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 Β· 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 receptorβmediated 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 AsnβGlcNAc 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. |
| 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 receptorβmediated endocytosis** |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: endoplasmic reticulum is retained as contextual support for Aga, but it is not the core function (ISO, GO_REF:0000121). Reason: endoplasmic reticulum 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: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. 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. |
| 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: The available evidence supports Aga's curated activity rather than biological_process; this annotation is unsupported, assigned to the wrong biological context, or too misleading to keep as non-core. Supporting Evidence: UniProtKB:P30919 FUNCTION: Cleaves the GlcNAc-Asn bond which joins oligosaccharides to the peptide of asparagine-linked glycoproteins. |
| GO:0042802 identical protein binding | IDA PMID:2775174 Purification and characterization of rat liver glycosylaspar... | MARK AS OVER ANNOTATED | Summary: identical protein binding reflects the homo-oligomeric assembly of active Aga (a dimer of identical alpha/beta protomers / alpha2beta2 tetramer) rather than its defining molecular activity, so it is marked as over-annotated (IDA, PMID:2775174). Reason: Falcon deep research clarifies that active Aga assembles by self-association of two identical alpha/beta heterodimers into an alpha2beta2 tetramer; the IDA identical protein binding annotation captures this oligomerization but is not informative of the enzyme's core catalytic function, so it is retained only as an over-annotation rather than removed. Supporting Evidence: PMID:2775174 Rat liver glycosylasparaginase [N4-(beta-N-acetylglucosaminyl)-L-asparaginase, EC 3.5.1.26] was purified to homogeneity. file:rat/Aga/Aga-deep-research-falcon.md Mature AGA assembles as an active **Ξ±Ξ² heterodimer** or more commonly an **Ξ±2Ξ²2 / (Ξ±Ξ²)2 tetramer**, depending on species and preparation. |
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