Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	REMOVE	Summary: Phylogenetic cytoplasm annotation conflicts with the established lysosomal-lumen localization of human GLA. Reason: The reviewed evidence supports lysosome/lysosomal lumen and secretory trafficking, not a cytoplasmic active location for this soluble lysosomal hydrolase. Supporting Evidence: file:human/GLA/GLA-notes.md Cytoplasm annotations are not supported by the accessible GLA evidence reviewed here; the direct localization papers support lysosome/lysosomal lumen, secretory trafficking, extracellular secretion/uptake, and overexpression-associated TGN aggregates instead.
GO:0004557 alpha-galactosidase activity	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen. file:human/GLA/GLA-deep-research-falcon.md Primary molecular function. Lysosomal α‑galactosidase A (EC 3.2.1.22) that removes terminal α‑galactose** from glycoconjugates
GO:0009311 oligosaccharide metabolic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Oligosaccharide metabolic process reflects the broader substrate class of alpha-galactosidases but is not the best summary of the human GLA core pathway. Reason: The central physiological process for GLA is lysosomal glycosphingolipid catabolism, while oligosaccharide substrate turnover is secondary/broader. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0016139 glycoside catabolic process	IBA GO_REF:0000033	MODIFY	Summary: Glycoside catabolic process is directionally correct but too broad for the characterized human GLA pathway. Reason: The specific core biological process supported for human GLA is glycosphingolipid catabolic process. Proposed replacements: glycosphingolipid catabolic process Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds	IEA GO_REF:0000002	MODIFY	Summary: Hydrolase activity hydrolyzing O-glycosyl compounds is true but too broad for the characterized GLA enzyme activity. Reason: The specific supported molecular function is alpha-galactosidase activity. Proposed replacements: alpha-galactosidase activity Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0004557 alpha-galactosidase activity	IEA GO_REF:0000120	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0005576 extracellular region	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Automated extracellular-region annotation reflects secretion/extracellular recovery of a lysosomal enzyme rather than the core site of action. Reason: GLA can be secreted or detected extracellularly, but the central functional compartment remains the lysosomal lumen. Supporting Evidence: file:human/GLA/GLA-notes.md Extracellular-region, extracellular-exosome, and azurophil-granule annotations are best treated as non-core localization/trafficking observations; they do not change the core function from lysosomal glycosphingolipid catabolism.
GO:0005764 lysosome	IEA GO_REF:0000120	ACCEPT	Summary: Automated lysosome annotation is consistent with the established subcellular location of alpha-galactosidase A. Reason: The enzyme is a lysosomal hydrolase acting in glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md The physiologically central compartment is the lysosomal lumen.
GO:0005975 carbohydrate metabolic process	IEA GO_REF:0000002	MODIFY	Summary: Carbohydrate metabolic process is a very broad automated inference from glycosidase domains. Reason: Human GLA should be represented by the more specific lysosomal glycosphingolipid catabolic process. Proposed replacements: glycosphingolipid catabolic process Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0046479 glycosphingolipid catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal GLA activity. Reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen: file:human/GLA/GLA-deep-research-falcon.md GLA function sits within lysosomal glycosphingolipid catabolism
GO:0005515 protein binding	IPI PMID:21949853 Receptor-mediated endocytosis of α-galactosidase A in human ...	MODIFY	Summary: Sortilin/M6PR/megalin uptake data support receptor binding rather than generic protein binding. Reason: The biologically interpretable function is binding endocytic/sorting receptors during uptake of secreted or therapeutic GLA. Proposed replacements: signaling receptor binding Supporting Evidence: file:human/GLA/GLA-notes.md Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors for uptake: file:human/GLA/GLA-deep-research-falcon.md Additional uptake routes reported in kidney cells include sortilin and megalin.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome evidence gives only a generic protein-binding annotation and does not define GLA function. Reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput interactions are not sufficient to add a core or specific GLA molecular function. Supporting Evidence: file:human/GLA/GLA-notes.md Generic protein binding is not informative for GLA.
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome evidence gives only a generic protein-binding annotation and does not define GLA function. Reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput interactions are not sufficient to add a core or specific GLA molecular function. Supporting Evidence: file:human/GLA/GLA-notes.md Generic protein binding is not informative for GLA.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome evidence gives only a generic protein-binding annotation and does not define GLA function. Reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput interactions are not sufficient to add a core or specific GLA molecular function. Supporting Evidence: file:human/GLA/GLA-notes.md Generic protein binding is not informative for GLA.
GO:0004557 alpha-galactosidase activity	IMP PMID:10838196 Characterization of two alpha-galactosidase mutants (Q279E a...	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0004557 alpha-galactosidase activity	IDA PMID:8804427 Only sphingolipid activator protein B (SAP-B or saposin B) s...	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0046479 glycosphingolipid catabolic process	IMP PMID:10838196 Characterization of two alpha-galactosidase mutants (Q279E a...	ACCEPT	Summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal GLA activity. Reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen:
GO:0046479 glycosphingolipid catabolic process	IDA PMID:8804427 Only sphingolipid activator protein B (SAP-B or saposin B) s...	ACCEPT	Summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal GLA activity. Reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen:
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798751	KEEP AS NON CORE	Summary: Reactome extracellular-region placement is compatible with neutrophil degranulation/exocytosis but is not the core GLA location. Reason: Extracellular release is a localization/trafficking observation; the catalytic role is lysosomal glycosphingolipid catabolism. Supporting Evidence: file:human/GLA/GLA-notes.md Extracellular-region, extracellular-exosome, and azurophil-granule annotations are best treated as non-core localization/trafficking observations; they do not change the core function from lysosomal glycosphingolipid catabolism.
GO:0035578 azurophil granule lumen	TAS Reactome:R-HSA-6798751	KEEP AS NON CORE	Summary: Azurophil-granule lumen placement is a specialized neutrophil granule localization and not the core site of GLA activity. Reason: Azurophil granules are lysosome-related secretory granules, whereas the conserved function is lysosomal lumen glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md Extracellular-region, extracellular-exosome, and azurophil-granule annotations are best treated as non-core localization/trafficking observations; they do not change the core function from lysosomal glycosphingolipid catabolism.
GO:0004557 alpha-galactosidase activity	IDA PMID:27211852 A novel mutation of α-galactosidase A gene causes Fabry dise...	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: High-throughput detection in urinary/prostatic exosome preparations is a non-core extracellular-vesicle localization. Reason: Exosome proteomics can capture secreted lysosomal enzymes, but it does not define the core compartment where GLA acts. Supporting Evidence: file:human/GLA/GLA-notes.md Extracellular-region, extracellular-exosome, and azurophil-granule annotations are best treated as non-core localization/trafficking observations; they do not change the core function from lysosomal glycosphingolipid catabolism.
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-1605736	ACCEPT	Summary: Reactome lysosomal-lumen annotation accompanies the modeled Gb3Cer hydrolysis reaction. Reason: The lysosomal lumen is the physiologically central compartment for GLA glycosphingolipid hydrolysis. Supporting Evidence: file:human/GLA/GLA-notes.md The physiologically central compartment is the lysosomal lumen.
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-9841189	ACCEPT	Summary: Reactome lysosomal-lumen annotation accompanies the modeled Gal2Cer hydrolysis reaction. Reason: The lysosomal lumen is the physiologically central compartment for GLA glycosphingolipid hydrolysis. Supporting Evidence: file:human/GLA/GLA-notes.md The physiologically central compartment is the lysosomal lumen.
GO:0046477 glycosylceramide catabolic process	ISS GO_REF:0000024	MODIFY	Summary: Glycosylceramide catabolic process is narrower/less appropriate than the established glycosphingolipid catabolic role for GLA. Reason: Human GLA acts on glycosphingolipids such as Gb3Cer and Gal2Cer; the replacement term captures that broader, well-supported pathway. Proposed replacements: glycosphingolipid catabolic process Supporting Evidence: file:human/GLA/GLA-notes.md Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen:
GO:0004557 alpha-galactosidase activity	IMP PMID:16372133 Comparison of the effects of agalsidase alfa and agalsidase ...	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0045019 negative regulation of nitric oxide biosynthetic process	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Nitric oxide biosynthesis regulation is a downstream disease/orthology phenotype, not a direct core process of the GLA hydrolase. Reason: The accessible evidence supports lysosomal glycosphingolipid degradation; NO regulation should not be represented as a human GLA core biological process. Supporting Evidence: file:human/GLA/GLA-notes.md Nitric-oxide and nitric-oxide-synthase regulation annotations are downstream Fabry-disease/orthology phenotypes rather than direct activities of the lysosomal hydrolase; they should not be represented as core biological processes for human GLA.
GO:0051001 negative regulation of nitric-oxide synthase activity	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Nitric-oxide synthase activity regulation is a downstream disease/orthology phenotype, not a direct process executed by GLA. Reason: The core biology is lysosomal glycosphingolipid catabolism, and NOS regulation is too indirect for a core GLA annotation. Supporting Evidence: file:human/GLA/GLA-notes.md Nitric-oxide and nitric-oxide-synthase regulation annotations are downstream Fabry-disease/orthology phenotypes rather than direct activities of the lysosomal hydrolase; they should not be represented as core biological processes for human GLA.
GO:0003824 catalytic activity	IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification...	MODIFY	Summary: Catalytic activity is too generic for the purified alpha-galactosidase A assay evidence. Reason: The direct assay supports the specific alpha-galactosidase activity term rather than generic catalytic activity. Proposed replacements: alpha-galactosidase activity Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0004557 alpha-galactosidase activity	IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification...	ACCEPT	Summary: Alpha-galactosidase activity is the core molecular function of GLA. Reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC 3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0005102 signaling receptor binding	IDA PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	KEEP AS NON CORE	Summary: Mannose-6-phosphate receptor binding is supported for secreted recombinant enzyme uptake/targeting, but it is not the core catalytic function. Reason: Receptor binding is a trafficking/uptake property of secreted or therapeutic enzyme; GLA remains primarily a lysosomal hydrolase. Supporting Evidence: file:human/GLA/GLA-notes.md Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors for uptake:
GO:0005515 protein binding	IPI PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	MODIFY	Summary: Generic protein binding masks the more specific mannose-6-phosphate receptor binding/lysosomal targeting evidence. Reason: The supported interaction is receptor binding by the secreted enzyme, not an unqualified protein-binding function. Proposed replacements: signaling receptor binding Supporting Evidence: file:human/GLA/GLA-notes.md Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors for uptake:
GO:0005515 protein binding	IPI PMID:6313412 ConA-mediated binding and uptake of purified alpha-galactosi...	REMOVE	Summary: ConA-mediated uptake uses an exogenous plant lectin and should not be treated as an endogenous GLA protein-binding function. Reason: The interaction is an experimental delivery/stabilization condition rather than a physiological human molecular function of GLA. Supporting Evidence: file:human/GLA/GLA-notes.md The ConA-mediated uptake study used concanavalin A to stabilize and deliver purified enzyme to Fabry fibroblasts, so a GO protein-binding annotation to ConA should not be treated as an endogenous GLA function
GO:0005576 extracellular region	IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	KEEP AS NON CORE	Summary: Extracellular region is supported for overexpressed/secreted enzyme but is secondary to lysosomal targeting. Reason: The paper describes selective secretion of overexpressed GLA while also showing lysosomal targeting; secretion is not the core location. Supporting Evidence: file:human/GLA/GLA-notes.md GLA enters the secretory/lysosomal trafficking pathway as a precursor and can be secreted under some conditions:
GO:0005576 extracellular region	IDA PMID:3029062 Synthesis and processing of alpha-galactosidase A in human f...	KEEP AS NON CORE	Summary: Secretion of precursor enzyme under NH4Cl/I-cell fibroblast conditions supports extracellular occurrence but not the core GLA location. Reason: This is a trafficking/secretion observation for a lysosomal enzyme rather than its catalytic compartment. Supporting Evidence: file:human/GLA/GLA-notes.md GLA enters the secretory/lysosomal trafficking pathway as a precursor and can be secreted under some conditions:
GO:0005737 cytoplasm	IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	REMOVE	Summary: The overexpression study localizes GLA aggregates to TGN and lysosomes and does not support cytoplasmic localization. Reason: Cytoplasm is inconsistent with the accessible localization evidence for this signal-peptide-containing lysosomal lumen enzyme. Supporting Evidence: file:human/GLA/GLA-notes.md Cytoplasm annotations are not supported by the accessible GLA evidence reviewed here; the direct localization papers support lysosome/lysosomal lumen, secretory trafficking, extracellular secretion/uptake, and overexpression-associated TGN aggregates instead.
GO:0005764 lysosome	IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	ACCEPT	Summary: Immunogold labeling of overexpressed enzyme in lysosomes supports lysosomal localization. Reason: This matches the established lysosomal hydrolase role of GLA. Supporting Evidence: file:human/GLA/GLA-notes.md The physiologically central compartment is the lysosomal lumen.
GO:0005764 lysosome	TAS PMID:3029062 Synthesis and processing of alpha-galactosidase A in human f...	ACCEPT	Summary: Fibroblast biosynthesis/processing data support delivery of mature alpha-galactosidase A to lysosomes. Reason: Processing and lysosomal delivery are part of the normal biogenesis of this lysosomal hydrolase. Supporting Evidence: file:human/GLA/GLA-notes.md GLA enters the secretory/lysosomal trafficking pathway as a precursor and can be secreted under some conditions:
GO:0005794 Golgi apparatus	IMP PMID:1332979 Overexpression of human alpha-galactosidase A results in its...	MARK AS OVER ANNOTATED	Summary: Golgi/TGN signal in this paper reflects overexpression-associated aggregation during trafficking, not a stable core localization. Reason: The TGN crystals arose under high overexpression and are better treated as a trafficking/overexpression phenotype than as a normal GLA cellular component. Supporting Evidence: file:human/GLA/GLA-notes.md Overexpression in CHO cells caused TGN and lysosomal crystalline aggregates and selective secretion; the authors explicitly proposed that aggregates forming in the acidic TGN are secreted when unable to bind M6P receptors, making Golgi/TGN accumulation an overexpression phenotype rather than the core location
GO:0009311 oligosaccharide metabolic process	IDA PMID:39940 Studies on human liver alpha-galactosidases. I. Purification...	KEEP AS NON CORE	Summary: Purified-enzyme work with oligosaccharide substrates supports a broader substrate range but not the main physiological process. Reason: This substrate-scope observation is secondary to the disease-relevant glycosphingolipid catabolic function. Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0016787 hydrolase activity	TAS PMID:7911050 Molecular basis of Fabry disease: mutations and polymorphism...	MODIFY	Summary: Hydrolase activity is too generic for a lysosomal alpha-galactosidase with known EC 3.2.1.22 activity. Reason: The annotation should use alpha-galactosidase activity to capture the specific enzymatic function. Proposed replacements: alpha-galactosidase activity Supporting Evidence: file:human/GLA/GLA-notes.md GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
GO:0042803 protein homodimerization activity	IDA PMID:6256390 Affinity purification of alpha-galactosidase A from human sp...	KEEP AS NON CORE	Summary: Protein homodimerization is directly supported for purified GLA and describes the active enzyme state. Reason: Homodimerization is a structural property important for the enzyme but not the primary molecular activity captured in the core function. Supporting Evidence: file:human/GLA/GLA-notes.md Purified human alpha-galactosidase A is a homodimeric enzyme:
GO:0046479 glycosphingolipid catabolic process	TAS PMID:2160973 Alpha-galactosidase A gene rearrangements causing Fabry dise...	ACCEPT	Summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal GLA activity. Reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid degradation. Supporting Evidence: file:human/GLA/GLA-notes.md Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen:

Core Functions

Hydrolyzes terminal alpha-D-galactose residues from lysosomal glycosphingolipids, especially globotriaosylceramide (Gb3Cer) and Gal2Cer, as a saposin-B-dependent homodimeric alpha-galactosidase A in the lysosomal lumen.

Molecular Function:

alpha-galactosidase activity

Directly Involved In:

glycosphingolipid catabolic process

Cellular Locations:

lysosomal lumen

Supporting Evidence:

file:human/GLA/GLA-notes.md
GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen.
file:human/GLA/GLA-notes.md
Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen:
file:human/GLA/GLA-notes.md
In a detergent-free liposomal system mimicking lysosomes, degradation of globotriaosylceramide was dependent on both recombinant human alpha-galactosidase and saposin B, and the authors concluded that "only SAP-B is essential for the degradation of GbOse3Cer by alpha-galactosidase"
file:human/GLA/GLA-deep-research-falcon.md
Pathway/process.** Lysosomal glycosphingolipid degradation; defects lead to Fabry disease pathophysiology
file:human/GLA/GLA-notes.md
Purified human alpha-galactosidase A is a homodimeric enzyme:

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10838196

Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease.

PMID:1332979

Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion.

PMID:16372133

Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice.

PMID:2160973

Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of short direct repeats at breakpoints in an Alu-rich gene.

PMID:21949853

Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:27211852

A novel mutation of α-galactosidase A gene causes Fabry disease mimicking primary erythromelalgia in a Chinese family.

PMID:3029062

Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:36115835

Quantitative fragmentomics allow affinity mapping of interactomes.

PMID:39940

Studies on human liver alpha-galactosidases. I. Purification of alpha-galactosidase A and its enzymatic properties with glycolipid and oligosaccharide substrates.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:6256390

Affinity purification of alpha-galactosidase A from human spleen, placenta, and plasma with elimination of pyrogen contamination. Properties of the purified splenic enzyme compared to other forms.

PMID:6313412

ConA-mediated binding and uptake of purified alpha-galactosidase A in Fabry fibroblasts.

PMID:7911050

Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene.

PMID:8804427

Only sphingolipid activator protein B (SAP-B or saposin B) stimulates the degradation of globotriaosylceramide by recombinant human lysosomal alpha-galactosidase in a detergent-free liposomal system.

Reactome:R-HSA-1605736

GLA hydrolyzes PSAP(195-273):Gb3Cer:PE

Reactome:R-HSA-6798751

Exocytosis of azurophil granule lumen proteins

Reactome:R-HSA-9841189

GLA hydrolyzes PSAP(195-273):Gal2Cer:PE

PMID:15003450

The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.

file:human/GLA/GLA-notes.md

Curator notes on GLA GO annotation review

file:human/GLA/GLA-deep-research-falcon.md

Falcon deep research on human GLA / alpha-galactosidase A

file:human/GLA/GLA-uniprot.txt

UniProtKB record for human GLA / alpha-galactosidase A

Suggested Experiments

Experiment: Compare endogenous GLA localization and receptor-dependent uptake in relevant human cell types with recombinant enzyme uptake assays.

Hypothesis: Extracellular/receptor-binding annotations represent trafficking and therapeutic-enzyme uptake rather than a distinct core GLA function.

Type: cell biology trafficking assay

Deep Research

Falcon

(GLA-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 32 citations 2026-05-13T20:49:25.444531

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: Human GLA (UniProt P06280) — functional annotation and translational relevance

1) Target verification (critical identity check)

The UniProt accession P06280 corresponds to human GLA, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A; “AGAL”) implicated in Fabry disease, an X‑linked lysosomal storage disorder. Multiple recent reviews explicitly state that GLA mutations/variants cause α‑Gal A deficiency, leading to lysosomal accumulation of globotriaosylceramide (Gb3; also referred to as GL‑3) and globotriaosylsphingosine (lyso‑Gb3). (umer2023treatmentoffabry pages 1-2, giliberti2024thelandscapeof pages 1-3, veldman2024establishingtreatmenteffectiveness pages 1-2)

2) Key concepts, definitions, and current understanding

2.1 Enzymatic function and substrate specificity

Biochemical role. α‑Gal A is a lysosomal glycosidase (reported as EC 3.2.1.22) that catalyzes removal of terminal α‑galactose residues from multiple glycoconjugate classes (glycolipids, glycoproteins, and oligosaccharides). (stancic2025aninvestigationinto pages 29-34)

Physiologic/pathologic substrates. The dominant disease-relevant substrate is Gb3/GL‑3, and deficiency results in progressive storage of Gb3 and its deacylated metabolite lyso‑Gb3 in multiple cell types (e.g., endothelium, cardiomyocytes, neurons, renal cells). (umer2023treatmentoffabry pages 1-2, giliberti2024thelandscapeof pages 1-3)

Catalytic mechanism (expert biochemical understanding). Mechanistic descriptions in the retrieved literature characterize α‑Gal A as a retaining glycosidase acting via double-displacement, with catalytic involvement of Asp residues (reported as Asp170 and Asp231). (stancic2025aninvestigationinto pages 29-34, kok2021oerkleefths pages 4-6)

2.2 Cellular localization, biogenesis, and trafficking

Lysosomal residency and targeting. α‑Gal A is synthesized in the endoplasmic reticulum and processed through the Golgi, where it acquires mannose‑6‑phosphate (M6P) on N‑linked glycans; M6P receptor (M6PR)–mediated trafficking/endocytosis delivers enzyme to lysosomes. (fibla2024advancedcharacterizationof pages 80-84, giliberti2024thelandscapeof pages 1-3)

Cross-correction principle. A fraction of lysosomal hydrolase can be secreted and recaptured via M6PR-mediated endocytosis into neighboring cells, a key concept underpinning enzyme replacement and some gene-therapy approaches for lysosomal enzymes. (fibla2024advancedcharacterizationof pages 80-84)

Additional uptake receptors/tissue specificity. Renal uptake of recombinant α‑Gal A is supported by receptor-mediated pathways including M6PR, sortilin, and megalin (notably in podocytes/tubules/endothelial compartments), and downregulation of M6P receptors in Fabry cardiomyopathy has been proposed as a barrier to optimal ERT efficacy in the heart. (giliberti2024thelandscapeof pages 13-14)

2.3 Pathway context

GLA function sits within lysosomal glycosphingolipid catabolism, where it is required to prevent lysosomal accumulation of Gb3 and downstream bioactive derivatives such as lyso‑Gb3. Storage is linked to multi-organ disease progression and is a central biochemical rationale for therapies that restore α‑Gal A function or reduce substrate burden. (umer2023treatmentoffabry pages 1-2, veldman2024establishingtreatmenteffectiveness pages 1-2)

3) Recent developments (prioritizing 2023–2024)

3.1 Biomarkers: lyso‑Gb3—utility and limitations

A 2024 expert consensus update (TSOC) states that Gb3 is converted to lyso‑Gb3, which is measurable in biological fluids and is a useful biomarker for diagnosis and severity assessment, including in females and late-onset Fabry disease. (hung20242024updateof pages 16-19)

The same consensus cautions that while lyso‑Gb3 is commonly used to monitor treatment, it has not been validated as a surrogate marker for long-term outcomes and may not reliably track endpoints such as LVMI (left ventricular mass index) or eGFR in treated patients. (hung20242024updateof pages 16-19, hung20242024updateof pages 15-16)

3.2 Evidence-quality challenges and expert analysis

A 2024 review focusing on treatment-effectiveness evaluation emphasizes that robust long-term evidence is hard to establish because Fabry disease cohorts are heterogeneous by sex, age, phenotype, and disease stage, and because study designs/outcomes vary; it advocates improved matching, harmonization, and registry-based approaches for future evidence generation. (veldman2024establishingtreatmenteffectiveness pages 1-2)

4) Current applications and real-world implementations (therapies targeting GLA biology)

4.1 Enzyme replacement therapy (ERT): agalsidase alfa/beta

ERT provides exogenous recombinant α‑Gal A to address the underlying enzyme deficiency and reduce progressive accumulation of Gb3/lyso‑Gb3. (germain2024pegunigalsidasealfaa pages 1-2, germain2024pegunigalsidasealfaa pages 2-3)

Dosing differences are summarized in recent reviews: agalsidase alfa 0.2 mg/kg IV q2w and agalsidase beta 1.0 mg/kg IV q2w, with otherwise identical amino acid sequence but different production/glycosylation. (germain2024pegunigalsidasealfaa pages 2-3)

Immunogenicity as a real-world limitation. Neutralizing anti-drug antibodies (ADAs) occur in a substantial fraction of treated males (reported ~40% for agalsidase alfa/beta), can cross-react, and are associated with worse prognosis; international recommendations highlight monitoring ADA presence/neutralizing activity and lyso‑Gb3 during ERT to support personalized management. (gomezcerezo2025currentstatusof pages 1-2, gomezcerezo2025currentstatusof pages 2-3)

4.2 Oral pharmacological chaperone: migalastat (amenable variants)

Migalastat is an oral pharmacological chaperone indicated for individuals with amenable GLA variants, stabilizing some mutant forms to improve lysosomal trafficking and function. (giliberti2024thelandscapeof pages 1-3, hung20242024updateof pages 15-16)

Amenability is defined by a validated cell assay; one summary describes criteria including an activity increase of ≥1.2-fold and ≥3% of wild-type in a HEK293 assay. (rydzek2026fabrydiseasea pages 12-14)

4.3 Next-generation (PEGylated) ERT: pegunigalsidase alfa (PRX‑102)

Concept. Pegunigalsidase alfa is a PEGylated recombinant α‑Gal A designed to improve stability and exposure, with the goal of mitigating limitations of conventional ERT such as rapid clearance and immunogenicity. (germain2024pegunigalsidasealfaa pages 1-2)

Quantitative pharmacology and outcomes (from recent synthesis). One recent synthesis reports an approximate plasma half-life of ~80–120 h for pegunigalsidase alfa compared with ≤2 h for agalsidase alfa/beta, and reports phase 3 trial evidence of non-inferiority to agalsidase beta on renal decline with an eGFR slope difference of −0.36 mL/min/1.73 m²/year (with confidence interval spanning 0 but meeting a prespecified non-inferiority boundary). (rydzek2026fabrydiseasea pages 12-14, germain2024pegunigalsidasealfaa pages 1-2)

Real-world implementation via labeled trials. Clinical trial registry information for the BRIGHT switchover study (NCT03180840) shows a phase 3, open-label single-group design switching stable ERT-treated adults to 2 mg/kg IV every 4 weeks for 52 weeks, with outcomes including treatment-related adverse events, eGFR, and plasma lyso‑Gb3; status is completed. (NCT03180840 chunk 1)

A table summarizing the pegunigalsidase alfa clinical development program (including BRIGHT/BRIDGE/BALANCE and NCT numbers) is shown in Germain & Linhart 2024. (germain2024pegunigalsidasealfaa media 6dadb80b)

5) Emerging/experimental directions (2023–2024 landscape framing)

5.1 Substrate reduction therapy (SRT)

Recent reviews include substrate reduction therapies (e.g., glucosylceramide synthase inhibition) as a strategy to decrease upstream glycosphingolipid burden, complementing or substituting for enzyme restoration in selected contexts. (giliberti2024thelandscapeof pages 1-3, carella2024overcomingresistancein pages 4-6)

5.2 Gene therapy and other delivery innovations

Reviews in the 2023–2024 period highlight gene therapy and mRNA approaches as key emerging modalities aiming for sustained α‑Gal A production and improved distribution. (lenders2025progressandchallenges pages 1-2, giliberti2024thelandscapeof pages 1-3)

A detailed summary of an ex vivo lentiviral gene therapy program (AVR‑RD‑01; NCT03454893) reports that 9 patients were treated; mean α‑Gal A activity increased and plasma/urine Gb3 decreased, with two renal biopsies showing 87% and 100% reductions of peritubular capillary Gb3, while 4/9 developed anti‑AGAL antibodies; the program was terminated prematurely for non-scientific (market/regulatory) reasons and variable responses. (lenders2025progressandchallenges pages 8-9)

6) Expert opinions and consensus points (authoritative sources)

Therapy initiation and monitoring (consensus). The 2024 TSOC expert consensus emphasizes early recognition and multimodal diagnosis (enzyme activity, genotyping, biomarkers including lyso‑Gb3, and advanced cardiac imaging) to support timely initiation of Fabry-specific therapy and longitudinal monitoring. (hung20242024updateof pages 1-2)

Monitoring nuances. TSOC explicitly supports lyso‑Gb3 as a useful diagnostic/severity biomarker but cautions against over-interpreting lyso‑Gb3 changes as a validated surrogate for long-term endpoints; the consensus also highlights that factors such as phenotype, sex, renal function, genotype amenability, and antidrug antibodies influence treatment decisions and monitoring. (hung20242024updateof pages 16-19)

7) Key quantitative statistics (recently cited in the retrieved evidence)

Topic	Key points (1–3 bullets)	Evidence/statistics	Key 2023–2024 (or nearest) sources with publication date and URL
Identity / enzymatic function	• UniProt P06280 corresponds to human GLA, encoding lysosomal alpha-galactosidase A. • Enzyme class: EC 3.2.1.22; a GH27 exo-retaining glycosidase that removes terminal α-galactose from glycolipids, glycoproteins, and oligosaccharides. • Key disease-relevant substrate is Gb3/GL-3; deficiency causes accumulation of Gb3 and lyso-Gb3 in Fabry disease. (umer2023treatmentoffabry pages 1-2, stancic2025aninvestigationinto pages 29-34, giliberti2024thelandscapeof pages 1-3)	• Catalytic mechanism described as double-displacement with catalytic Asp170 and Asp231. • Mature enzyme reported as a homodimer; monomer 429 aa including a 31-aa signal peptide. • Classic Fabry phenotype often associated with <2% AGAL activity; late-onset phenotypes around 2–20%. (stancic2025aninvestigationinto pages 29-34, lenders2025progressandchallenges pages 1-2, kok2021oerkleefths pages 4-6)	• Umer & Kalra, Pharmaceuticals (Feb 2023): https://doi.org/10.3390/ph16020320 (umer2023treatmentoffabry pages 1-2) • Giliberti et al., J Transl Genet Genom (Dec 2024): https://doi.org/10.20517/jtgg.2024.41 (giliberti2024thelandscapeof pages 1-3) • Stancic, 2025 nearest source in library (2025): no journal URL available in excerpt (stancic2025aninvestigationinto pages 29-34)
Localization / trafficking	• GLA is a lysosomal hydrolase synthesized in the ER, processed in the Golgi, and targeted via mannose-6-phosphate (M6P). • Recombinant or secreted enzyme can be recaptured by M6P receptor (M6PR)-mediated endocytosis and delivered to lysosomes. • Additional uptake routes reported in kidney cells include sortilin and megalin. (fibla2024advancedcharacterizationof pages 80-84, giliberti2024thelandscapeof pages 13-14, giliberti2024thelandscapeof pages 1-3)	• Lysosomal hydrolase activity occurs in acidic lumen at about pH 4.5–5. • Downregulation of M6P receptors in Fabry cardiomyopathy is noted as a possible barrier to ERT efficacy. (fibla2024advancedcharacterizationof pages 80-84, giliberti2024thelandscapeof pages 13-14)	• Giliberti et al., J Transl Genet Genom (Dec 2024): https://doi.org/10.20517/jtgg.2024.41 (giliberti2024thelandscapeof pages 13-14, giliberti2024thelandscapeof pages 1-3) • Fibla, 2024 nearest source in library (2024): no journal URL available in excerpt (fibla2024advancedcharacterizationof pages 80-84)
Biomarkers (lyso-Gb3)	• Lyso-Gb3 is a major circulating biomarker derived from accumulated Gb3. • It is useful for diagnosis, phenotyping/severity assessment, and pharmacodynamic monitoring, including in females and late-onset disease. • Important limitation: current consensus notes lyso-Gb3 is commonly used to monitor treatment but not fully validated as a surrogate for long-term clinical outcomes. (hung20242024updateof pages 16-19, hung20242024updateof pages 15-16, hung20242024updateof pages 1-2, gomezcerezo2025currentstatusof pages 1-2)	• TSOC consensus: ERT reduces plasma lyso-Gb3, with reported nadir around 11.1 months. • ADA monitoring is also recommended because neutralizing antibodies can alter pharmacodynamics and clinical response. (hung20242024updateof pages 15-16, gomezcerezo2025currentstatusof pages 1-2, gomezcerezo2025currentstatusof pages 2-3)	• Hung et al., Acta Cardiologica Sinica (Sep 2024): https://doi.org/10.6515/acs.202409_40(5).20240731a (hung20242024updateof pages 16-19, hung20242024updateof pages 15-16, hung20242024updateof pages 1-2) • Gómez-Cerezo et al., Orphanet J Rare Dis (May 2025, nearest): https://doi.org/10.1186/s13023-025-03705-4 (gomezcerezo2025currentstatusof pages 1-2, gomezcerezo2025currentstatusof pages 2-3)
Approved therapies	• Approved Fabry therapies directly linked to GLA biology include agalsidase alfa, agalsidase beta, migalastat (for amenable variants), and pegunigalsidase alfa. • Migalastat acts as a pharmacologic chaperone that stabilizes some mutant endogenous GLA proteins. • Pegunigalsidase alfa is a PEGylated recombinant α-Gal A with prolonged exposure and potentially lower immunogenicity. (germain2024pegunigalsidasealfaa pages 1-2, germain2024pegunigalsidasealfaa pages 2-3, lenders2025progressandchallenges pages 1-2, giliberti2024thelandscapeof pages 1-3)	• Dosing: agalsidase alfa 0.2 mg/kg IV q2w; agalsidase beta 1.0 mg/kg IV q2w; pegunigalsidase alfa 1.0 mg/kg IV q2w; migalastat 123 mg PO every other day. • Migalastat amenability assay threshold: ≥1.2-fold increase and ≥3% of wild-type activity in a validated HEK293 assay. • Pegunigalsidase alfa half-life about 80–120 h vs ≤2 h for agalsidase alfa/beta; BALANCE trial eGFR slope difference −0.36 mL/min/1.73 m²/year (95% CI −2.44 to 1.73), meeting non-inferiority criteria. • Neutralizing ADAs occur in about 40% of treated males receiving agalsidase alfa/beta; preliminary evidence suggests lower affinity/inhibition against pegunigalsidase alfa. (lenders2025progressandchallenges pages 1-2, germain2024pegunigalsidasealfaa pages 1-2, rydzek2026fabrydiseasea pages 12-14, gomezcerezo2025currentstatusof pages 1-2, gomezcerezo2025currentstatusof pages 2-3)	• Germain & Linhart, Front Genet (Apr 2024): https://doi.org/10.3389/fgene.2024.1395287 (germain2024pegunigalsidasealfaa pages 1-2, germain2024pegunigalsidasealfaa pages 2-3) • Giliberti et al., J Transl Genet Genom (Dec 2024): https://doi.org/10.20517/jtgg.2024.41 (giliberti2024thelandscapeof pages 1-3) • Umer & Kalra, Pharmaceuticals (Feb 2023): https://doi.org/10.3390/ph16020320 (umer2023treatmentoffabry pages 1-2)
Gene therapy trials	• Ex vivo lentiviral AVR-RD-01 and cardiac-tropic AAV 4D-310 are examples of emerging GLA gene-delivery strategies. • AVR-RD-01 trial enrolled treatment-naïve classic Fabry patients; study was later terminated. • 4D-310 remains listed as an active, not recruiting phase 1/2 study in adults with Fabry disease. (lenders2025progressandchallenges pages 8-9)	• AVR-RD-01 / NCT03454893: open-label Phase 1/2, planned enrollment 15; registry status terminated; review notes 9 treated patients, 4/9 developed anti-AGAL antibodies, and 2 renal biopsies showed 87% and 100% reductions in peritubular capillary Gb3. • 4D-310 / NCT04519749: Phase 1/2, enrollment 18, registry status active, not recruiting. • Migalastat comparator trial AT1001 / NCT01218659 (not gene therapy but relevant comparator): Phase 3, enrollment 68, completed. (lenders2025progressandchallenges pages 8-9)	• ClinicalTrials.gov registry entries: NCT04519749 (4D-310), NCT03454893 (AVR-RD-01), NCT01218659 (AT1001 comparator) as retrieved in current session (nearest sources; registry URLs not provided in excerpt) (lenders2025progressandchallenges pages 8-9) • Lenders et al., Biodrugs (May 2025, nearest): https://doi.org/10.1007/s40259-025-00723-3 (lenders2025progressandchallenges pages 8-9)

Table: This table summarizes the most relevant functional-annotation facts for human GLA (UniProt P06280), linking core enzymology and lysosomal trafficking to Fabry disease biomarkers and therapies. It is useful as a compact evidence-backed reference for gene/protein function and current translational relevance.

8) Visual evidence: PRX‑102 clinical trial landscape

A key table summarizing pegunigalsidase alfa (PRX‑102) trials (including NCT identifiers and study characteristics) is available from Germain & Linhart (Frontiers in Genetics, Apr 2024). (germain2024pegunigalsidasealfaa media 6dadb80b)

9) Practical functional-annotation summary (for databases / bench scientists)

Primary molecular function. Lysosomal α‑galactosidase A (EC 3.2.1.22) that removes terminal α‑galactose from glycoconjugates; physiologically critical for catabolism of Gb3/GL‑3 (and related α‑galactosylated glycolipids), preventing pathologic accumulation of Gb3 and lyso‑Gb3. (stancic2025aninvestigationinto pages 29-34, umer2023treatmentoffabry pages 1-2, giliberti2024thelandscapeof pages 1-3)

Cellular component. Lysosomal lumen enzyme, synthesized in ER/Golgi and targeted to lysosomes via M6P/M6PR-dependent trafficking; renal uptake of therapeutic enzyme also involves receptors such as sortilin/megalin in specific compartments. (fibla2024advancedcharacterizationof pages 80-84, giliberti2024thelandscapeof pages 13-14, giliberti2024thelandscapeof pages 1-3)

Pathway/process. Lysosomal glycosphingolipid degradation; defects lead to Fabry disease pathophysiology and define therapeutic strategies (ERT, chaperone therapy for amenable variants, next-generation ERT, and emerging gene/SRT approaches). (veldman2024establishingtreatmenteffectiveness pages 1-2, giliberti2024thelandscapeof pages 1-3, germain2024pegunigalsidasealfaa pages 1-2)

URLs and publication dates (where available in retrieved sources)

Umer M, Kalra DK. Treatment of Fabry Disease: Established and Emerging Therapies. Pharmaceuticals. 2023-02. https://doi.org/10.3390/ph16020320 (umer2023treatmentoffabry pages 1-2)
Germain DP, Linhart A. Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease. Frontiers in Genetics. 2024-04. https://doi.org/10.3389/fgene.2024.1395287 (germain2024pegunigalsidasealfaa pages 1-2)
Giliberti M et al. The landscape of current and future therapeutic opportunities for Fabry disease. Journal of Translational Genetics and Genomics. 2024-12. https://doi.org/10.20517/jtgg.2024.41 (giliberti2024thelandscapeof pages 1-3)
Veldman BCF et al. Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement. International Journal of Molecular Sciences. 2024-09. https://doi.org/10.3390/ijms25179752 (veldman2024establishingtreatmenteffectiveness pages 1-2)
Hung C-L et al. 2024 Update of the TSOC Expert Consensus of Fabry Disease. Acta Cardiologica Sinica. 2024-09. https://doi.org/10.6515/acs.202409_40(5).20240731a (hung20242024updateof pages 1-2)
ClinicalTrials.gov: NCT03180840 (BRIGHT; PRX‑102). (Registry URL typically: https://clinicaltrials.gov/study/NCT03180840) (NCT03180840 chunk 1)

Limitations of this report

Some mechanistic enzyme-chemistry details (e.g., full reaction equation and comprehensive substrate panel) are referenced indirectly via mechanistic summaries in the retrieved library rather than directly extracted from the classic structural enzymology primary papers; however, catalytic residues/mechanistic class and disease-relevant substrates are explicitly supported by the retrieved evidence. (stancic2025aninvestigationinto pages 29-34, kok2021oerkleefths pages 4-6)

References

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Citations

stancic2025aninvestigationinto pages 29-34
fibla2024advancedcharacterizationof pages 80-84
giliberti2024thelandscapeof pages 13-14
veldman2024establishingtreatmenteffectiveness pages 1-2
germain2024pegunigalsidasealfaa pages 2-3
rydzek2026fabrydiseasea pages 12-14
germain2024pegunigalsidasealfaa pages 1-2
lenders2025progressandchallenges pages 8-9
umer2023treatmentoffabry pages 1-2
giliberti2024thelandscapeof pages 1-3
kok2021oerkleefths pages 4-6
gomezcerezo2025currentstatusof pages 1-2
gomezcerezo2025currentstatusof pages 2-3
carella2024overcomingresistancein pages 4-6
lenders2025progressandchallenges pages 1-2
https://doi.org/10.3390/ph16020320
https://doi.org/10.20517/jtgg.2024.41
https://doi.org/10.6515/acs.202409_40(5
https://doi.org/10.1186/s13023-025-03705-4
https://doi.org/10.3389/fgene.2024.1395287
https://doi.org/10.1007/s40259-025-00723-3
https://doi.org/10.3390/ijms25179752
https://clinicaltrials.gov/study/NCT03180840
https://doi.org/10.3390/ph16020320,
https://doi.org/10.20517/jtgg.2024.41,
https://doi.org/10.3390/ijms25179752,
https://doi.org/10.6515/acs.202409_40(5
https://doi.org/10.3389/fgene.2024.1395287,
https://doi.org/10.1186/s13023-025-03705-4,
https://doi.org/10.3390/antiox15020168,
https://doi.org/10.3390/jcm13237195,
https://doi.org/10.1007/s40259-025-00723-3,

📚 Additional Documentation

Notes

(GLA-notes.md)

GLA notes

Core function and evidence

GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in the lysosomal lumen. UniProt states that GLA "Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome" and lists EC 3.2.1.22 alpha-galactosidase activity with reactions for globoside Gb3Cer hydrolysis [file:human/GLA/GLA-uniprot.txt].
Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized Gb3Cer and Gal2Cer in the lysosomal lumen: "Alpha-galactosidase A (GLA) ... removes the terminal galactose residue from glycolipids or glycoproteins, mobilized by PSAP(195-273) (Saposin B), resulting in galactose and an alcohol" [Reactome:R-HSA-1605736; Reactome:R-HSA-9841189].
In a detergent-free liposomal system mimicking lysosomes, degradation of globotriaosylceramide was dependent on both recombinant human alpha-galactosidase and saposin B, and the authors concluded that "only SAP-B is essential for the degradation of GbOse3Cer by alpha-galactosidase" PMID:8804427.
Mutant enzyme studies in Fabry variants confirm the same natural-substrate activity context: "the degradation of the natural substrate, globotriaosylceramide, by the alpha-galactosidases was analyzed in a detergent-free-liposomal system, in the presence of sphingolipid activator protein B" PMID:10838196.
Purified human alpha-galactosidase A is a homodimeric enzyme: Bishop and Desnick reported that "The purified enzyme was a homodimer with a native molecular weight of 101,000 and a subunit weight of 49,800" PMID:6256390, and the crystal structure likewise states that "The structure is a homodimer" PMID:15003450.

Localization and trafficking

The physiologically central compartment is the lysosomal lumen. UniProt lists subcellular location as "Lysosome" and Reactome places the Gb3Cer and Gal2Cer hydrolysis reactions in the lysosomal lumen [file:human/GLA/GLA-uniprot.txt; Reactome:R-HSA-1605736; Reactome:R-HSA-9841189].
GLA enters the secretory/lysosomal trafficking pathway as a precursor and can be secreted under some conditions: normal fibroblasts synthesize a phosphorylated precursor that is processed to a mature form, while NH4Cl and I-cell fibroblasts cause most newly synthesized enzyme to be secreted PMID:3029062.
Overexpression in CHO cells caused TGN and lysosomal crystalline aggregates and selective secretion; the authors explicitly proposed that aggregates forming in the acidic TGN are secreted when unable to bind M6P receptors, making Golgi/TGN accumulation an overexpression phenotype rather than the core location PMID:1332979.
Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors for uptake: the CHO overexpression study found that secreted enzyme had mannose-6-phosphate moieties and bound immobilized 215-kD M6PR PMID:1332979, and podocyte work identified M6PR, megalin, and sortilin as alpha-Gal A binding proteins important for uptake PMID:21949853.
Extracellular-region, extracellular-exosome, and azurophil-granule annotations are best treated as non-core localization/trafficking observations; they do not change the core function from lysosomal glycosphingolipid catabolism.
Cytoplasm annotations are not supported by the accessible GLA evidence reviewed here; the direct localization papers support lysosome/lysosomal lumen, secretory trafficking, extracellular secretion/uptake, and overexpression-associated TGN aggregates instead.

Annotation cautions

Generic protein binding is not informative for GLA. Physiologically interpretable binding evidence concerns receptor-mediated uptake by M6PR/sortilin/megalin, while BioPlex, fragmentomics/PDZ, and multimodal cell-map interaction datasets are high-throughput interactome resources that do not establish a core GLA molecular function [PMID:33961781; PMID:36115835; PMID:40205054].
The ConA-mediated uptake study used concanavalin A to stabilize and deliver purified enzyme to Fabry fibroblasts, so a GO protein-binding annotation to ConA should not be treated as an endogenous GLA function PMID:6313412.
Nitric-oxide and nitric-oxide-synthase regulation annotations are downstream Fabry-disease/orthology phenotypes rather than direct activities of the lysosomal hydrolase; they should not be represented as core biological processes for human GLA.

Falcon deep-research cross-check

Falcon deep research completed on 2026-05-13 and independently reinforced the existing review model: the target is human UniProt P06280 GLA/alpha-galactosidase A, a lysosomal enzyme whose primary molecular function is alpha-galactosidase activity and whose pathway context is lysosomal glycosphingolipid degradation [file:human/GLA/GLA-deep-research-falcon.md "Primary molecular function. Lysosomal α‑galactosidase A (EC 3.2.1.22) that removes terminal α‑galactose from glycoconjugates"; file:human/GLA/GLA-deep-research-falcon.md "Pathway/process. Lysosomal glycosphingolipid degradation; defects lead to Fabry disease pathophysiology"].
The Falcon report adds recent-review support that Fabry disease biochemistry is described in terms of Gb3/GL-3 plus downstream lyso-Gb3 accumulation, but this does not change the core GO curation from lysosomal alpha-galactosidase activity and glycosphingolipid catabolic process [file:human/GLA/GLA-deep-research-falcon.md "deficiency causes accumulation of Gb3 and lyso-Gb3 in Fabry disease"].
Falcon also corroborates treating M6PR/sortilin/megalin receptor evidence as trafficking or therapeutic-enzyme uptake rather than as the core enzyme function [file:human/GLA/GLA-deep-research-falcon.md "Additional uptake routes reported in kidney cells include sortilin and megalin."].

📄 View Raw YAML

id: P06280
gene_symbol: GLA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GLA encodes alpha-galactosidase A, a soluble lysosomal glycosidase and homodimeric
  glycoprotein that hydrolyzes terminal alpha-D-galactose residues from glycosphingolipids,
  especially globotriaosylceramide (Gb3Cer) and related glycolipids, in the lysosomal lumen.
  Loss of GLA activity causes Fabry disease, where Gb3/GL-3 and downstream lyso-Gb3
  accumulate in lysosomes; recombinant or secreted enzyme can be taken up by cells through mannose-6-phosphate/sortilin/megalin
  receptor-mediated trafficking, but receptor binding and extracellular detection are secondary
  to the core lysosomal catabolic role.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetic cytoplasm annotation conflicts with the established lysosomal-lumen
      localization of human GLA.
    action: REMOVE
    reason: The reviewed evidence supports lysosome/lysosomal lumen and secretory trafficking,
      not a cytoplasmic active location for this soluble lysosomal hydrolase.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Cytoplasm annotations are not supported by the accessible GLA evidence
        reviewed here; the direct localization papers support lysosome/lysosomal lumen, secretory
        trafficking, extracellular secretion/uptake, and overexpression-associated TGN aggregates
        instead.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
    - reference_id: file:human/GLA/GLA-deep-research-falcon.md
      supporting_text: 'Primary molecular function.** Lysosomal **α‑galactosidase A** (EC
        **3.2.1.22**) that removes terminal **α‑galactose** from glycoconjugates'
- term:
    id: GO:0009311
    label: oligosaccharide metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Oligosaccharide metabolic process reflects the broader substrate class of alpha-galactosidases
      but is not the best summary of the human GLA core pathway.
    action: KEEP_AS_NON_CORE
    reason: The central physiological process for GLA is lysosomal glycosphingolipid catabolism,
      while oligosaccharide substrate turnover is secondary/broader.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0016139
    label: glycoside catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Glycoside catabolic process is directionally correct but too broad for the characterized
      human GLA pathway.
    action: MODIFY
    reason: The specific core biological process supported for human GLA is glycosphingolipid
      catabolic process.
    proposed_replacement_terms: &id001
    - id: GO:0046479
      label: glycosphingolipid catabolic process
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0004553
    label: hydrolase activity, hydrolyzing O-glycosyl compounds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Hydrolase activity hydrolyzing O-glycosyl compounds is true but too broad for
      the characterized GLA enzyme activity.
    action: MODIFY
    reason: The specific supported molecular function is alpha-galactosidase activity.
    proposed_replacement_terms: &id002
    - id: GO:0004557
      label: alpha-galactosidase activity
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Automated extracellular-region annotation reflects secretion/extracellular recovery
      of a lysosomal enzyme rather than the core site of action.
    action: KEEP_AS_NON_CORE
    reason: GLA can be secreted or detected extracellularly, but the central functional compartment
      remains the lysosomal lumen.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Extracellular-region, extracellular-exosome, and azurophil-granule
        annotations are best treated as non-core localization/trafficking observations; they
        do not change the core function from lysosomal glycosphingolipid catabolism.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Automated lysosome annotation is consistent with the established subcellular
      location of alpha-galactosidase A.
    action: ACCEPT
    reason: The enzyme is a lysosomal hydrolase acting in glycosphingolipid degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: The physiologically central compartment is the lysosomal lumen.
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Carbohydrate metabolic process is a very broad automated inference from glycosidase
      domains.
    action: MODIFY
    reason: Human GLA should be represented by the more specific lysosomal glycosphingolipid
      catabolic process.
    proposed_replacement_terms: *id001
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal
      GLA activity.
    action: ACCEPT
    reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid
      degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
        Gb3Cer and Gal2Cer in the lysosomal lumen:'
    - reference_id: file:human/GLA/GLA-deep-research-falcon.md
      supporting_text: GLA function sits within lysosomal **glycosphingolipid catabolism**
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21949853
  review:
    summary: Sortilin/M6PR/megalin uptake data support receptor binding rather than generic
      protein binding.
    action: MODIFY
    reason: The biologically interpretable function is binding endocytic/sorting receptors
      during uptake of secreted or therapeutic GLA.
    proposed_replacement_terms: &id003
    - id: GO:0005102
      label: signaling receptor binding
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors
        for uptake:'
    - reference_id: file:human/GLA/GLA-deep-research-falcon.md
      supporting_text: Additional uptake routes reported in kidney cells include **sortilin**
        and **megalin**.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: High-throughput interactome evidence gives only a generic protein-binding annotation
      and does not define GLA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput
      interactions are not sufficient to add a core or specific GLA molecular function.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Generic protein binding is not informative for GLA.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36115835
  review:
    summary: High-throughput interactome evidence gives only a generic protein-binding annotation
      and does not define GLA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput
      interactions are not sufficient to add a core or specific GLA molecular function.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Generic protein binding is not informative for GLA.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: High-throughput interactome evidence gives only a generic protein-binding annotation
      and does not define GLA function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for a lysosomal enzyme and these high-throughput
      interactions are not sufficient to add a core or specific GLA molecular function.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Generic protein binding is not informative for GLA.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IMP
  original_reference_id: PMID:10838196
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IDA
  original_reference_id: PMID:8804427
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: IMP
  original_reference_id: PMID:10838196
  review:
    summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal
      GLA activity.
    action: ACCEPT
    reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid
      degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
        Gb3Cer and Gal2Cer in the lysosomal lumen:'
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8804427
  review:
    summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal
      GLA activity.
    action: ACCEPT
    reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid
      degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
        Gb3Cer and Gal2Cer in the lysosomal lumen:'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  review:
    summary: Reactome extracellular-region placement is compatible with neutrophil degranulation/exocytosis
      but is not the core GLA location.
    action: KEEP_AS_NON_CORE
    reason: Extracellular release is a localization/trafficking observation; the catalytic
      role is lysosomal glycosphingolipid catabolism.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Extracellular-region, extracellular-exosome, and azurophil-granule
        annotations are best treated as non-core localization/trafficking observations; they
        do not change the core function from lysosomal glycosphingolipid catabolism.
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  review:
    summary: Azurophil-granule lumen placement is a specialized neutrophil granule localization
      and not the core site of GLA activity.
    action: KEEP_AS_NON_CORE
    reason: Azurophil granules are lysosome-related secretory granules, whereas the conserved
      function is lysosomal lumen glycosphingolipid degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Extracellular-region, extracellular-exosome, and azurophil-granule
        annotations are best treated as non-core localization/trafficking observations; they
        do not change the core function from lysosomal glycosphingolipid catabolism.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IDA
  original_reference_id: PMID:27211852
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: High-throughput detection in urinary/prostatic exosome preparations is a non-core
      extracellular-vesicle localization.
    action: KEEP_AS_NON_CORE
    reason: Exosome proteomics can capture secreted lysosomal enzymes, but it does not define
      the core compartment where GLA acts.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Extracellular-region, extracellular-exosome, and azurophil-granule
        annotations are best treated as non-core localization/trafficking observations; they
        do not change the core function from lysosomal glycosphingolipid catabolism.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605736
  review:
    summary: Reactome lysosomal-lumen annotation accompanies the modeled Gb3Cer hydrolysis
      reaction.
    action: ACCEPT
    reason: The lysosomal lumen is the physiologically central compartment for GLA glycosphingolipid
      hydrolysis.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: The physiologically central compartment is the lysosomal lumen.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9841189
  review:
    summary: Reactome lysosomal-lumen annotation accompanies the modeled Gal2Cer hydrolysis
      reaction.
    action: ACCEPT
    reason: The lysosomal lumen is the physiologically central compartment for GLA glycosphingolipid
      hydrolysis.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: The physiologically central compartment is the lysosomal lumen.
- term:
    id: GO:0046477
    label: glycosylceramide catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Glycosylceramide catabolic process is narrower/less appropriate than the established
      glycosphingolipid catabolic role for GLA.
    action: MODIFY
    reason: Human GLA acts on glycosphingolipids such as Gb3Cer and Gal2Cer; the replacement
      term captures that broader, well-supported pathway.
    proposed_replacement_terms: *id001
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
        Gb3Cer and Gal2Cer in the lysosomal lumen:'
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IMP
  original_reference_id: PMID:16372133
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0045019
    label: negative regulation of nitric oxide biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Nitric oxide biosynthesis regulation is a downstream disease/orthology phenotype,
      not a direct core process of the GLA hydrolase.
    action: MARK_AS_OVER_ANNOTATED
    reason: The accessible evidence supports lysosomal glycosphingolipid degradation; NO regulation
      should not be represented as a human GLA core biological process.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Nitric-oxide and nitric-oxide-synthase regulation annotations are downstream
        Fabry-disease/orthology phenotypes rather than direct activities of the lysosomal
        hydrolase; they should not be represented as core biological processes for human GLA.
- term:
    id: GO:0051001
    label: negative regulation of nitric-oxide synthase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Nitric-oxide synthase activity regulation is a downstream disease/orthology phenotype,
      not a direct process executed by GLA.
    action: MARK_AS_OVER_ANNOTATED
    reason: The core biology is lysosomal glycosphingolipid catabolism, and NOS regulation
      is too indirect for a core GLA annotation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Nitric-oxide and nitric-oxide-synthase regulation annotations are downstream
        Fabry-disease/orthology phenotypes rather than direct activities of the lysosomal
        hydrolase; they should not be represented as core biological processes for human GLA.
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IDA
  original_reference_id: PMID:39940
  review:
    summary: Catalytic activity is too generic for the purified alpha-galactosidase A assay
      evidence.
    action: MODIFY
    reason: The direct assay supports the specific alpha-galactosidase activity term rather
      than generic catalytic activity.
    proposed_replacement_terms: *id002
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0004557
    label: alpha-galactosidase activity
  evidence_type: IDA
  original_reference_id: PMID:39940
  review:
    summary: Alpha-galactosidase activity is the core molecular function of GLA.
    action: ACCEPT
    reason: Multiple biochemical, disease-variant, Reactome, and UniProt lines support EC
      3.2.1.22 alpha-galactosidase activity toward alpha-D-galactosides/glycosphingolipids.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IDA
  original_reference_id: PMID:1332979
  review:
    summary: Mannose-6-phosphate receptor binding is supported for secreted recombinant enzyme
      uptake/targeting, but it is not the core catalytic function.
    action: KEEP_AS_NON_CORE
    reason: Receptor binding is a trafficking/uptake property of secreted or therapeutic enzyme;
      GLA remains primarily a lysosomal hydrolase.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors
        for uptake:'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:1332979
  review:
    summary: Generic protein binding masks the more specific mannose-6-phosphate receptor
      binding/lysosomal targeting evidence.
    action: MODIFY
    reason: The supported interaction is receptor binding by the secreted enzyme, not an unqualified
      protein-binding function.
    proposed_replacement_terms: *id003
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Recombinant or secreted alpha-Gal A can bind endocytic/sorting receptors
        for uptake:'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:6313412
  review:
    summary: ConA-mediated uptake uses an exogenous plant lectin and should not be treated
      as an endogenous GLA protein-binding function.
    action: REMOVE
    reason: The interaction is an experimental delivery/stabilization condition rather than
      a physiological human molecular function of GLA.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: The ConA-mediated uptake study used concanavalin A to stabilize and
        deliver purified enzyme to Fabry fibroblasts, so a GO protein-binding annotation to
        ConA should not be treated as an endogenous GLA function
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IMP
  original_reference_id: PMID:1332979
  review:
    summary: Extracellular region is supported for overexpressed/secreted enzyme but is secondary
      to lysosomal targeting.
    action: KEEP_AS_NON_CORE
    reason: The paper describes selective secretion of overexpressed GLA while also showing
      lysosomal targeting; secretion is not the core location.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'GLA enters the secretory/lysosomal trafficking pathway as a precursor
        and can be secreted under some conditions:'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:3029062
  review:
    summary: Secretion of precursor enzyme under NH4Cl/I-cell fibroblast conditions supports
      extracellular occurrence but not the core GLA location.
    action: KEEP_AS_NON_CORE
    reason: This is a trafficking/secretion observation for a lysosomal enzyme rather than
      its catalytic compartment.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'GLA enters the secretory/lysosomal trafficking pathway as a precursor
        and can be secreted under some conditions:'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IMP
  original_reference_id: PMID:1332979
  review:
    summary: The overexpression study localizes GLA aggregates to TGN and lysosomes and does
      not support cytoplasmic localization.
    action: REMOVE
    reason: Cytoplasm is inconsistent with the accessible localization evidence for this signal-peptide-containing
      lysosomal lumen enzyme.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Cytoplasm annotations are not supported by the accessible GLA evidence
        reviewed here; the direct localization papers support lysosome/lysosomal lumen, secretory
        trafficking, extracellular secretion/uptake, and overexpression-associated TGN aggregates
        instead.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IMP
  original_reference_id: PMID:1332979
  review:
    summary: Immunogold labeling of overexpressed enzyme in lysosomes supports lysosomal localization.
    action: ACCEPT
    reason: This matches the established lysosomal hydrolase role of GLA.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: The physiologically central compartment is the lysosomal lumen.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: TAS
  original_reference_id: PMID:3029062
  review:
    summary: Fibroblast biosynthesis/processing data support delivery of mature alpha-galactosidase
      A to lysosomes.
    action: ACCEPT
    reason: Processing and lysosomal delivery are part of the normal biogenesis of this lysosomal
      hydrolase.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'GLA enters the secretory/lysosomal trafficking pathway as a precursor
        and can be secreted under some conditions:'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IMP
  original_reference_id: PMID:1332979
  review:
    summary: Golgi/TGN signal in this paper reflects overexpression-associated aggregation
      during trafficking, not a stable core localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: The TGN crystals arose under high overexpression and are better treated as a trafficking/overexpression
      phenotype than as a normal GLA cellular component.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: Overexpression in CHO cells caused TGN and lysosomal crystalline aggregates
        and selective secretion; the authors explicitly proposed that aggregates forming in
        the acidic TGN are secreted when unable to bind M6P receptors, making Golgi/TGN accumulation
        an overexpression phenotype rather than the core location
- term:
    id: GO:0009311
    label: oligosaccharide metabolic process
  evidence_type: IDA
  original_reference_id: PMID:39940
  review:
    summary: Purified-enzyme work with oligosaccharide substrates supports a broader substrate
      range but not the main physiological process.
    action: KEEP_AS_NON_CORE
    reason: This substrate-scope observation is secondary to the disease-relevant glycosphingolipid
      catabolic function.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: TAS
  original_reference_id: PMID:7911050
  review:
    summary: Hydrolase activity is too generic for a lysosomal alpha-galactosidase with known
      EC 3.2.1.22 activity.
    action: MODIFY
    reason: The annotation should use alpha-galactosidase activity to capture the specific
      enzymatic function.
    proposed_replacement_terms: *id002
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
        core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids
        in the lysosomal lumen.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:6256390
  review:
    summary: Protein homodimerization is directly supported for purified GLA and describes
      the active enzyme state.
    action: KEEP_AS_NON_CORE
    reason: Homodimerization is a structural property important for the enzyme but not the
      primary molecular activity captured in the core function.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Purified human alpha-galactosidase A is a homodimeric enzyme:'
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: TAS
  original_reference_id: PMID:2160973
  review:
    summary: Glycosphingolipid catabolic process captures the core biological process of lysosomal
      GLA activity.
    action: ACCEPT
    reason: GLA hydrolyzes Gb3Cer/Gal2Cer and Fabry disease results from impaired glycosphingolipid
      degradation.
    supported_by:
    - reference_id: file:human/GLA/GLA-notes.md
      supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
        Gb3Cer and Gal2Cer in the lysosomal lumen:'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10838196
  title: Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an
    atypical variant of Fabry disease.
  findings: []
- id: PMID:1332979
  title: Overexpression of human alpha-galactosidase A results in its intracellular aggregation,
    crystallization in lysosomes, and selective secretion.
  findings: []
- id: PMID:16372133
  title: Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human
    Fabry fibroblasts and Fabry mice.
  findings: []
- id: PMID:2160973
  title: Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of
    short direct repeats at breakpoints in an Alu-rich gene.
  findings: []
- id: PMID:21949853
  title: Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions
    in urine.
  findings: []
- id: PMID:27211852
  title: A novel mutation of α-galactosidase A gene causes Fabry disease mimicking primary
    erythromelalgia in a Chinese family.
  findings: []
- id: PMID:3029062
  title: Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence
    for different mutations in Fabry disease.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:36115835
  title: Quantitative fragmentomics allow affinity mapping of interactomes.
  findings: []
- id: PMID:39940
  title: Studies on human liver alpha-galactosidases. I. Purification of alpha-galactosidase
    A and its enzymatic properties with glycolipid and oligosaccharide substrates.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:6256390
  title: Affinity purification of alpha-galactosidase A from human spleen, placenta, and plasma
    with elimination of pyrogen contamination. Properties of the purified splenic enzyme compared
    to other forms.
  findings: []
- id: PMID:6313412
  title: ConA-mediated binding and uptake of purified alpha-galactosidase A in Fabry fibroblasts.
  findings: []
- id: PMID:7911050
  title: 'Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase
    A gene.'
  findings: []
- id: PMID:8804427
  title: Only sphingolipid activator protein B (SAP-B or saposin B) stimulates the degradation
    of globotriaosylceramide by recombinant human lysosomal alpha-galactosidase in a detergent-free
    liposomal system.
  findings: []
- id: Reactome:R-HSA-1605736
  title: GLA hydrolyzes PSAP(195-273):Gb3Cer:PE
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9841189
  title: GLA hydrolyzes PSAP(195-273):Gal2Cer:PE
  findings: []
- id: PMID:15003450
  title: 'The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.'
  findings: []
- id: file:human/GLA/GLA-notes.md
  title: Curator notes on GLA GO annotation review
  findings: []
- id: file:human/GLA/GLA-deep-research-falcon.md
  title: Falcon deep research on human GLA / alpha-galactosidase A
  findings: []
- id: file:human/GLA/GLA-uniprot.txt
  title: UniProtKB record for human GLA / alpha-galactosidase A
  findings: []
core_functions:
- description: Hydrolyzes terminal alpha-D-galactose residues from lysosomal glycosphingolipids,
    especially globotriaosylceramide (Gb3Cer) and Gal2Cer, as a saposin-B-dependent homodimeric
    alpha-galactosidase A in the lysosomal lumen.
  molecular_function:
    id: GO:0004557
    label: alpha-galactosidase activity
  directly_involved_in:
  - id: GO:0046479
    label: glycosphingolipid catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: file:human/GLA/GLA-notes.md
    supporting_text: GLA encodes lysosomal alpha-galactosidase A, a glycosyl hydrolase whose
      core function is hydrolysis of terminal alpha-D-galactose from glycosphingolipids in
      the lysosomal lumen.
  - reference_id: file:human/GLA/GLA-notes.md
    supporting_text: 'Reactome models the core lysosomal reaction as GLA hydrolyzing saposin-B-mobilized
      Gb3Cer and Gal2Cer in the lysosomal lumen:'
  - reference_id: file:human/GLA/GLA-notes.md
    supporting_text: In a detergent-free liposomal system mimicking lysosomes, degradation
      of globotriaosylceramide was dependent on both recombinant human alpha-galactosidase
      and saposin B, and the authors concluded that "only SAP-B is essential for the degradation
      of GbOse3Cer by alpha-galactosidase"
  - reference_id: file:human/GLA/GLA-deep-research-falcon.md
    supporting_text: Pathway/process.** Lysosomal glycosphingolipid degradation; defects lead
      to Fabry disease pathophysiology
  - reference_id: file:human/GLA/GLA-notes.md
    supporting_text: 'Purified human alpha-galactosidase A is a homodimeric enzyme:'
suggested_questions:
- question: Should lysosomal enzyme uptake by M6PR/sortilin/megalin be captured by a more
    specific GO molecular-function term than signaling receptor binding?
  experts:
  - GO molecular function editors
  - lysosomal trafficking experts
suggested_experiments:
- description: Compare endogenous GLA localization and receptor-dependent uptake in relevant
    human cell types with recombinant enzyme uptake assays.
  experiment_type: cell biology trafficking assay
  hypothesis: Extracellular/receptor-binding annotations represent trafficking and therapeutic-enzyme
    uptake rather than a distinct core GLA function.

GLA

Gene Description

Existing Annotations Review

Core Functions

Hydrolyzes terminal alpha-D-galactose residues from lysosomal glycosphingolipids, especially globotriaosylceramide (Gb3Cer) and Gal2Cer, as a saposin-B-dependent homodimeric alpha-galactosidase A in the lysosomal lumen.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive research report: Human GLA (UniProt P06280) — functional annotation and translational relevance

1) Target verification (critical identity check)

2) Key concepts, definitions, and current understanding

2.1 Enzymatic function and substrate specificity

2.2 Cellular localization, biogenesis, and trafficking

2.3 Pathway context

3) Recent developments (prioritizing 2023–2024)

3.1 Biomarkers: lyso‑Gb3—utility and limitations

3.2 Evidence-quality challenges and expert analysis

4) Current applications and real-world implementations (therapies targeting GLA biology)

4.1 Enzyme replacement therapy (ERT): agalsidase alfa/beta

4.2 Oral pharmacological chaperone: migalastat (amenable variants)

4.3 Next-generation (PEGylated) ERT: pegunigalsidase alfa (PRX‑102)

5) Emerging/experimental directions (2023–2024 landscape framing)

5.1 Substrate reduction therapy (SRT)

5.2 Gene therapy and other delivery innovations

6) Expert opinions and consensus points (authoritative sources)

7) Key quantitative statistics (recently cited in the retrieved evidence)

8) Visual evidence: PRX‑102 clinical trial landscape

9) Practical functional-annotation summary (for databases / bench scientists)

URLs and publication dates (where available in retrieved sources)

Limitations of this report

Citations

📚 Additional Documentation

Notes

GLA notes

Core function and evidence

Localization and trafficking

Annotation cautions

Falcon deep-research cross-check

📄 View Raw YAML