Alpha-galactosidase A (alpha-Gal A; encoded by the [GLA gene](/genes/gla)) is a lysosomal hydrolase that cleaves terminal alpha-galactosyl residues from glycolipids and glycoproteins. Deficiency causes Fabry disease, a lysosomal storage disorder with significant cerebrovascular and neurological manifestations.
Overview
Alpha-galactosidase A is a homodimeric lysosomal glycoprotein of ~46 kDa per subunit that catalyzes the hydrolysis of terminal α-1,4-galactosyl moieties from globotriaosylceramide (Gb3/GL-3) and related glycosphingolipids<sup>[1]</sup>. Deficiency of this enzyme, caused by X-linked mutations in GLA, results in Fabry disease, characterized by progressive accumulation of Gb3 in vascular endothelium, [neurons](/entities/neurons), and visceral organs<sup>[2]</sup>. Cerebrovascular involvement (stroke, white matter lesions) and peripheral neuropathy make Fabry disease highly relevant to neurodegeneration. [@germain2010]
| | | [@sims2009] |---|---| [@aerts2019] | Protein Name | Alpha-Galactosidase A (α-Gal A) | | Gene | [GLA](/genes/gla) | | UniProt ID | [P06280](https://www.uniprot.org/uniprot/P06280) | | Molecular Weight | ~46 kDa (monomer), ~101 kDa (active homodimer, glycosylated) | | Subcellular Localization | Lysosome | | Function | Lysosomal glycoside hydrolase; cleaves α-galactosyl residues | | EC Number | 3.2.1.22 |
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Structure
Molecular Architecture
α-Gal A functions as a homodimer<sup>[3]</sup>:
TIM barrel domain (aa 32-330): (β/α)₈ barrel fold containing the active site
C-terminal domain (aa 331-429): Antiparallel β-sheet domain involved in dimerization
Active site: Contains catalytic residues Asp170 (nucleophile) and Asp231 (acid/base)
N-glycosylation: Three N-linked glycosylation sites (Asn139, Asn192, Asn215) important for folding, stability, and mannose-6-phosphate receptor-mediated lysosomal targeting
Catalytic Mechanism
α-Gal A cleaves α-galactosyl linkages through a retaining double-displacement mechanism<sup>[3]</sup>:
Asp170 performs nucleophilic attack on the anomeric carbon of galactose
Asp231 protonates the leaving group
Galactosyl-enzyme intermediate is hydrolyzed by water
Products (galactose + truncated glycolipid) are released
Function
Primary: Glycosphingolipid Catabolism
α-Gal A degrades glycosphingolipids in the lysosome<sup>[1]</sup>:
Globotriaosylceramide (Gb3/GL-3): Primary substrate; accumulates in Fabry disease
Globotriaosylsphingosine (lyso-Gb3): Deacylated form; accumulates and is directly cytotoxic
Blood group B antigens: α-Gal A can cleave blood group B terminal galactose
Galabiosylceramide: Alternative substrate in kidney
Cellular Homeostasis
Beyond glycolipid catabolism, α-Gal A activity maintains<sup>[2]</sup>:
Lysosomal function: Prevents Gb3 accumulation that disrupts lysosomal pH and enzyme activity
Hearing loss: Sensorineural hearing loss from cochlear involvement
Cognitive decline: White matter disease can cause progressive cognitive impairment
Lysosomal Dysfunction Parallels
α-Gal A deficiency highlights shared pathways with major neurodegenerative diseases<sup>[5]</sup>:
Lysosomal storage → [autophagy](/entities/autophagy) impairment: Common with [GBA1](/genes/gba1)-related [Parkinson's disease](/diseases/parkinsons-disease)
Endolysosomal disturbance: Parallels endosomal enlargement seen in [Alzheimer's disease](/diseases/alzheimers-disease)
Neuroinflammation: Gb3/lyso-Gb3 activate [TLR4](/genes/tlr4) and [NF-κB](/mechanisms/nf-kb-signaling-neurodegeneration) inflammatory cascades
Vascular neurodegeneration: Cerebrovascular Gb3 accumulation causes stroke and vascular dementia
Clinical Significance
Enzyme Replacement Therapy (ERT)
Agalsidase alfa (Replagal): 0.2 mg/kg IV every 2 weeks
Agalsidase beta (Fabrazyme): 1.0 mg/kg IV every 2 weeks
Efficacy: Clears Gb3 from endothelium and some organs; limited CNS penetration
Pharmacological Chaperone
Migalastat (Galafold): Oral small molecule that stabilizes amenable GLA mutants, improving their trafficking to lysosomes
Biomarkers
Plasma Gb3 and lyso-Gb3: Elevated in Fabry disease; correlate with disease severity
α-Gal A enzyme activity: Measured in leukocytes or dried blood spots for diagnosis
Protein Interactions
| Interactor | Type | Function | |-----------|------|----------| | Saposin B | Activator | Presents Gb3 substrate to α-Gal A in the lysosome | | Mannose-6-phosphate receptor | Trafficking | Directs α-Gal A from Golgi to lysosome | | Migalastat | Pharmacological chaperone | Stabilizes folding-competent mutants | | LIMP-2/SCARB2 | Lysosomal | Lysosomal membrane protein interactor |
[Unknown, Garman SC & Garboczi DN, The molecular defect leading to Fabry disease: structure of human alpha-galactosidase (2004) (2004)](https://doi.org/10.1016/j.jmb.2003.10.010)
[Sims K et al., Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events (2009) (2009)](https://doi.org/10.1161/STROKEAHA.108.537480)
[Aerts JM et al., Glycosphingolipids and lysosomal storage disorders as illustrated by gaucher disease (2019) (2019)](https://doi.org/10.1016/j.cbpa.2018.11.005)