title: Enzyme enhancement activity of N-octyl-beta-valienamine on beta-glucosidase mutants associated with Gaucher disease.
abstract: Gaucher disease (GD), caused by a defect of beta-glucosidase (beta-Glu), is the most common form of sphingolipidosis. We have previously shown that a carbohydrate mimic N-octyl-beta-valienamine (NOV), an inhibitor of beta-Glu, could increase the protein level and enzyme activity of F213I mutant beta-Glu in cultured GD fibroblasts, suggesting that NOV acted as a pharmacological chaperone to accelerate transport and maturation of this mutant enzyme. In the current study, NOV effects were evaluated in GD fibroblasts with various beta-Glu mutations and in COS cells transiently expressing recombinant mutant proteins. In addition to F213I, NOV was effective on N188S, G202R and N370S mutant forms of beta-Glu, whereas it was ineffective on G193W, D409H and L444P mutants. When expressed in COS cells, the mutant proteins as well as the wild-type protein were localized predominantly in the endoplasmic reticulum and were sensitive to Endo-H treatment. NOV did not alter this localization or Endo-H sensitivity, suggesting that it acted in the endoplasmic reticulum. Profiling of N-alkyl-beta-valienamines with various lengths of the acyl chain showed that N-dodecyl-beta-valienamine was as effective as NOV. These results suggest a potential therapeutic value of NOV and related compounds for GD with a broad range of beta-Glu mutations.
authors.affiliation: Department of Child Neurology, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors.forename: Ke
authors.initials: K
authors.lastname: Lei
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Michitaka
authors.initials: M
authors.lastname: Suzuki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Inoue
authors.forename: Miwa
authors.initials: M
authors.lastname: Sawa
authors.forename: Masami
authors.initials: M
authors.lastname: Iida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ida
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ogawa
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics*; D006026:Glycoside Hydrolases / Q000378:metabolism; D006595:Hexosamines / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D006595:Hexosamines; C116532:N-octyl-beta-valienamine; D011994:Recombinant Proteins; D006026:Glycoside Hydrolases; D001617:beta-Glucosidase