1554372 describes the native mammalian enzymes as heterodimers; alpha-beta association by itself is not binding between identical proteins. But the same gene product does engage in identical protein binding at two stages. Precursor activation requires two identical P30919 precursor chains to dimerise before autocatalytic cleavage exposes the Thr206 nucleophile, and UniProt records the mature enzyme as a heterotetramer arranged as a dimer of alpha/beta heterodimers (by similarity to human AGA), i.e. self-association of identical alpha/beta units. Either satisfies GO:0042802, so the term is correct for Aga even though the rat abstract is weak support for it, and the curator may have used full-text data not visible here. An earlier draft marked the row over-annotated on the heterodimer argument alone without engaging precursor dimerisation; changed to KEEP_AS_NON_CORE in response to review. Non-core because oligomerisation is a prerequisite for maturation rather than the enzyme's defining activity. GO:0042803 protein homodimerization activity would be more precise for the precursor dimer but was not adopted, since the mature unit is a dimer of heterodimers and the cited paper assayed neither form directly. Supporting Evidence: PMID:2775174 The native enzyme had a molecular mass of 49 kDa and was composed of two non-identical subunits joined by strong non-covalent forces PMID:1554372 The native enzyme appeared as a heterodimer among the mammals file:rat/Aga/Aga-deep-research-falcon.md Mature AGA assembles as an active **ฮฑฮฒ heterodimer** or more commonly an **ฮฑ2ฮฒ2 / (ฮฑฮฒ)2 tetramer**, depending on species and preparation. UniProtKB:P30919 SUBUNIT: Heterotetramer of two alpha and two beta chains arranged as a dimer of alpha/beta heterodimers. file:rat/Aga/Aga-deep-research-falcon.md Precursor molecules dimerize and undergo **autocatalytic cleavage** |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | ISO GO_REF:0000121 | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity transferred by orthology from pig AGA (RGD:13972209) matches the directly measured activity of rat liver Aga (ISO, GO_REF:0000121). Reason: Donor RGD:13972209 is the RGD record for pig (Sus scrofa) AGA. Pig liver glycosylasparaginase was characterised alongside the rat enzyme and shares the same alpha/beta subunit architecture and N-terminal sequence of both subunits, and the rat enzyme has its own direct activity measurement (IDA, PMID:2775174), so this orthology transfer is consistent with target-specific evidence. Duplicates the MGI- and human-donor ISO rows for the same term. Propagation Review Root cause: NO FAILURE CORE Sources checked: RGD:13972209 SUPPORTS TRANSFER RGD gene record for pig AGA (RGD species key 9 = pig, checked via the RGD REST API); the pig and rat liver enzymes are orthologous glycosylasparaginases with conserved subunit structure. Supporting Evidence: PMID:1554372 Identity of 80% of the amino acids was found between the N-terminal sequences of corresponding pig and rat glycosylasparaginase alpha- and beta-subunits PMID:2775174 The purified enzyme had a specific activity of 3.8 mumol of N-acetylglucosamine/min per mg with N4-(beta-N-acetylglucosaminyl)-L-asparagine as substrate. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | ISO GO_REF:0000121 | ACCEPT | Summary: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity transferred by orthology from human AGA (P20933) matches the directly measured activity of rat liver Aga (ISO, GO_REF:0000121). Reason: Donor UniProtKB:P20933 is human aspartylglucosaminidase, the well-characterised ortholog whose deficiency causes aspartylglucosaminuria. Rat Aga carries the same EC 3.5.1.26 activity by direct assay (IDA, PMID:2775174), so the transfer is consistent with target-specific evidence. Duplicates the MGI- and pig-donor ISO rows for the same term. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P20933 ยท AGA SUPPORTS TRANSFER Human AGA, the experimentally characterised ortholog; its glycosylasparaginase activity is the same EC 3.5.1.26 reaction measured for the purified rat enzyme. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. PMID:2775174 The purified enzyme had a specific activity of 3.8 mumol of N-acetylglucosamine/min per mg with N4-(beta-N-acetylglucosaminyl)-L-asparagine as substrate. |
| GO:0005764 lysosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: lysosome transferred by orthology from human AGA (P20933) is the correct compartment for this soluble lysosomal hydrolase, kept as non-core localization context (ISO, GO_REF:0000121). Reason: Donor UniProtKB:P20933 is human AGA, a soluble lysosomal hydrolase delivered via the mannose 6-phosphate pathway; UniProt places rat Aga in the lysosome. The localization is correct but records where the enzyme acts rather than its defining activity, consistent with the MGI-donor ISO, IBA and IEA lysosome rows. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P20933 ยท AGA SUPPORTS TRANSFER Human AGA donor; lysosomal localization of the human enzyme transfers directly to the rat ortholog. Supporting Evidence: UniProtKB:P30919 SUBCELLULAR LOCATION: Lysosome. file:rat/Aga/Aga-deep-research-falcon.md trafficked to lysosomes through the **mannose-6-phosphate (M6P) pathway**, and secreted AGA can be **recaptured by M6P receptorโmediated endocytosis** |
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