Alpha-galactosidase A (GLA / α-Gal A)

Class

Pharmacological chaperone (small molecule)

Pathway

Glycosphingolipid (Gb3) catabolism -- stabilizes misfolded endogenous/infused α-Gal A in Fabry disease

Alpha-galactosidase A (α-Gal A) is a lysosomal enzyme that hydrolyzes glycosphingolipids, cleaving terminal galactose residues from substrates such as globotriaosylceramide (Gb3). Its activity is essential for glycosphingolipid catabolism; when it is deficient, as in the X-linked lysosomal storage disorder Fabry disease, Gb3 and related lipids accumulate progressively in vascular endothelium, kidney podocytes, cardiac myocytes, and peripheral nerve tissue, producing renal failure, cardiomyopathy, and neuropathic pain. Two complementary therapeutic strategies address this deficiency. Enzyme replacement therapy supplies an exogenous, catalytically active recombinant enzyme to substitute directly for the missing activity. Pharmacological chaperones instead target a subset of missense mutations that produce a misfolded but catalytically capable enzyme; the chaperone binds the enzyme's active site, stabilizing its native conformation so that it escapes premature degradation in the endoplasmic reticulum, traffics normally to the lysosome, and resumes substrate turnover there. This class of intervention broadly matters in inherited metabolic and storage disorders where a mutant protein retains partial function but is destroyed for folding reasons rather than loss of catalytic capacity — restoring stability, rather than replacing the protein outright, can be an efficient way to rescue endogenous function.