title: Chemical modification of the glucosidase inhibitor 1-deoxynojirimycin. Structure-activity relationships.
abstract: The ability of the glucosidase inhibitor 1-deoxynojirimycin (dNM) and a series of N-alkylated dNM derivatives to interfere with biosynthesis, transport, and maturation of the glycoprotein alpha 1-antitrypsin in HepG2 cells was investigated. Inhibition of endoplasmic reticulum glucosidase I and II by dNM and its derivatives resulted in an intracellular accumulation of alpha 1-antitrypsin with glucose-containing high mannose type oligosaccharides (precursor). N-alkylation of dNM increased its potency in inhibiting endoplasmic reticulum glucosidases, as determined from the concentration required for half maximal inhibition. N-Alkylated derivatives of dNM were better able to inhibit glucosidase I than glucosidase II (deduced from the number of glucose residues retained in Endo H-releasable oligosaccharides). The inhibition of glucosidase activity imposed by alkylated dNM derivatives was less easily reversed than that by dNM, an effect most pronounced for N-methyl-dNM. Branching of the alkyl group of dNM derivatives decreased the inhibitory potency. Although dNM and its derivatives interfered strongly with intracellular oligosaccharide processing, they did not completely block N-glycan maturation of alpha 1-antitrypsin even at the highest concentrations tested.
authors.affiliation: The Netherlands Cancer Institute, Division of Cellular Biochemistry, Amsterdam.
authors.forename: A
authors.initials: A
authors.lastname: Tan
authors.forename: L
authors.initials: L
authors.lastname: van den Broek
authors.forename: S
authors.initials: S
authors.lastname: van Boeckel
authors.forename: H
authors.initials: H
authors.lastname: Ploegh
authors.forename: J
authors.initials: J
authors.lastname: Bolscher
mesh_terms: D017485:1-Deoxynojirimycin; D000478:Alkylation; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002850:Chromatography, Gel; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005959:Glucosidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008113:Liver Neoplasms / Q000473:pathology; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: D000515:alpha 1-Antitrypsin; D017485:1-Deoxynojirimycin; D005959:Glucosidases; D005944:Glucosamine