Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine.

摘要: To elucidate the genetic heterogeneity in Gaucher disease, residual beta-glucosidase cultured fibroblasts from affected patients with each of major phenotypes was investigated vitro and/or viable cells by inhibitor studies using covalent catalytic site inhibitors, conduritol B epoxide or its bromo derivative, and reversible cationic inhibitor, sphingosine. These delineated three distinct groups (designated A, B, C) activities characteristic responses to these inhibitors. Group A enzymes had normal I50 values (i.e., concentration that results 50% inhibition) for inhibitors nearly t1/2 epoxide. All neuronopathic (types 2 3) most non-Jewish nonneuronopathic (type 1) group and, thus, could not be distinguished studies. about four- fivefold increased similarly Ashkenazi Jewish type 1 only two activities. The differences between also were confirmed determining uninhibited enzyme activity after culturing presence bromo-conduritol C intermediate represented a single Afrikaner patient: this patient compound 2) mutations. inhibition indicated that: disease is biochemically heterogeneous, cannot reliably studies, form unique mutation specific active domain acid leads defective decreased Vmax.