AGA encodes aspartylglucosaminidase (glycosylasparaginase, EC 3.5.1.26), a lysosomal N-terminal nucleophile (Ntn) hydrolase of the asparaginase type 2 family. It is synthesized as a single-chain precursor that is cleaved autocatalytically in the endoplasmic reticulum into alpha and beta subunits, exposing the N-terminal threonine that serves both as the autocatalytic and the catalytic nucleophile; the mature enzyme is a dimer of alpha/beta heterodimers delivered to lysosomes by the mannose 6-phosphate pathway. In the lysosomal lumen AGA hydrolyses the N-glycosidic GlcNAc-Asn bond that links N-glycans to asparagine, a late step of N-glycoprotein degradation that requires prior removal of core fucose by FUCA1. Biallelic loss of AGA causes aspartylglucosaminuria, a progressive neurodegenerative glycoproteinosis with lysosomal storage and urinary excretion of aspartylglucosamine (GlcNAc-Asn).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | EXP PMID:1703489 Aspartylglucosaminuria: cDNA encoding human aspartylglucosam... | ACCEPT | Summary: cDNA cloning of human AGA and identification of the Finnish AGU missense allele; the activity is deficient in AGU. Reason: Core catalytic activity. Supporting Evidence: PMID:1703489 We have isolated a 2.1 kb cDNA which encodes human aspartylglucosaminidase (AGA, E.C. 3.5.1.26). The activity of this lysosomal enzyme is deficient in aspartylglucosaminuria (AGU) |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | EXP PMID:2401370 Cloning and sequence analysis of a cDNA for human glycosylas... | ACCEPT | Summary: cDNA cloning of human glycosylasparaginase showing it is encoded as a single precursor processed into two subunits. Reason: Core catalytic activity. Supporting Evidence: PMID:2401370 The human enzyme is encoded as a 34.6 kDa polypeptide that is post-translationally processed to generate two subunits |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of glycosylasparaginase activity; consistent with experimental data for the human enzyme. Reason: Core catalytic activity. Supporting Evidence: PMID:1281977 which hydrolyses the asparagine to N-acetylglucosamine linkages of glycoproteins and glycopeptides |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IDA PMID:1281977 Purification and structure of human liver aspartylglucosamin... | ACCEPT | Summary: Purified human liver aspartylglucosaminidase hydrolyses the GlcNAc-Asn linkage. Reason: Direct assay of the core activity. Supporting Evidence: PMID:1281977 which hydrolyses the asparagine to N-acetylglucosamine linkages of glycoproteins and glycopeptides |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (ARBA / mouse ortholog) to glycosylasparaginase activity; correct. Reason: Core catalytic activity. Supporting Evidence: PMID:27906067 AGU is caused by deficient activity of the lysosomal enzyme glycosylasparaginase that cleaves the N-glycosidic bond between the L-asparagine and N-acetylglucosamine moieties of GlcNAc-Asn. |
| GO:0003948 N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity | IMP PMID:1904874 Characterization of the mutation responsible for aspartylglu... | ACCEPT | Summary: The Finnish C163S mutation abolishes glycosylasparaginase activity and precursor processing on expression. Reason: Mutant analysis ties the activity to AGA. Supporting Evidence: PMID:1904874 Expression studies in COS-1 cells revealed only the Cys163----Ser mutation caused a deficiency of glycosylasparaginase activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction with KRTAP1-3 (HuRI). Reason: Uninformative protein binding from a systematic interaction screen with no functional context for a lysosomal lumenal hydrolase (removal does not mean the interaction is false). |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput binary interaction with KIF1B isoform (neurodegeneration-focused Y2H interactome). Reason: Uninformative protein binding from a systematic interaction screen with no functional context for a lysosomal lumenal hydrolase (removal does not mean the interaction is false). |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput binary interaction with WFS1 (neurodegeneration-focused Y2H interactome). Reason: Uninformative protein binding from a systematic interaction screen with no functional context for a lysosomal lumenal hydrolase (removal does not mean the interaction is false). |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: High-throughput binary interaction with NEFL (neurodegeneration-focused Y2H interactome). Reason: Uninformative protein binding from a systematic interaction screen with no functional context for a lysosomal lumenal hydrolase (removal does not mean the interaction is false). |
| GO:0005576 extracellular region | IDA PMID:25645918 Human neutrophils secrete bioactive paucimannosidic proteins... | KEEP AS NON CORE | Summary: Detected among proteins secreted from neutrophil azurophilic granules into infected sputum. Reason: Secretion by degranulation is real but not the site of the physiological function, which is the lysosome. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome neutrophil degranulation places AGA in the extracellular region after granule release. Reason: Secondary location after degranulation. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic is_active_in cytoplasm propagated from PANTHER node PTN000022481, which sits deeper than the node carrying the lysosome assertion; human AGA acts in the lysosomal lumen. Reason: AGA acts in the lysosomal lumen, and lysosomal lumen is the appropriate specific location. The qualifier is is_active_in, so replacing the term keeps that qualifier and gains precision, which is more useful than marking the row over-annotated; cytoplasm is not false, since lysosome is part of the cytoplasm in GO, but it does not say where a soluble acid hydrolase works. This matches the treatment of the identical IBA is_active_in cytoplasm row in NAGA. Proposed replacements: lysosomal lumen Supporting Evidence: PMID:27906067 AGU is caused by deficient activity of the lysosomal enzyme glycosylasparaginase that cleaves the N-glycosidic bond between the L-asparagine and N-acetylglucosamine moieties of GlcNAc-Asn. file:human/AGA/AGA-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic is_active_in lysosome; correct. Reason: Core location. Supporting Evidence: PMID:27906067 AGU is caused by deficient activity of the lysosomal enzyme glycosylasparaginase that cleaves the N-glycosidic bond between the L-asparagine and N-acetylglucosamine moieties of GlcNAc-Asn. |
| GO:0005764 lysosome | IDA PMID:8776587 Ser72Pro active-site disease mutation in human lysosomal asp... | ACCEPT | Summary: Wild-type and Ser72Pro mutant AGA are mannose-6-phosphorylated and targeted to lysosomes. Reason: Core location. Supporting Evidence: PMID:8776587 The mutant enzyme is, however, folded correctly enough to allow mannose-6-phosphorylation and targeting to lysosomes. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic lysosome annotation; correct. Reason: Core location. Supporting Evidence: PMID:27906067 AGU is caused by deficient activity of the lysosomal enzyme glycosylasparaginase that cleaves the N-glycosidic bond between the L-asparagine and N-acetylglucosamine moieties of GlcNAc-Asn. |
| GO:0005783 endoplasmic reticulum | IDA PMID:8776587 Ser72Pro active-site disease mutation in human lysosomal asp... | KEEP AS NON CORE | Summary: The AGA precursor undergoes its proteolytic activation cleavage in the ER. Reason: Biosynthetic transit and autoactivation site, not the site of the catabolic function. Supporting Evidence: PMID:8776587 specifically prevents the proteolytic activation cleavage of AGA in the endoplasmic reticulum (ER) |
| GO:0006517 protein deglycosylation | IDA PMID:1281977 Purification and structure of human liver aspartylglucosamin... | ACCEPT | Summary: Purified liver AGA removes the N-glycan from asparagine by hydrolysing the GlcNAc-Asn linkage. Reason: AGA cleaves the protein-glycan linkage; core process (together with glycoprotein catabolic process). Supporting Evidence: PMID:1281977 which hydrolyses the asparagine to N-acetylglucosamine linkages of glycoproteins and glycopeptides |
| GO:0006517 protein deglycosylation | IMP PMID:1904874 Characterization of the mutation responsible for aspartylglu... | ACCEPT | Summary: Loss of activity with the C163S AGU mutation. Reason: Core process. Supporting Evidence: PMID:1904874 Expression studies in COS-1 cells revealed only the Cys163----Ser mutation caused a deficiency of glycosylasparaginase activity. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic hydrolase activity from InterPro; correct but uninformative. Reason: The specific activity is experimentally established. Proposed replacements: N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity Supporting Evidence: PMID:1281977 which hydrolyses the asparagine to N-acetylglucosamine linkages of glycoproteins and glycopeptides |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome lists AGA as an azurophil granule cargo. Reason: Cell-type-specific lysosome-related storage compartment. |
| GO:0006516 glycoprotein catabolic process | TAS PMID:27906067 Aspartylglycosaminuria: a review. | NEW | Summary: AGA cleaves the GlcNAc-Asn linkage, a late step of lysosomal N-glycoprotein degradation; its deficiency is the commonest glycoprotein degradation disorder. Reason: AGA itself catalyses a step of the process; protein deglycosylation alone does not convey the catabolic, lysosomal context. Supporting Evidence: PMID:27906067 AGU is caused by deficient activity of the lysosomal enzyme glycosylasparaginase that cleaves the N-glycosidic bond between the L-asparagine and N-acetylglucosamine moieties of GlcNAc-Asn. PMID:27906067 AGU is the most common lysosomal storage disease caused by a disorder in degradation of glycoproteins. |
| GO:0016540 protein autoprocessing | IMP PMID:14616088 Autoproteolytic activation of human aspartylglucosaminidase. | NEW | Summary: The AGA precursor is activated by intramolecular autoproteolysis; the N-terminal nucleophile is both the autocatalytic and catalytic residue, and an active-site mutant precursor still self-activates extracellularly. Reason: Autoprocessing is performed by AGA on itself (the autoprocessing case in which the substrate does the work); non-core, maturation step. Supporting Evidence: PMID:14616088 the critical nucleophile functions both as the catalytic and autocatalytic residue PMID:8776587 suggest that the driving mechanism of AGA precursor cleavage is autocatalytic |
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Download this section (compressed HTML)Q: Beyond GlcNAc-Asn, which glycoasparagine and isoaspartyl substrates does human AGA process in vivo in neurons?
Suggested experts: lysosomal glycobiology experts
Experiment: Substrate profiling of recombinant human AGA against core-fucosylated and non-fucosylated glycoasparagines.
Hypothesis: Core fucosylation blocks AGA, making FUCA1 action a prerequisite.
Type: enzymology
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