tailieunhanh - Báo cáo khoa học: The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of b-glucosidase

Gaucher disease is caused by mutations in the gene that encodes the lyso-somal enzyme acid b-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. | The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of b-glucosidase Richie Khanna1 Elfrida R. Benjamin1 Lee Pellegrino1 Adriane Schilling1 Brigitte A. Rigat2 Rebecca Soska1 Hadis Nafar3 Brian E. Ranes1 Jessie Feng1 Yi Lun1 Allan C. Powe1 David J. Palling1 Brandon A. Wustman3 Raphael Schiffmann4 Don J. Mahuran2 David J. Lockhart3 and Kenneth J. Valenzano1 1 Amicus Therapeutics Cranbury NJ USA 2 Genetics and Genome Biology Program Research Institute The Hospitalfor Sick Children Toronto Canada 3 Amicus Therapeutics La Jolla CA USA 4 Baylor Research Institute Dallas TX USA Keywords Gaucherdisease isofagomine L444P p-glucocerebrosidase lysosomal storage disorder pharmacologicalchaperone Correspondence R. Khanna Amicus Therapeutics 6 Cedar Brook Drive Cranbury NJ 08512 USA Fax 1 609 662 2002 Tel 1 609 662 2018 E-mail rkhanna@ Received 30 November 2009 revised 11 January 2010 accepted 20 January 2010 doi Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid b-glucosidase GCase . We have shown previously that the small molecule pharmacological chaperone isofagomine IFG binds and stabilizes N370S GCase resulting in increased lysosomal trafficking and cellular activity. In this study we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines LCLs or fibroblasts with IFG led to approximately and increases in L444P GCase activity respectively as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment GCase-immunocapture or by incubating cells overnight in IFG-free media prior to assay methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells as .

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