کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8323240 | 1539890 | 2014 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Selective chaperone effect of aminocyclitol derivatives on G202R and other mutant glucocerebrosidases causing Gaucher disease
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کلمات کلیدی
GBA2Sap CIsofagomineD-MEMGlcCerCBEGBA1LCSRMSFIFGN-butyldeoxynojirimycin3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide - 3- (4،5-dimethylthiazol-2-yl) -2،5-difenyltetrazolium bromideMTT - MTTenzyme replacement therapy - آنزیم جایگزین درمانsphingomyelin - اسفنگومیلینGaucher disease - بیماری گوچهMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیSaposin C - ساپوزین سیBlood–brain barrier - سد خونی مغزیBBB - سد خونی مغزیCer - سرceramide - سرامیدPharmacological chaperone - شاپرن فارماکولوژیکFibroblast - فیبروبلاستroot mean square fluctuation - نوسان میانگین مربع ریشهwild type - نوع وحشیERT - هستندglucosylceramide - گلوکوزیلسرامیدglucosylceramide synthase - گلوکوزیلسرامید سنتاز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Gaucher disease is an autosomal recessive lysosomal disorder characterized by the accumulation of glucosylceramide as a result of a deficiency of the enzyme glucocerebrosidase. Several competitive glucocerebrosidase inhibitors are able to act as pharmacological chaperones for an efficient rescue of the mutated, misfolded forms of the enzyme. Along this line, we report in this work on the ability of several aminocyclitols to increase the residual glucocerebrosidase activity in patient fibroblasts with different genotypes. Some of the compounds were slightly active on fibroblasts bearing some mutations, including the highly prevalent N370S mutation. All compounds were highly active as enzyme activity enhancers on fibroblasts from Gaucher disease patients containing the G202R mutation. Moreover, using the novel tagged sphingolipid Ï-azidosphingosine, a reduction in the tagged glucosylceramide accumulation was also observed for selected aminocyclitols. Attempts to explain the activity impairment observed in glucocerebrosidase bearing the G202R mutation by comparative molecular dynamic studies on wild type and the G202R mutated proteins (free and isofagomine-bound, in both cases) were unsuccessful. Under the simulation conditions used, no clear effect of the G202R mutation neither over the global structure of the protein nor on the loops that constitute the glucocerebrosidase active site was observed. Since the G202R residue is located on the protein surface, altered protein-membrane or protein-protein interactions could account for the observed differences. In conclusion, we have tested novel compounds that have shown some chaperone effect on particular glucocerebrosidase mutant enzymes, supporting the enhancement therapy as an alternative approach for Gaucher disease.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 54, September 2014, Pages 245-254
Journal: The International Journal of Biochemistry & Cell Biology - Volume 54, September 2014, Pages 245-254
نویسندگان
Jenny Serra-Vinardell, LucÃa DÃaz, Hugo Gutiérrez-de-Terán, Gessamà Sánchez-Ollé, Jordi Bujons, Helen Michelakakis, Irene Mavridou, Johannes M.F.G. Aerts, Antonio Delgado, Daniel Grinberg, Lluïsa Vilageliu, Josefina Casas,