EFFECTS OF GLYCOSIDASE INHIBITORY SUGAR-MIMIC ALKALOIDS AGAINST LYSOSOME DISEASE.

点击翻译按钮获取中文摘要

Gaucher disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal β-glucocerebrosidase. Studies of residual activities of mutant enzyme in many Gaucher patients showed that some of them had kinetic properties similar to those for nomal β-glucocerebrosidase, but were significantly less stable. So, we searched the compounds, which stabilized the mutant β-glucocerebrosidase. A very thorough examination of the roots of Lycium chinense(Solanaceae) has resulted in the discovery of ten calystegines. Calystegine A_3,B_1,B_2 and C_1 is a potent competitive inhibitor of β-glucocerebrosidase, with K_i, value of 0.9,1.4,1.5,and 0.49μM, respectively. We found that those calystegines, potent competitive inhibitors of β-glucocerebrosidase, effectively enhanced β-glucocerebrosidase activity in Gaucher lymphoblast, when administrated at concentrations lower than that usually requied for intercellular inhibition of the enzyme. The enzyme activity increased two or three-fold after cultivation of Gaucher lymphoblast(L444P) with calystegine at 10μM for 3 days. Those calystegines seemed to accelerate transport and maturation of the mutant enzyme. Our results indicate that administration of calystegines may be used as a new molecular therapy for Gaucher disease.