N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease.

Abstract	Gaucher disease (GD) is the most common form of sphingolipidosis and is caused by a defect of beta-glucosidase (beta-Glu). A carbohydrate mimic N-octyl-beta-valienamine (NOV) is an inhibitor of beta-Glu. When applied to cultured GD fibroblasts with F213I beta-Glu mutation, NOV increased the protein level of the mutant enzyme and up-regulated cellular enzyme activity. The maximum effect of NOV was observed in F213I homozygous cells in which NOV treatment at 30 microM for 4 days caused a approximately 6-fold increase in the enzyme activity, up to approximately 80% of the activity in control cells. NOV was not effective in cells with other beta-Glu mutations, N370S, L444P, 84CG and RecNciI. Immunofluorescence and cell fractionation showed localization of the F213I mutant enzyme in the lysosomes of NOV-treated cells. Consistent with this, NOV restored clearance of 14C-labeled glucosylceramide in F213I homozygous cells. F213I mutant beta-Glu rapidly lost its activity at neutral pH in vitro and this pH-dependent loss of activity was attenuated by NOV. These results suggest that NOV works as a chemical chaperone to accelerate transport and maturation of F213I mutant beta-Glu and may suggest a therapeutic value of this compound for GD.
Authors	Hou Lin, Yuko Sugimoto, Yuki Ohsaki, Haruaki Ninomiya, Akira Oka, Miyako Taniguchi, Hiroyuki Ida, Yoshikatsu Eto, Seiichiro Ogawa, Yuji Matsuzaki, Miwa Sawa, Takehiko Inoue, Katsumi Higaki, Eiji Nanba, Kousaku Ohno, Yoshiyuki Suzuki
Journal	Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1689 Issue 3 Pg. 219-28 (Aug 04 2004) ISSN: 0006-3002 [Print] Netherlands
PMID	15276648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Hexosamines N-octyl-beta-valienamine beta-Glucosidase
Topics	Blotting, Western Cells, Cultured Gaucher Disease (drug therapy) Hexosamines (pharmacology) Humans Up-Regulation (drug effects) beta-Glucosidase (metabolism)

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