Acid β-Glucosidase: Enzymology and Molecular Biology of Gaucher Diseas

Abstract

Human lysosomal β-glucosidase (D-glucosyl-acylsphingo-sine glucohydrolase, EC 3.2.1.45) is a membrane-associated enzyme that cleaves the β-glucosidic linkage of glucosylcer-amide (glucocerebroside), its natural substrate, as well as synthetic β-glumsides. Experiments with cultured cells suggest that in vivo this glycoprotein requires interaction with negatively charged lipids and a small acidic protein, SAP-2, for optimal glucosylceramide hydrolytic rates. In vitro, detergents (Triton? X-100 or bile acids) or negatively charged gangliosides or phos-pholipids and one of several “activator proteins” increase hydrolytic rate of lipid and water-soluble substrates. Using such in vitro assay systems and active site-directed covalent inhibitors, kinetic and structural properties of the active site have been elucidated. The defective activity of this enzyme leads to the variants of Gaucher disease, the most prevalent lysosomal storage disease. The nonneuronopathic (type 1) and neuronopathic (types 2 and 3) variants of this inherited (autosomal recessive) disease but panethnic, but type 1 is most prevalent in the Ashkenazi Jewish population. Several missense mutations, identified in the structural gene for lysosomal β-glucosidase from Gaucher disease patients, are presumably casual to the specifically altered post-translational oligosaccharide processing or stability of the enzyme as well as the alterecA in vitro kinetic properties of the residual enzyme from patient tissues.