title: Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase.
abstract: Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-beta-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER alpha-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Steet
authors.forename: Stephen
authors.initials: S
authors.lastname: Chung
authors.forename: Wang-Sik
authors.initials: WS
authors.lastname: Lee
authors.forename: Corey W
authors.initials: CW
authors.lastname: Pine
authors.forename: Hung
authors.initials: H
authors.lastname: Do
authors.forename: Stuart
authors.initials: S
authors.lastname: Kornfeld
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004186:Disaccharidases / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics; D005962:Glucosylceramidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005964:Glucosyltransferases / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000494:pharmacology; D008247:Lysosomes / Q000201:enzymology; D009154:Mutation; D009844:Oligosaccharides / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D050112:Imino Pyranoses; D009844:Oligosaccharides; D010880:Piperidines; C098432:isofagomine; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D004186:Disaccharidases; D006026:Glycoside Hydrolases; D000520:alpha-Glucosidases; D005962:Glucosylceramidase