Acid-beta-glucosidase
From Proteopedia
Acid-beta-glucosidase
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Acid-beta-glucosidase is a lysozomal enzyme, which cleaves glucoceramide to glucose and ceramide. It acts through an acid-base hydrolysis.
The enzyme is a lysosomal, membrane-associated glycoprotein, and its 3D structure revealed that its catalytic domain is a TIM barrel. It catalyzes hydrolysis of the sphingolipid, glucosylceramide (GlcCer), to glucose and ceramide at the acidic pH prevailing within the lysosome.
According to the mechanism, an enzyme, which acts through the acid-base reacion has to contain in the a proton donor, an acid, and a nuclophile - the base. The nuclophile is involved in formation and stabilization of the intermediate state, were a proton is transferred from an anomeric carbon to the leaving group. At that stage, the proton donor would donate its proton to the intermediate complex, releasing the second product and hence acting as a catalytic acid. Such a mechanism depends strongly on the pH of the environment. Fine changes in acidity of the solution might affect the ionization states of the residues involved in the catalysis. Therefore there would be a strong dependence of the enzyme's activity on the pH of the solution.
Several x-ray structures of the enzyme have been solved. PDB codes:
1y7v - acid-beta-glucosidase conjugated with an irreversible inhibitor, conduritol-B-epoxide (CBE);
1ogs - the first structure of acid-beta-glucosidase, the enzyme involved in Gacher disease. Structure of deglycosylated Cerezyme®. 2f61; 2nt0; 2nt1; 2v3d; 2v3e; 2nsx; 2j25</p>
Gaucher disease
Gaucher diseaseis the most common lysosomal storage disease, and is associated with mutations in the gene coding for the enzyme acid-β-glucosidase (enzyme classification E.C. 3.2.1.45). There are ~200 known mutations, mostly missense mutations which result in substitution of amino acids in the protein. Some mutations cause complete deactivation of the enzyme; others impair its stability, and some affect both activity and stability. There are three known phenotypes of the disease: a mild, severe and acute. The acute phenotype is neuropathic, while severe and mild symptoms are caused by accumulation of GlcCer in macrophage cells resulting in bone atrophy, spleen enlargement, etc.
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Michal Harel, Boris Brumshtein, Alexander Berchansky, Joel L. Sussman, Eran Hodis, David Canner
