GAA encodes lysosomal acid alpha-glucosidase (acid maltase; EC 3.2.1.20), a glycoside-hydrolase-family-31 (GH31) enzyme that acts within the acidic lysosomal lumen to completely hydrolyse glycogen to glucose. It cleaves terminal, non-reducing alpha-1,4-glucosidic bonds with highest activity and, more slowly, alpha-1,6 branch linkages, degrading the glycogen delivered to lysosomes by autophagy (glycophagy). This lysosomal glycogenolysis is distinct from the cytosolic pathway carried out by glycogen phosphorylase and the debranching enzyme. The enzyme is synthesised as a ~110 kDa N-glycosylated precursor, tagged with mannose-6-phosphate for delivery to the lysosome via the mannose-6-phosphate receptor, and proteolytically matured into shorter (76 kDa and 70 kDa) forms. Catalysis proceeds by a retaining GH31 double-displacement mechanism using an aspartate nucleophile (Asp518) and an acid/base aspartate (Asp616). Loss of GAA activity causes Pompe disease (glycogen storage disease type II / acid maltase deficiency), an autosomal recessive lysosomal storage disorder in which glycogen accumulates in muscle, heart and other tissues; the infantile-onset form presents with hypertrophic cardiomyopathy and hypotonia, while late-onset disease manifests as a progressive limb-girdle and respiratory myopathy. Recombinant human GAA (alglucosidase alfa) is used for enzyme replacement therapy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004558 alpha-1,4-glucosidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred alpha-1,4-glucosidase activity. This is the well-established, experimentally supported core molecular function of GAA and is annotated at an appropriate level of specificity. Reason: GAA is the lysosomal acid alpha-glucosidase; UniProt records EC 3.2.1.20 with the catalytic reaction being hydrolysis of terminal, non-reducing (1->4)-linked alpha-D-glucose residues. The IBA is consistent with the GH31 family assignment and with the direct experimental annotations below. Supporting Evidence: file:human/GAA/GAA-uniprot.txt glucose residues with release of alpha-D-glucose.; EC=3.2.1.20; file:human/GAA/GAA-uniprot.txt Belongs to the glycosyl hydrolase 31 family. |
| GO:0005980 glycogen catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in glycogen catabolism. This is the core biological process of GAA: lysosomal degradation of glycogen to glucose. Reason: UniProt states GAA is essential for the degradation of glycogen in lysosomes, and PMID:29061980 describes GAA as involved in the lysosomal breakdown of glycogen. The IBA is supported by direct experimental annotations (PMID:29061980, PMID:9505277). Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes PMID:29061980 involved in the lysosomal breakdown of glycogen |
| GO:0007040 lysosome organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred role in lysosome organization. This reflects the downstream consequence of GAA activity (undegraded lysosomal glycogen distends and disrupts lysosomes when GAA is deficient) rather than a direct molecular role in organising the lysosome. Reason: GAA does not build or organise the lysosome; the connection is that loss of its catalytic activity leads to lysosomal glycogen accumulation and secondary lysosomal/autophagic pathology. This is a valid but non-core, consequence-of-deficiency association, so it is retained as non-core. Supporting Evidence: PMID:16917947 glycogen degradation and its accumulation in the lysosomes |
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based mapping to the broad O-glycosyl hydrolase parent term. This is correct but less informative than the specific alpha-1,4-glucosidase activity. Reason: GAA is an O-glycosyl-hydrolase (GH31), so this parent term is not wrong, but the specific and informative molecular function is alpha-1,4-glucosidase activity (GO:0004558). Retained as a correct broader classification. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Belongs to the glycosyl hydrolase 31 family. |
| GO:0004558 alpha-1,4-glucosidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt combined-methods / EC 3.2.1.20) assignment of the core alpha-1,4-glucosidase activity. Reason: The IEA maps EC:3.2.1.20 to GO:0004558, matching the experimentally established catalytic activity of GAA. Correct and at the right level of specificity. Supporting Evidence: file:human/GAA/GAA-uniprot.txt glucose residues with release of alpha-D-glucose.; EC=3.2.1.20; |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic subcellular-location assignment to lysosome, the primary site of action of GAA. Reason: GAA is the lysosomal acid alpha-glucosidase; UniProt records Lysosome as the subcellular location and it is directly demonstrated (PMID:9505277, PMID:29061980). Correct core localization. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Subcellular-location-vocabulary mapping to lysosomal membrane. GAA is a soluble lumenal enzyme that co-purifies with / is associated with the lysosomal membrane fraction. Reason: The mature enzyme is a soluble lumenal glucosidase, not an integral membrane protein, but UniProt lists Lysosome membrane as a location (detected in lysosomal membrane proteomics, PMID:17897319). This peripheral membrane association is retained as non-core; the core localization is the lysosomal lumen. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome PMID:17897319 In membranes purified from placental lysosomes, we identified 58 |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based mapping to the broad carbohydrate metabolic process parent. Reason: Correct but very general; the specific and informative process is glycogen catabolic process (GO:0005980). Retained as a correct broader classification. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0005980 glycogen catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic assignment of the core glycogen catabolic process. Reason: Matches the experimentally and phylogenetically supported core biological process of GAA (lysosomal glycogen degradation). Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0005984 disaccharide metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic assignment reflecting GAA's in-vitro ability to hydrolyse disaccharides such as maltose (hence "acid maltase"). Reason: GAA can cleave the disaccharide maltose in vitro, but its physiological substrate is lysosomal glycogen (a polymer), not free disaccharides; dietary disaccharide metabolism is the role of intestinal sucrase-isomaltase/maltase-glucoamylase. This is an over-annotation of the in-vitro substrate scope rather than the biological function. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro (galactose-mutarotase-like domain) mapping to carbohydrate binding. Reason: GAA necessarily binds its carbohydrate substrate (and a secondary carbohydrate-binding site exists in the trefoil domain, PMID:29061980), but "carbohydrate binding" is an uninformative molecular function that is subsumed by, and less useful than, the specific glucosidase catalytic activity. Flagged as over-annotation. Supporting Evidence: file:human/GAA/GAA-uniprot.txt GH31; Glycoside Hydrolase Family 31. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic "membrane" location transferred electronically from the mouse ortholog. Reason: "Membrane" is an uninformative cellular-component term for a soluble lumenal lysosomal enzyme; the informative locations are lysosome / lysosomal lumen. Over-annotation. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0061723 glycophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Involvement in glycophagy (autophagy-mediated delivery and lysosomal degradation of glycogen), transferred from the mouse ortholog. GAA performs the terminal lysosomal glucosidase step of this pathway. Reason: Glycophagy is the physiological pathway by which glycogen reaches the lysosome for GAA-mediated degradation, so involvement is well justified. Retained as non-core relative to the direct molecular-function-linked process glycogen catabolic process. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0120282 autolysosome lumen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Activity in the autolysosome lumen, transferred from the mouse ortholog. The autolysosome (autophagosome-lysosome fusion product) is where autophagy-delivered glycogen is degraded by GAA. Reason: Consistent with GAA's role in degrading autophagy-delivered glycogen; the autolysosome lumen is a specific compartment of the broader lysosomal system. Retained as non-core; the core location is the lysosomal lumen. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0005980 glycogen catabolic process | TAS Reactome:R-HSA-70221 | ACCEPT | Summary: Reactome traceable assertion placing GAA in glycogen breakdown (glycogenolysis), specifically the lysosomal glycogen degradation reaction. Reason: Reactome curates GAA-mediated hydrolysis of lysosomal glycogen; consistent with the core biological process. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:18429042 Molecular and functional characterization of eight novel GAA... | ACCEPT | Summary: Experimental characterization of alpha-1,4-glucosidase activity through enzyme-activity assays of GAA and disease-causing missense mutants. Reason: Pittis et al. functionally characterized eight novel GAA mutations using enzyme activity and protein processing, confirming their detrimental effect on the protein and its (glucosidase) function; this directly supports the alpha-1,4-glucosidase activity of GAA. Supporting Evidence: PMID:18429042 detrimental effect of the eight mutations on the protein and its function |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:1856189 Human lysosomal alpha-glucosidase. Characterization of the c... | ACCEPT | Summary: Experimental characterization of the catalytic site of human lysosomal alpha-glucosidase, identifying Asp-518 as the essential active-site carboxylate. Reason: Hermans et al. used the active-site-directed inhibitor CBE and site-directed mutagenesis to define the catalytic residues (Trp-516, Asp-518) of GAA, with glycogen as the natural substrate; strong direct evidence for alpha-1,4-glucosidase activity. Supporting Evidence: PMID:1856189 Asp-518 is predicted to be the essential carboxylate in the active site PMID:1856189 The residues Trp-516 and Asp-518 are demonstrated |
| GO:0004558 alpha-1,4-glucosidase activity | EXP PMID:7717400 Leaky splicing mutation in the acid maltase gene is associat... | ACCEPT | Summary: GAA (acid alpha-glucosidase) catalytic activity assessed in the context of a leaky-splicing GSD II mutation, where residual normally-spliced mRNA yielded ~12% of normal active enzyme. Reason: Boerkoel et al. measured residual acid alpha-glucosidase activity in patients, directly relating enzyme activity to phenotype; supports the alpha-1,4-glucosidase activity of GAA. Supporting Evidence: PMID:7717400 An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II |
| GO:0090599 alpha-glucosidase activity | EXP PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-... | KEEP AS NON CORE | Summary: Demonstration that both alpha-1,4-glucosidase and alpha-1,6-glucosidase activities (at acidic pH 4) are absent in tissues of GSD II (Pompe) children, establishing GAA as the acid alpha-glucosidase. Reason: Correct but this is the broad parent (alpha-glucosidase activity) of the specific alpha-1,4-glucosidase activity (GO:0004558) that is annotated elsewhere; retained as a valid, less-specific classification. Supporting Evidence: PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-glucosidase |
| GO:0090599 alpha-glucosidase activity | TAS Reactome:R-HSA-9036729 | KEEP AS NON CORE | Summary: Reactome traceable assertion of alpha-glucosidase activity (in the module describing defective GAA that does not hydrolyse lysosomal glycogen). Reason: Correct broad molecular function; less specific than GO:0004558 alpha-1,4-glucosidase activity. Retained as non-core. Supporting Evidence: file:human/GAA/GAA-uniprot.txt glucose residues with release of alpha-D-glucose.; EC=3.2.1.20; |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:24417 The molecular heterogeneity of purified human liver lysosoma... | ACCEPT | Summary: Direct assay of purified human liver lysosomal alpha-glucosidase (acid alpha-glucosidase) supporting alpha-1,4-glucosidase activity. Reason: Murray et al. purified and characterized human liver acid alpha-glucosidase; direct biochemical evidence for the core catalytic activity of GAA. (Cached record is abstract/title only; deferring to the curator who read the full text.) Supporting Evidence: PMID:24417 The molecular heterogeneity of purified human liver lysosomal alpha-glucosidase |
| GO:0043896 glucan 1,6-alpha-glucosidase activity | IDA PMID:24417 The molecular heterogeneity of purified human liver lysosoma... | KEEP AS NON CORE | Summary: Direct evidence that purified human lysosomal alpha-glucosidase also hydrolyses alpha-1,6-linked glucans (branch points), a genuine secondary activity of GAA. Reason: GAA can hydrolyse alpha-1,6-linkages, which is important in the lysosome because no debranching enzyme is present there; however this activity is secondary, with a ~32-fold lower specificity constant than for alpha-1,4-linkages (PMID:29061980). Retained as a valid non-core secondary function. Supporting Evidence: PMID:29061980 Within the lysosome, no debranching enzyme is present and GAA must assure the hydrolysis of both Ξ±-1,4- and Ξ±-1,6-glycosidic linkages PMID:29061980 rhGAA shows clear preference for the former linkage, as the specificity constant on maltose is 32-fold higher when compared to the specificity constant on isomaltose |
| GO:0061723 glycophagy | IMP PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-... | KEEP AS NON CORE | Summary: Involvement in glycophagy inferred from the loss of acid glucosidase activities and consequent lysosomal glycogen storage in GSD II patients. Reason: The GSD II phenotype (absent acid alpha-1,4/1,6-glucosidase activities, lysosomal glycogen accumulation) places GAA in the glycophagy pathway. Retained as non-core relative to the direct process glycogen catabolic process. (Cached record is title-only; deferring to the curator.) Supporting Evidence: PMID:5264799 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-glucosidase |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:29061980 Structure of human lysosomal acid Ξ±-glucosidase-a guide for ... | ACCEPT | Summary: Structural and biochemical characterization of recombinant human GAA confirming alpha-1,4-glucosidase activity, catalytic residues, and substrate recognition. Reason: Roig-Zamboni et al. solved the rhGAA structure with substrate analogues and assigned the catalytic nucleophile/acid-base (D518/D616), directly supporting alpha-1,4-glucosidase activity with preference for alpha-1,4 over alpha-1,6 linkages. Supporting Evidence: PMID:29061980 the catalytic nucleophile and acid/base can be assigned to D518 and D616, respectively PMID:29061980 rhGAA shows clear preference for the former linkage, as the specificity constant on maltose is 32-fold higher when compared to the specificity constant on isomaltose |
| GO:0005980 glycogen catabolic process | IDA PMID:29061980 Structure of human lysosomal acid Ξ±-glucosidase-a guide for ... | ACCEPT | Summary: Direct evidence that GAA is involved in the lysosomal breakdown of glycogen. Reason: PMID:29061980 explicitly describes GAA as involved in the lysosomal breakdown of glycogen and characterizes its activity on glycogen-derived substrates; core biological process. Supporting Evidence: PMID:29061980 involved in the lysosomal breakdown of glycogen |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: Plasma-membrane localization asserted via Reactome neutrophil-degranulation (azurophil granule exocytosis) pathway. Reason: GAA is detected in neutrophil secretory granules (lysosome-related organelles) and appears at the plasma membrane upon degranulation/exocytosis; this is a specialized secretory context, not GAA's core lysosomal localization. Retained as non-core. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: Plasma-membrane localization asserted via Reactome neutrophil-degranulation (tertiary granule exocytosis) pathway. Reason: Duplicate of the plasma-membrane assignment from a related neutrophil degranulation module; specialized secretory context, non-core. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Plasma-membrane localization asserted via Reactome neutrophil-degranulation (ficolin-rich granule exocytosis) pathway. Reason: Duplicate of the plasma-membrane assignment from a related neutrophil degranulation module; specialized secretory context, non-core. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: Localization to azurophil (primary) granule membrane via Reactome neutrophil-degranulation curation. Reason: Azurophil granules are lysosome-related organelles; GAA is detected there, consistent with its lysosomal identity, but this is a specialized neutrophil context rather than the core lysosomal function. Retained as non-core. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0070821 tertiary granule membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: Localization to tertiary granule membrane via Reactome neutrophil-degranulation curation. Reason: Neutrophil tertiary (gelatinase) granules are lysosome-related organelles where GAA is detected; specialized context, non-core relative to the lysosomal lumen. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0101003 ficolin-1-rich granule membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Localization to ficolin-1-rich granule membrane via Reactome neutrophil-degranulation curation. Reason: Ficolin-1-rich (specific) granules are lysosome-related organelles where GAA is detected; specialized context, non-core relative to the lysosomal lumen. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | Summary: High-throughput detection of GAA in exosomes purified from expressed prostatic secretions in urine. Reason: Generic large-scale exosome proteomics detects many lysosomal/secreted proteins; this does not represent a specific functional localization of GAA and is uninformative relative to its lysosomal role. Flagged as over-annotation. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput detection of GAA in an NK-cell (YTS) membrane-proteome analysis. Reason: Generic "membrane" from a large-scale membrane-proteome dataset; uninformative for a soluble lysosomal lumenal enzyme. Over-annotation. Supporting Evidence: PMID:19946888 predicted as plausible membrane proteins |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9036729 | ACCEPT | Summary: Reactome traceable assertion placing mature GAA in the lysosomal lumen. Reason: The mature, proteolytically processed GAA is a soluble enzyme acting in the lysosomal lumen; this is the core, most-specific localization. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9036727 | ACCEPT | Summary: Reactome traceable assertion (GAA hydrolyzes lysosomal glycogen module) placing GAA in the lysosomal lumen. Reason: Core, most-specific localization of the mature soluble enzyme; consistent with the lysosomal glycogen-degradation reaction. Supporting Evidence: file:human/GAA/GAA-uniprot.txt SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:17897319}. Lysosome |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: High-throughput detection of GAA in urinary exosomes. Reason: Generic large-scale urinary-exosome proteomics; not a specific functional localization of GAA. Over-annotation (duplicate of the other exosome HDA). Supporting Evidence: PMID:19056867 we used |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Detection of GAA in a placental lysosomal-membrane proteome, reflecting association of the lumenal enzyme with the lysosomal membrane fraction. Reason: GAA co-purifies with lysosomal membranes but is a soluble lumenal enzyme, not an integral membrane protein; UniProt lists Lysosome membrane as a location based on this dataset. Retained as non-core; core location is the lysosomal lumen. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 |
| GO:0000023 maltose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | MARK AS OVER ANNOTATED | Summary: Curator inference (from GO:0004558) that GAA participates in maltose metabolism, reflecting its historical name "acid maltase" and its in-vitro hydrolysis of maltose. Reason: Maltose is a convenient in-vitro substrate for GAA, but the physiological substrate is lysosomal glycogen (a polymer); there is no evidence GAA has a biological role in maltose metabolism (dietary maltose is handled by intestinal maltase-glucoamylase/sucrase-isomaltase). This IC extrapolation from the enzyme activity over-states the biological process. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0004558 alpha-1,4-glucosidase activity | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Direct assay of recombinant human acid alpha-glucosidase (GAA) activity in enzyme-replacement experiments correcting deficient fibroblasts/myoblasts. Reason: Yang et al. showed recombinant GAA normalizes intracellular GAA and glycogen levels in deficient cells; the enzyme is endocytosed via mannose-6-phosphate receptor and localizes to lysosomes. Direct evidence for the alpha-1,4-glucosidase activity of GAA. Supporting Evidence: PMID:9505277 and glycogen levels in deficient human |
| GO:0005764 lysosome | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Immunofluorescence demonstration that endocytosed recombinant GAA localizes to lysosomes (mannose-6-phosphate-receptor-mediated uptake). Reason: Yang et al. showed the endocytosed enzyme localized to the lysosomes on immunofluorescence staining, with uptake inhibited by mannose-6-phosphate. Direct evidence for the core lysosomal localization. Supporting Evidence: PMID:9505277 the endocytosed enzyme localized to the PMID:9505277 endocytosis was inhibited by |
| GO:0005980 glycogen catabolic process | IDA PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | ACCEPT | Summary: Direct evidence that GAA activity reduces intracellular glycogen, correcting the storage defect in GAA-deficient cells. Reason: Recombinant GAA normalized both intracellular GAA and glycogen levels in deficient human fibroblasts, directly demonstrating its role in glycogen catabolism. Supporting Evidence: PMID:9505277 and glycogen levels in deficient human |
| GO:0005985 sucrose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | MARK AS OVER ANNOTATED | Summary: Curator inference (from GO:0004558) that GAA participates in sucrose metabolism. Reason: GAA is not a sucrase; sucrose hydrolysis is the role of intestinal sucrase-isomaltase. This IC extrapolation from alpha-glucosidase activity to sucrose metabolism is not biologically supported for GAA and is an over-annotation. Supporting Evidence: file:human/GAA/GAA-uniprot.txt Essential for the degradation of glycogen in lysosomes |
| GO:0006006 glucose metabolic process | IC PMID:9505277 Recombinant human acid alpha-glucosidase corrects acid alpha... | KEEP AS NON CORE | Summary: Curator inference (from GO:0004558) that GAA participates in glucose metabolism, reflecting that its reaction releases free glucose from glycogen. Reason: GAA does release alpha-D-glucose as its product, so glucose metabolic process is a valid but broad parent-type association; retained as non-core relative to the specific glycogen catabolic process. Supporting Evidence: file:human/GAA/GAA-uniprot.txt glucose residues with release of alpha-D-glucose.; EC=3.2.1.20; |
| GO:0007040 lysosome organization | IMP PMID:7717400 Leaky splicing mutation in the acid maltase gene is associat... | KEEP AS NON CORE | Summary: Involvement in lysosome organization inferred from a GSD II patient phenotype (leaky-splicing mutation with reduced enzyme causing lysosomal glycogen storage). Reason: As with the IBA lysosome-organization annotation, this reflects the downstream consequence of GAA deficiency (lysosomal glycogen accumulation and secondary lysosomal disruption) rather than a direct organizing role. Retained as non-core. (Cached record is abstract-only; deferring to the curator's full-text reading.) Supporting Evidence: PMID:7717400 An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II |
| GO:0002086 diaphragm contraction | IMP PMID:16917947 Mutation profile of the GAA gene in 40 Italian patients with... | MARK AS OVER ANNOTATED | Summary: Involvement in diaphragm contraction inferred from the respiratory/diaphragm muscle failure seen in late-onset Pompe disease patients. Reason: Diaphragm/respiratory muscle failure is a clinical consequence of glycogen accumulation in GAA-deficient muscle, not a molecular function of GAA in muscle contraction. This disease-phenotype-to-process annotation over-states GAA's biological role; the underlying defect is impaired lysosomal glycogen degradation. (Cached record is abstract-only; deferring to the curator on the specific evidence.) Supporting Evidence: PMID:16917947 deficiency of acid alpha-glucosidase (GAA) that results in impaired |
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Download this section (compressed HTML)Q: Does GAA have any physiological substrate beyond lysosomal glycogen (e.g. a biological role for its in-vitro maltose/disaccharide-hydrolysing activity)?
Q: What is the functional significance of GAA's presence in neutrophil secretory granules and its detection at the plasma membrane upon degranulation?
Experiment: Quantify the relative in-vivo contribution of GAA's alpha-1,6 (debranching) activity to complete lysosomal glycogen clearance, e.g. using structurally defined branched substrates or branch-specific mutants.
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