GAA encodes lysosomal acid alpha-glucosidase, a glycoside hydrolase family 31 enzyme that releases glucose from glycogen in the acidic lysosomal lumen. It cleaves terminal alpha-1,4 linkages and the alpha-1,6 linkages needed to clear glycogen branches. The glycosylated precursor is targeted through mannose-6-phosphate-dependent trafficking and undergoes proteolytic maturation into active lysosomal forms. Deficient GAA activity causes Pompe disease, with lysosomal glycogen accumulation and prominent cardiac, skeletal-muscle and respiratory manifestations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000023 maltose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | KEEP AS NON CORE | Summary: Maltose metabolism is compatible with GAA chemistry and the termβs glycogen-intermediate scope. Reason: GO:0000023 explicitly includes maltose as an intermediate in glycogen and starch catabolism; it is not restricted to dietary digestion. The original IC infers this process from alpha-1,4-glucosidase activity, and PMID:29061980 directly measures human GAA maltose hydrolysis. PMID:9505277 establishes cellular glycogen correction rather than a separate maltose flux assay. Retain the inferred, non-core process with that distinction, instead of treating the lysosomal glycogen role as evidence against all maltose metabolism. No intestinal digestion role is asserted. |
| GO:0002086 diaphragm contraction | IMP PMID:16917947 Mutation profile of the GAA gene in 40 Italian patients with... | UNDECIDED | Summary: The diaphragm-contraction assertion remains unresolved at its experimental and mechanistic scope. Reason: PMID:16917947 describes 40 Italian late-onset patients and GAA variant activity/processing assays in deficient human cells. The accessible abstract does not establish the diaphragm-contraction endpoint. GO:0002086 concerns force generation by diaphragm muscle; GAA glycogen hydrolysis and respiratory disease alone do not establish that participation. The original full experimental evidence remains inaccessible, so this assertion is unresolved rather than treated as a demonstrated direct contractile role or a refuted curator claim. Supporting Evidence: |
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000002 | MODIFY | Summary: Refine the correct general O-glycosyl hydrolase assignment to the two established GAA linkage activities. Reason: The IPR000322 mapping is biologically correct, but direct human GAA evidence supports both alpha-1,4-glucosidase and glucan 1,6-alpha-glucosidase activities already asserted elsewhere in this review. Official GO typed is_a paths place both beneath alpha-glucosidase activity, glucosidase activity and GO:0004553. Replace the general parent with both supported descendants; this refinement does not label the InterPro assertion false or create new activities. Proposed replacements: alpha-1,4-glucosidase activity glucan 1,6-alpha-glucosidase activity |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:18429042 Molecular and functional characterization of eight novel GAA... | ACCEPT | Summary: The human Pompe variant study supports the established GAA catalytic function. Reason: The accessible PMID:18429042 abstract reports 29 unrelated patients and functional characterization of eight novel GAA mutations, including detrimental effects on the protein and its function. The complete assay details were not recovered, so no particular substrate concentration, activity value or construct result is asserted here. Retain the curator experimental annotation because its function is independently established by direct human biochemical work, including PMID:1856189 and PMID:29061980. |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:1856189 Human lysosomal alpha-glucosidase. Characterization of the c... | ACCEPT | Summary: Human GAA active-site inhibition and mutagenesis directly support glucosidase catalysis. Reason: The PMID:1856189 abstract reports competitive inhibition by conduritol B epoxide with glycogen and an artificial glucoside, covalent inhibitor labeling dependent on catalysis, and mutagenized human GAA cDNA expressed in COS cells. Trp516 and Asp518 were demonstrated to be important for catalytic function. The mechanistic assignment of Asp518 as the essential carboxylate was initially an inference from sequence and inhibitor chemistry; it should not be confused with a direct measurement of every catalytic intermediate. |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:7717400 Leaky splicing mutation in the acid maltase gene is associat... | ACCEPT | Summary: Residual active human GAA links the leaky-splicing allele to the established enzyme function. Reason: PMID:7717400 reports a leaky splice defect and approximately 12% of normal active enzyme from correctly spliced mRNA in an adult patient. This directly connects the human gene and retained enzymatic function; it is not merely a disease-title association. Detailed substrate-assay conditions remain outside the accessible abstract, while the alpha-1,4 activity is independently established in human biochemical studies. |
| GO:0004558 alpha-1,4-glucosidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The actual PAINT ancestry supports GAA alpha-1,4-glucosidase activity. Reason: In the retained PTHR22762 tree, human P10253 is AN454/PTN002503674 and descends from the literal IBD origin AN318/PTN002333501. The 952-residue target sequence matches the current canonical sequence, and the retained family records show no intervening loss annotation. The literal donor set matches the retained IBD and main PAINT slice. Human GAA is itself an experimentally annotated descendant, so its presence among donors is legitimate, not circular. This phylogenetic assertion agrees with the directly measured human catalytic activity. |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:24417 The molecular heterogeneity of purified human liver lysosoma... | ACCEPT | Summary: Alpha-1,4-glucosidase activity is established, although the original 1978 assays remain inaccessible. Reason: PMID:24417 resolves to the intended human liver lysosomal alpha-glucosidase paper, but the retained record and targeted access attempts provide no original experimental text. Do not infer detailed assays from its title. The annotated activity is nevertheless independently demonstrated for human GAA in PMID:1856189 and PMID:29061980, so the curator assertion is retained on that corroborating evidence, with the original reference and evidence code unchanged. |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:29061980 Structure of human lysosomal acid Ξ±-glucosidase-a guide for ... | ACCEPT | Summary: The recombinant human GAA study directly measures alpha-1,4 substrate hydrolysis. Reason: PMID:29061980 reports human CHO-derived recombinant enzyme structures with active-site inhibitors and kinetic measurements on maltose and glycogen at acidic pH. The crystallographic preparation was proteolyzed experimentally and retained comparable activity; it is not a newly established natural isoform. The inhibitor contacts and catalytic assignments support the same alpha-1,4 activity measured biochemically, without presenting the modeled isomaltose pose as a co-crystal. Supporting Evidence: |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Recombinant human GAA restores enzyme activity and glycogen handling in deficient cells. Reason: The PMID:9505277 abstract explicitly describes CHO-produced human GAA, uptake into deficient human fibroblasts and quail cells, restoration of intracellular enzyme activity, and normalization of glycogen in human fibroblasts. These experiments support the established glucosidase function. Human and quail recipient experiments are kept distinct; no claim that all assays used human recipient cells is made. |
| GO:0004558 alpha-1,4-glucosidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic assignment identifies the established alpha-1,4-glucosidase activity. Reason: The original combined-methods record retains its ARBA, ortholog and EC identifiers. EC 3.2.1.20 and the curated GAA chemistry agree with human active-site inhibition/mutagenesis and recombinant enzyme measurements. These independent biochemical observations support this activity; the electronic method is not being treated as a separate enzyme assay. |
| GO:0005764 lysosome | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Immunofluorescence places internalized recombinant human GAA in lysosomes. Reason: The PMID:9505277 abstract explicitly reports lysosomal localization in deficient human fibroblasts and the two quail recipient cell types after human recombinant GAA uptake. Mannose-6-phosphate inhibited uptake, and precursor processing was observed. These are direct localization/trafficking findings, not an inference from the protein name alone. Supporting Evidence: |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic lysosome assignment agrees with direct human-enzyme localization. Reason: The original combined-method identifiers and SL-0158 mapping are preserved. In PMID:9505277, internalized human GAA localized to lysosomes by immunofluorescence, and the human biochemical literature establishes its lysosomal glycogen-hydrolyzing role. The location is core; electronic provenance is not a reason to downgrade a well-supported compartment. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Human placental proteomics identifies GAA in an enriched lysosomal-membrane fraction. Reason: PMID:17897319 Table 1 identifies IPI00293088 with 24 peptides, 36.2% coverage and 112 spectral counts, enriched against the dense-pool reference. Retain this positive membrane-associated location as non-core. Peripheral proteins were not stripped, so integral topology remains unresolved. The selected original row and source provenance are reproduced in the linked evidence extract. Supporting Evidence: file:human/GAA/GAA-bioinformatics/RESULTS.md IPI00293088 | 24 | 36.2 | 112 | 1.80 | 1E-04 |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The lysosomal-membrane mapping is corroborated by human membrane-fraction proteomics. Reason: The literal SL-0157 mapping agrees with the human GAA identification in PMID:17897319 Table 1. The enriched placental fraction supports lysosomal-membrane association in addition to lumenal catalysis, without determining peripheral versus integral topology. The historical 957-residue accession and predicted transmembrane count are not current natural-product evidence. Supporting Evidence: GO_REF:0000044 file:human/GAA/GAA-bioinformatics/RESULTS.md file:human/GAA/GAA-uniprot.txt |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: The azurophil-exocytosis model explicitly places GAA in its plasma-membrane output set. Reason: Official R-HSA-6798739 output set 6806267 contains human GAA entity 6801041/P10253 at the plasma membrane; its input set 6798738 contains azurophil GAA entity 6800877. This literal membership supports the specialized TAS location rather than an absent-target inference. Retain it as non-core, with no claim that GAA catalyzes exocytosis or spans the membrane. The underlying granule-paper peptide/topology experiment was not independently read, and the modeled 70β952 range is not a distinct isoform assay. Supporting Evidence: Reactome:R-HSA-6798739 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: The tertiary-granule model explicitly includes GAA in its plasma-membrane output. Reason: Official R-HSA-6798747 output set 6806434 resolves to human GAA entity 6801041/P10253; input set 6799718 resolves to tertiary-granule entity 6801021. Retain this non-core, model-supported location. No GAA catalystActivity is assigned to the exocytosis event, and no integral topology or target-specific primary peptide assay was established in this reading. Supporting Evidence: Reactome:R-HSA-6798747 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: The ficolin-rich-granule model explicitly includes GAA in its plasma-membrane output. Reason: Official R-HSA-6800426 output set 6806514 includes GAA entity 6801041/P10253, linked to input set 6800437 with granule entity 6800913. This provides literal support for the specialized TAS location. Retain it as non-core without inventing a GAA role in the secretion machinery, membrane-spanning topology, or a separately assayed processed product. Supporting Evidence: Reactome:R-HSA-6800426 |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: Refine general carbohydrate metabolism to the established glycogen-catabolic process. Reason: The InterPro assignment is correct but less specific than direct human GAA evidence, which establishes glycogen hydrolysis and correction of glycogen accumulation. GO:0005980 is already asserted and is an is_a descendant of GO:0005975 through glycogen metabolism, glucan metabolism and polysaccharide metabolism in the official GO response. Replace this broad parent with glycogen catabolic process; the change refines specificity rather than refuting carbohydrate metabolism or adding a new process. Proposed replacements: glycogen catabolic process |
| GO:0005980 glycogen catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: The actual vertebrate PAINT origin supports the core glycogen-catabolic role. Reason: The literal GO:0005980 IBD is at AN444/PTN002734140 in PTHR22762, ancestral to human AN454/PTN002503674. The current 952-residue target matches the alignment, the incoming donor set matches the retained origin and main PAINT row, and no target-path loss is present in the retained records. Human P10253 is a legitimate experimental descendant among the donors. Human recombinant enzyme measurements and glycogen correction independently establish the inherited process; donor number is not used to grade the inference. |
| GO:0005980 glycogen catabolic process | IDA PMID:29061980 Structure of human lysosomal acid Ξ±-glucosidase-a guide for ... | ACCEPT | Summary: Human recombinant GAA directly hydrolyzes glycogen. Reason: The selected Methods in PMID:29061980 measure reducing equivalents released from bovine and rabbit glycogens by recombinant human GAA at pH 4 and 37 degrees Celsius. The organism supplying the carbohydrate substrate does not change the human identity of the enzyme. This is direct catalytic participation in glycogen catabolism, supported by the structurally and biochemically characterized human protein. Supporting Evidence: |
| GO:0005980 glycogen catabolic process | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Recombinant human GAA corrects glycogen accumulation in deficient human fibroblasts. Reason: The PMID:9505277 abstract states that intracellular GAA and glycogen levels in deficient human fibroblasts normalized after enzyme incubation and that the correction persisted for seven days. Together with GAAβs independently measured glycosidase activity, this supports direct glycogen degradation rather than only an unspecified rescue phenotype. Quail-cell results are additional recipient-model observations and are not mislabeled as human experiments. |
| GO:0005980 glycogen catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA glycogen-catabolism prediction agrees with direct human GAA evidence. Reason: ARBA00034181 remains the literal machine provenance. The process is independently supported by human GAA glycogen hydrolysis and correction of lysosomal glycogen accumulation in deficient human fibroblasts. This supports the predicted function without claiming that the ARBA rule itself is an experiment or that every rule condition was independently audited. |
| GO:0005980 glycogen catabolic process | TAS Reactome:R-HSA-70221 | ACCEPT | Summary: The glycogen-breakdown pathway explicitly contains the normal lysosomal GAA reaction. Reason: The official R-HSA-70221 record contains R-HSA-9036727 as a direct hasEvent child. That normal reaction assigns human GAA the hydrolysis of lysosomal glycogen to glucose. The broad pathway also includes cytosolic glycogenolysis, but its pathway-level cytosol compartment does not relocate the separately modeled lysosomal child. GAA performs the hydrolysis step; this is participation, not just membership in a disease-associated gene list. |
| GO:0005984 disaccharide metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The broad disaccharide process is supported by GAA maltose and isomaltose chemistry. Reason: ARBA00027065 is retained as the machine source. Human GAA directly hydrolyzes the disaccharides maltose and isomaltose, and the official maltose-process definition includes its glycogen-intermediate context. These observations support non-core retention of the broad disaccharide-metabolism annotation. They do not establish an intestinal dietary-digestion role or justify extending the claim to every disaccharide. |
| GO:0005985 sucrose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | MARK AS OVER ANNOTATED | Summary: The inference from alpha-1,4-glucosidase activity does not establish sucrose metabolism. Reason: The original IC cites GO:0004558, which specifies alpha-(1β4)-linked glucose hydrolysis, whereas sucrose is the distinct fructofuranosyl-glucopyranoside named in GO:0005985. The accessible PMID:9505277 experiments establish uptake and glycogen correction; the directly read PMID:29061980 substrate panel supports maltose, isomaltose and glycogen, not a sucrose pathway. The inferred process therefore exceeds the established substrate/process evidence. This is not a claim that a definitive negative sucrose assay was performed or that GAA can never act on sucrose under any condition. |
| GO:0006006 glucose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | KEEP AS NON CORE | Summary: Release of glucose during glycogen hydrolysis supports the broad glucose-metabolism inference. Reason: GAA catalyzes glycosidic-bond cleavage that releases free glucose; it is doing chemical work in the process, not simply being required upstream. The original IC is consistent with the measured human enzyme chemistry and cellular glycogen correction. Retain this broad process as non-core relative to lysosomal glycogen catabolism, without extending it to glucose transport, glycolysis or systemic glucose regulation. |
| GO:0007040 lysosome organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Valid ancestral placement and glycogen-clearance biology support a non-core lysosome-organization role. Reason: The actual GO:0007040 origin AN444/PTN002734140 lies on the human target path; its mouse and human descendant sources match the retained IBD. Combined with GAA-dependent lysosomal glycogen clearance, this supports the organizational/homeostatic context as non-core. The human self-donor is legitimate evidence used for ancestral placement. This assessment does not assign a separate lysosome-biogenesis activity. |
| GO:0007040 lysosome organization | IMP PMID:7717400 Leaky splicing mutation in the acid maltase gene is associat... | KEEP AS NON CORE | Summary: Retain lysosome organization as a non-core claim on the combined gene-level evidence. Reason: GAA-dependent lysosomal glycogen clearance and the verified GO:0007040 ancestral assertion support this non-core organizational context. PMID:7717400 establishes human residual-enzyme and disease relationships, but its accessible abstract does not expose the particular lysosomal endpoint behind this row. Retention uses the combined evidence for the gene-level claim; the original paper-specific morphology or organization assay remains unverified. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Refine the general membrane claim to the independently established lysosomal-membrane association. Reason: Human placental proteomics in PMID:17897319 provides positive GAA-specific evidence for the already-asserted descendant GO:0005765. The PMID:19946888 YTS abstract describes membrane isolation but does not expose a GAA target row; that original experimental context remains unverified. This conservative gene-level refinement rests on the independently supported compartment and does not claim that the YTS assay localized GAA to lysosomes. Proposed replacements: lysosomal membrane |
| GO:0016020 membrane | IEA GO_REF:0000107 | MODIFY | Summary: Refine the orthology-derived membrane claim to the supported lysosomal-membrane descendant. Reason: The original mouse ortholog identifiers and transfer provenance remain unchanged. Independent human placental proteomics identifies GAA in an enriched lysosomal-membrane fraction, supporting the already-asserted GO:0005765 and its verified is_a path to GO:0016020. Restrict this broad-row replacement to that experimentally supported compartment. The separate specialized Reactome location rows retain their own model-specific evidence and scope. Proposed replacements: lysosomal membrane |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: A second carbohydrate-analogue binding pocket supports broad binding as a non-core activity. Reason: PMID:29061980 directly resolves a second acarbose-derived ligand in the N-terminal trefoil pocket, about 25 Γ
from the catalytic-site ligand. This positive observation is additional to active-site substrate contacts and supports the broad carbohydrate-binding claim; neither GO:0030246 nor this evidence requires a lectin function. The preparation was proteolytically processed near G116βM122, and a contribution to endogenous glycogen processivity remains hypothetical. The domain mapping alone is not the basis for retention. |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: The azurophil-granule membrane set explicitly contains human GAA. Reason: In official R-HSA-6798739, input set 6798738 contains GAA entity 6800877/P10253 in the azurophil-granule membrane compartment. Retain the specific model-based location as non-core. This is not a generic lysosome quotation standing in for target evidence; nor does set membership establish GAA as an exocytosis catalyst or an integral membrane protein. Supporting Evidence: Reactome:R-HSA-6798739 |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9036727 | ACCEPT | Summary: The normal glycogen-hydrolysis model places the catalytic GAA species in the lysosomal lumen. Reason: Official R-HSA-9036727 assigns alpha-glucosidase catalysis through 5357535 to normal human GAA set 5357562, containing the modeled 70/76-kDa species in the lysosomal lumen. This agrees with direct human lysosomal localization and enzyme chemistry. The modelβs mature-species start coordinates are not used to invent exact end coordinates or new natural splice products. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9036729 | ACCEPT | Summary: The disease reaction preserves lysosomal-lumen context while distinguishing inactive mutant GAA. Reason: R-HSA-9036729 is a failed reaction involving the E521K/M318T GAA set, with an explicit normalReaction link to R-HSA-9036727 and loss-of-function linkage to the normal GAA set. Its disease status concerns catalysis; it is not evidence against the normal enzymeβs lysosomal-lumen location. Retain the original location annotation on this model context and the independently demonstrated human localization, without asserting that either named mutant has normal activity. |
| GO:0043896 glucan 1,6-alpha-glucosidase activity | IDA PMID:24417 The molecular heterogeneity of purified human liver lysosoma... | ACCEPT | Summary: Alpha-1,6-linkage hydrolysis is a core component of complete lysosomal glycogen breakdown. Reason: The original PMID:24417 experimental text is inaccessible, but PMID:29061980 independently measures recombinant human GAA hydrolysis of isomaltose and explicitly relates alpha-1,6 cleavage to lysosomal glycogen branches. The approximately 32-fold specificity-constant difference compares maltose with isomaltose under the reported assay conditions; it is not a universal glycogen linkage-rate ratio and does not make branch cleavage physiologically dispensable. Accept this established complementary catalytic activity. The modeled isomaltose pose is not claimed to be an observed human co-crystal. |
| GO:0061723 glycophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GAA hydrolysis supports a non-core role in the glycophagic degradation context. Reason: GAA performs glycogen hydrolysis after autophagic delivery to lysosomes, a catalytic contribution to degradation rather than an inert-substrate relationship. The literal mouse P70699 donor record contains an experimental glycophagy annotation as well as a separate ISO row. Combined with human GAA chemistry, this supports the specialized process as non-core. The donor record is method provenance; its complete primary experimental protocol has not been independently read. |
| GO:0061723 glycophagy | IMP PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-... | KEEP AS NON CORE | Summary: Retain glycophagy as a non-core gene-level claim while preserving the classic source-access limit. Reason: GO:0061723 covers selective glycogen degradation by macroautophagy, and GAA can catalyze the terminal lysosomal hydrolysis. Human enzyme evidence and the independently checked donor-based context support that participation. PMID:5264799 remains metadata/title-only; no specific macroautophagy assay or measurement is attributed to its unread full text. The original citation and relation are preserved while the action reflects the combined biological claim. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Urinary-exosome proteomics provides positive GAA fraction-membership evidence. Reason: The original NHLBI table links GAA identifications NP_000143 and NP_001073272 to PMID:19056867 through its reference-2 legend, with four and five peptides respectively. Retain this experimentally observed, non-core fraction association and the literal urine extension. A soluble protein need not be a surface receptor to be detected in this preparation; intravesicular topology and physiological EV function remain unresolved. The prior October 10 MO rationale is retained and reassessed explicitly in the notes. Independent PMID:27805059 additionally identifies GAA after three tetraspanin-specific urinary EV immunocaptures and detergent-free on-bead digestion, strengthening observed EV association without assigning an EV function. Supporting Evidence: file:human/GAA/GAA-bioinformatics/RESULTS.md NP_000143 | GAA | 4 | 1,2 |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: The original EPS-urine exosome supplement identifies P10253/GAA in both pooled groups. Reason: PMID:23533145 Supplemental Table 2 identifies GAA with 15, 14, 29 and 28 unique peptides across duplicate measurements of cancer and control pools. Differential ultracentrifugation, DTT/sucrose washing and an identification FDR below 1% support the observed fraction membership. Retain this non-core association while preserving the authorsβ caveats about soluble material and contaminants. These results do not resolve vesicle topology or a physiological EV function; the selected original data are reproduced in the linked extract. Independent PMID:27805059 additionally identifies GAA after three tetraspanin-specific urinary EV immunocaptures and detergent-free on-bead digestion, strengthening observed EV association without assigning an EV function. Supporting Evidence: file:human/GAA/GAA-bioinformatics/RESULTS.md P10253 | GAA | 15 | 14 | 29 | 28 file:human/GAA/GAA-bioinformatics/RESULTS.md GAA | P10253 | 23β39 |
| GO:0070821 tertiary granule membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: The tertiary-granule membrane model contains an explicit human GAA participant. Reason: Official R-HSA-6798747 input set 6799718 resolves to GAA entity 6801021/P10253 in the tertiary-granule membrane compartment. This supports a specialized non-core TAS location, with no claim that the underlying original granule proteomics or integral topology was independently verified. The same event transports this participant to a plasma-membrane output rather than assigning GAA an exocytosis catalyst role. Supporting Evidence: Reactome:R-HSA-6798747 |
| GO:0090599 alpha-glucosidase activity | EXP PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-... | MODIFY | Summary: Refine the correct broad alpha-glucosidase classification to both established linkage activities. Reason: PMID:5264799 remains the original source, but only bibliographic metadata and its title were accessible; no detailed historical assay is reconstructed. Independently read human GAA measurements in PMID:29061980 establish alpha-1,4 and alpha-1,6 hydrolysis. Both already-asserted activity terms are direct is_a children of GO:0090599 in the official GO response. Replace this parent with both supported descendants as a specificity refinement, without claiming the historical source or broad chemistry is false. Proposed replacements: alpha-1,4-glucosidase activity glucan 1,6-alpha-glucosidase activity |
| GO:0090599 alpha-glucosidase activity | TAS Reactome:R-HSA-9036729 | MODIFY | Summary: Refine the disease-model alpha-glucosidase parent using the linked normal GAA mechanism. Reason: Official R-HSA-9036729 is a FailedReaction involving mutant set 5357599 (E521K/M318T), with loss-of-function status 5357601 linking it to normal GAA set 5357562 and normalReaction 9036727. The linked normal catalyst 5357535 and independent human biochemical evidence establish alpha-1,4 and alpha-1,6 hydrolysis. Both already-asserted terms are direct is_a children of GO:0090599. Refine the correct broad annotation to both activities while preserving the original TAS reference; do not assign normal activity to the mutant products or interpret the failed-reaction title as a negative wild-type experiment. Proposed replacements: alpha-1,4-glucosidase activity glucan 1,6-alpha-glucosidase activity |
| GO:0101003 ficolin-1-rich granule membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: The ficolin-1-rich-granule membrane model explicitly includes GAA. Reason: Official R-HSA-6800426 input set 6800437 contains GAA entity 6800913/P10253 in the ficolin-1-rich-granule membrane compartment. Retain this specific non-core location on the actual target membership. It does not demonstrate membrane-spanning topology, a unique processed-product experiment, or GAA participation in the exocytotic machinery; those questions remain separate from the compartment assertion. Supporting Evidence: Reactome:R-HSA-6800426 |
| GO:0120282 autolysosome lumen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Autolysosome-lumen activity is a plausible, curated specialized localization of lysosomal GAA. Reason: The literal mouse P70699 donor has an experimental is_active_in autolysosome-lumen record, and the human annotation preserves the specified orthology identifiers. Human GAA is delivered to and active in the lysosomal lumen; autolysosomal glycogen degradation is compatible with that established activity. Retain this specialized compartment as non-core without replacing the original relation or claiming that the human source directly imaged autolysosomes. The official donor-record reading did not independently verify the full donor experiment. |
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Download this section (compressed HTML)Q: Do endogenous GAA molecules associate directly with lysosomal or neutrophil-granule membranes, and what distinguishes peripheral association from co-fractionation?
Q: What fraction of detected urinary or EPS-urine GAA is enclosed within extracellular vesicles rather than surface-associated or co-isolated soluble material?
Q: Does the secondary carbohydrate pocket observed after proteolysis contribute to glycogen binding or processivity in endogenous mature GAA?
Q: Which original measurements underlie the classic glycophagy, lysosome-organization and diaphragm-contraction annotations, and do the diaphragm data establish participation beyond downstream storage pathology?
Q: Is there a physiological sucrose-processing context for GAA beyond the currently supported glycogen, maltose and isomaltose chemistry?
Experiment: Measure cleavage of structurally defined branched glycogen substrates by mature human GAA, separating alpha-1,4 and alpha-1,6 turnover without extrapolating the disaccharide specificity ratio to whole polymers.
Experiment: Combine density-resolved extracellular-vesicle isolation with protease protection, detergent controls and target-specific GAA detection to distinguish enclosed, surface-associated and soluble co-isolated protein.
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