GLA encodes alpha-galactosidase A, a soluble lysosomal glycosidase that removes terminal alpha-D-galactose from glycosphingolipids and soluble oligosaccharides. Its substrates include globotriaosylceramide; saposin B assists hydrolysis of membrane-associated substrate. The glycosylated precursor enters the secretory pathway and matures after lysosomal delivery. Native human enzyme forms a homodimer. A fraction can be secreted and recaptured through uptake receptors. Deficient activity causes X-linked Fabry disease, with lysosomal lipid storage and multisystem manifestations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003824 catalytic activity | IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification... | TOO GENERAL | Summary: Human GLA is a glycosidase. Reason: The original enzymology supports catalysis; existing alpha-galactosidase annotations provide the informative specificity. Supporting Evidence: |
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000002 | TOO GENERAL | Summary: The hydrolase-family inference fits GLA chemistry. Reason: The existing alpha-galactosidase term is more informative than this parent activity. Supporting Evidence: GO_REF:0000002 |
| GO:0004557 alpha-galactosidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GLA retains ancestral alpha-galactosidase activity. Reason: The inspected AN5 assertion reaches human GLA without a loss. Human self-donation is valid experimental grounding. Supporting Evidence: GO_REF:0000033 |
| GO:0004557 alpha-galactosidase activity | IDA PMID:27211852 A novel mutation of Ξ±-galactosidase A gene causes Fabry dise... | ACCEPT | Summary: GLA substitutions reduce measured enzyme activity. Reason: The accessible abstract reports 293T expression assays. Independent enzymology supports the unqualified function; complete Methods remain unavailable. Supporting Evidence: |
| GO:0004557 alpha-galactosidase activity | IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification... | ACCEPT | Summary: Purified human GLA hydrolyzes alpha-galactosides. Reason: Original human-liver assays establish hydrolysis; the index-only cache has no quotable experimental passage. Supporting Evidence: |
| GO:0004557 alpha-galactosidase activity | IDA PMID:8804427 Only sphingolipid activator protein B (SAP-B or saposin B) s... | ACCEPT | Summary: Recombinant human GLA hydrolyzes Gb3. Reason: The labeled-liposome assay demonstrates catalysis. Sf9 production does not change the protein's species. Supporting Evidence: |
| GO:0004557 alpha-galactosidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The EC/Rhea inference matches GLA catalysis. Reason: Accept the established enzyme activity; these mappings are not additional experiments. |
| GO:0004557 alpha-galactosidase activity | IMP PMID:10838196 Characterization of two alpha-galactosidase mutants (Q279E a... | ACCEPT | Summary: Variant assays support alpha-galactosidase activity. Reason: The accessible abstract compares wild type and variants. Independent human enzymology supports acceptance despite unavailable complete Methods. Supporting Evidence: |
| GO:0004557 alpha-galactosidase activity | IMP PMID:16372133 Comparison of the effects of agalsidase alfa and agalsidase ... | ACCEPT | Summary: Replacement enzymes supply GLA activity. Reason: The accessible abstract corroborates established catalysis. Treatment preparations are not natural splice products; complete Methods remain unavailable. Supporting Evidence: |
| GO:0005102 signaling receptor binding | IDA PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | MARK AS OVER ANNOTATED | Summary: GLA binds a sorting receptor. Reason: The receptor-column experiment establishes M6PR cargo-sorting affinity; it does not test a signaling-receptor role. Flag that specificity while preserving the positive binding result. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | REMOVE | Summary: M6P-receptor affinity is retained. Reason: Generic binding is uninformative. Preserve literal bovine P08169; gifted-column Methods do not independently establish receptor species. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21949853 Receptor-mediated endocytosis of Ξ±-galactosidase A in human ... | REMOVE | Summary: Recombinant GLA directly binds purified human sortilin. Reason: SPR supports direct binding, and engineered HEK293 uptake supplies a delivery context. The enzyme is the cargo; sortilin performs receptor-mediated uptake. Generic protein binding therefore does not identify a more informative GLA activity, and no receptor, adaptor or signaling activity should be inferred. This removal preserves the positive pair. Individual in-vivo receptor contributions and exact purified construct boundaries remain unresolved. Supporting Evidence: PMID:21949853 SPR analysis showed binding of Ξ±-Gal A to purified and immobilized sortilin |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: GLA affinity purification recovered ALG11. Reason: Both BioPlex cell-line networks contain the exact P06280βQ2TAA5 pair, with GLA as bait in the directed releases. Preserve this positive association. Generic protein binding does not identify a specific GLA function; lysate AP-MS neither demonstrates direct molecular contact nor transfers the partnerβs catalytic role to GLA. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: TAX1BP3 pair retained. Reason: Generic binding is uninformative; the shared source guide explains fragment and compartment limitations. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: MPDZ pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: DLG1 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: SCRIB pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PDZK1 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: FRMPD2 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: MAGI2 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: NHERF4 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: LNX2 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: PATJ pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: LNX1 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: MAGI1 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: APBA2 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: GRIP2 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: WHRN pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: GRIP1 pair retained. Reason: Generic binding is uninformative. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: The U2OS interaction network links GLA with TAX1BP3. Reason: The original network contains the TAX1BP3-to-GLA edge; official UniProt identifies O14907 as TAX1BP3. Preserve the positive affinity-purification association while removing the uninformative generic-binding term. Global SEC or imaging validation is not pair-specific direct-binding evidence, and the partner does not establish a new GLA adapter function. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:6313412 ConA-mediated binding and uptake of purified alpha-galactosi... | REMOVE | Summary: Concanavalin A associates with human placental GLA in a delivery experiment. Reason: The authentic abstract reports enzyme stabilization and increased activity in Fabry fibroblasts with the lectin; the complete original remains unavailable. Preserve the reported association without asserting its uninspected molecular geometry. Generic protein binding does not describe a distinct GLA activity, and the added lectin is an experimental delivery aid. Supporting Evidence: |
| GO:0005576 extracellular region | IDA PMID:3029062 Synthesis and processing of alpha-galactosidase A in human f... | KEEP AS NON CORE | Summary: Human fibroblasts secrete GLA. Reason: Pulse-chase and altered-targeting experiments support secretion; processing bands are not natural isoforms. Supporting Evidence: PMID:3029062 in I-cell fibroblasts, the majority of newly synthesized alpha-galactosidase A was secreted |
| GO:0005576 extracellular region | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Extracellular GLA is experimentally supported. Reason: Human-fibroblast secretion corroborates this electronic location; lysosomal catalysis remains central. |
| GO:0005576 extracellular region | IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | KEEP AS NON CORE | Summary: Expressed GLA is secreted. Reason: Extracellular recovery is valid in the CHO expression context and secondary to lysosomal catalysis. Supporting Evidence: |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome places released GLA in the extracellular region. Reason: The event output set contains the exact P06280 entity in this compartment. This supports the existing location, not a claim that GLA performs exocytosis. Its modeled role here is released granule cargo. Supporting Evidence: Reactome:R-HSA-6798751 |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | TOO GENERAL | Summary: GLA acts within cytoplasmic organelles. Reason: The AN5 compartment assertion is compatible with lysosomal targeting. Cytoplasm includes organelles; the existing lysosomal terms are more informative. Supporting Evidence: GO_REF:0000033 |
| GO:0005737 cytoplasm | IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | TOO GENERAL | Summary: GLA occupies cytoplasmic organelles. Reason: Immunogold-positive vesicles support the broad location. Cytoplasm does not mean cytosol; existing lysosomal terms are more informative. Supporting Evidence: |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: GLA is lysosomal. Reason: Independent localization supports the electronic assertion. Preserve the root organelle alongside its lumen. |
| GO:0005764 lysosome | IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | ACCEPT | Summary: Expressed human GLA reaches lysosomes. Reason: Immunogold localization supports this organelle. Human protein and hamster expression host remain distinct. Supporting Evidence: PMID:1332979 in lysosomes which stained with immunogold particles using affinity-purified anti-human alpha-Gal A antibodies. |
| GO:0005764 lysosome | TAS PMID:3029062 Synthesis and processing of alpha-galactosidase A in human f... | ACCEPT | Summary: GLA reaches lysosomes during maturation. Reason: Selective organelle-rupture controls support localization. Precursor processing does not establish distinct natural products. Supporting Evidence: PMID:3029062 rapidly degraded following delivery to lysosomes. |
| GO:0005794 Golgi apparatus | IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its... | KEEP AS NON CORE | Summary: GLA enters presumed trans-Golgi structures. Reason: Retain the qualified overexpression-associated location as non-core; it does not establish Golgi-resident catalysis. Supporting Evidence: |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | TOO GENERAL | Summary: GLA participates in carbohydrate breakdown. Reason: This parent omits direction and substrate class; existing catabolic annotations are more informative. Supporting Evidence: GO_REF:0000002 |
| GO:0009311 oligosaccharide metabolic process | IBA GO_REF:0000033 | MODIFY | Summary: GLA inherits oligosaccharide breakdown. Reason: The AN5 placement is sound; human hydrolysis resolves the broader inherited process to its catabolic descendant. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000155295 Β· PTN000155295 SUPPORTS TRANSFER AN5 supports inheritance; the refinement concerns granularity, not transfer. Proposed replacements: oligosaccharide catabolic process Supporting Evidence: GO_REF:0000033 |
| GO:0009311 oligosaccharide metabolic process | IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification... | MODIFY | Summary: Human GLA hydrolyzes oligosaccharides. Reason: Original galactose-release assays establish catabolism. The immutable index-only cache supplies no experimental quotation; selected original Methods/Results ground this judgment. Proposed replacements: oligosaccharide catabolic process Supporting Evidence: |
| GO:0016139 glycoside catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: GLA retains glycoside catabolism. Reason: The AN5 assertion reaches GLA without a loss. Single-donor ancestry is valid; no worm-specific substrate is transferred. Supporting Evidence: GO_REF:0000033 |
| GO:0016787 hydrolase activity | TAS PMID:7911050 Molecular basis of Fabry disease: mutations and polymorphism... | TOO GENERAL | Summary: GLA is a hydrolase. Reason: This mutation review supplies disease context; the existing alpha-galactosidase term supplies the informative activity. Supporting Evidence: |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome includes GLA in the azurophil-granule lumen. Reason: The exact P06280 member belongs to the granule-lumen input set. Retain this specialized secretory compartment while keeping the lysosomal catalytic role central. Presence as cargo does not establish an exocytosis function. Supporting Evidence: Reactome:R-HSA-6798751 |
| GO:0042803 protein homodimerization activity | IDA PMID:6256390 Affinity purification of alpha-galactosidase A from human sp... | ACCEPT | Summary: Native splenic GLA forms a homodimer. Reason: Native human splenic enzyme is homodimeric. Retain this characteristic association without requiring every active recombinant preparation to be dimeric. Supporting Evidence: PMID:6256390 The purified enzyme was a homodimer |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605736 | ACCEPT | Summary: GLA acts in the lysosomal lumen. Reason: The reactionβs catalyst is the GLA dimer, whose component maps to human P06280 in the lumen. This directly supports the compartment of catalysis rather than merely placing an unrelated substrate nearby. Supporting Evidence: Reactome:R-HSA-1605736 |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9841189 | ACCEPT | Summary: Reactome assigns the GLA catalyst to the lysosomal lumen. Reason: The catalyst-to-dimer-to-P06280 chain explicitly identifies the enzyme in this compartment. Retain this location independently of the second substrate context; the same catalytic protein can support both existing location assertions. Supporting Evidence: Reactome:R-HSA-9841189 |
| GO:0045019 negative regulation of nitric oxide biosynthetic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The mouse donor supports a vascular NO-associated phenotype, with a broader functional inference. Reason: Mouse Gla loss increased vascular iNOS abundance and nitration, including an aged ApoE-wild-type comparison. This supports a downstream relationship, but the study did not measure NO biosynthetic flux or resolve a GLA-dependent NO-regulatory mechanism. The human process transfer overstates the functional specificity established by those readouts. |
| GO:0046477 glycosylceramide catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: GLA contributes to glycosylceramide breakdown. Reason: Mouse donor experiments and independent human catalysis support the transfer. Donor qualifiers are not new human experiments. |
| GO:0046479 glycosphingolipid catabolic process | IDA PMID:8804427 Only sphingolipid activator protein B (SAP-B or saposin B) s... | ACCEPT | Summary: GLA directly catalyzes Gb3 degradation. Reason: Labeled-substrate conversion establishes participation; saposin B assists presentation. Supporting Evidence: PMID:8804427 degradation of GbOse3Cer was dependent on the presence of both alpha-galactosidase and sphingolipid activator protein B |
| GO:0046479 glycosphingolipid catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: GLA catalyzes glycosphingolipid breakdown. Reason: The electronic inference agrees with direct chemistry, rather than depending only on storage phenotypes. |
| GO:0046479 glycosphingolipid catabolic process | IMP PMID:10838196 Characterization of two alpha-galactosidase mutants (Q279E a... | ACCEPT | Summary: Wild-type and variant GLA act on Gb3. Reason: The authentic abstract reports natural-substrate degradation. Independent enzymology supports acceptance despite unavailable complete Methods. Supporting Evidence: |
| GO:0046479 glycosphingolipid catabolic process | TAS PMID:2160973 Alpha-galactosidase A gene rearrangements causing Fabry dise... | ACCEPT | Summary: GLA participates in glycosphingolipid breakdown. Reason: Genetic deficiency supplies context; independent enzymology establishes GLA's actual catalytic step. Supporting Evidence: |
| GO:0051001 negative regulation of nitric-oxide synthase activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: NOS activity regulation is more specific than the donor measurements establish. Reason: The donor measured iNOS expression and tissue nitrotyrosine, rather than NOS catalytic activity. These observations support a vascular consequence of mouse Gla loss but do not resolve regulation of enzyme activity. Mark the transferred specificity as over-annotation without denying the observations or requiring direct physical GLAβNOS binding. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: GLA was detected in exosome-enriched prostatic-fluid urine preparations. Reason: Original supplementary Table 2 identifies P06280, including eight and six unique peptides in the two control pools. The supplementary methods describe differential ultracentrifugation and mass spectrometry. Retain the observed preparation-associated location; this does not establish vesicle topology, a diagnostic abundance difference or an exosome-mediated GLA function. Supporting Evidence: PMID:23533145 Exosomes were isolated by standard differential ultracentrifugation |
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Download this section (compressed HTML)Q: Which receptor contributions govern endogenous GLA recapture in individual tissues, and how can cargo recognition be represented without assigning signaling or uptake-receptor activity to the enzyme?
Suggested experts: Lysosomal trafficking researchers, GO molecular-function editors
Q: Which GLA terminal-peptide interactions remain measurable for the mature, glycosylated enzyme in its physiological compartment?
Q: Does the historical RNA-editing observation yield a reproducible endogenous protein product with altered activity? Current sequence records do not establish such a product.
Experiment: Compare endogenous GLA secretion and lysosomal recapture across relevant human cell types using individual receptor perturbations, compartment markers and catalytic-substrate measurements.
Experiment: Test selected terminal-peptide associations using mature GLA, appropriate compartment controls and reciprocal assays; distinguish contact from an effect on catalysis or trafficking.
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