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Isofagomine Induced Stabilization of Glucocerebrosidase
Author(s) -
Kornhaber Gregory J.,
Tropak Michael B.,
Maegawa Gustavo H.,
Tuske Steven J.,
Coales Stephen J.,
Mahuran Don J.,
Hamuro Yoshitomo
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800249
Subject(s) - chemistry , mutant , hydrogen bond , stereochemistry , biochemistry , molecule , organic chemistry , gene
Structurally destabilizing mutations in acid β‐glucosidase (GCase) can result in Gaucher disease (GD). The iminosugar isofagomine (IFG), a competitive inhibitor and a potential pharmacological chaperone of GCase, is currently undergoing clinical evaluation for the treatment of GD. An X‐ray crystallographic study of the GCase‐IFG complex revealed a hydrogen bonding network between IFG and certain active site residues. It was suggested that this network may translate into greater global stability. Here it is demonstrated that IFG does increase the global stability of wild‐type GCase, shifting its melting curve by ∼15 °C and that it enhances mutant GCase activity in pre‐treated N370S/N370S and F213I/L444P patient fibroblasts. Additionally, amide hydrogen/deuterium exchange mass spectroscopy (H/D‐Ex) was employed to identify regions within GCase that undergo stabilization upon IFG‐binding. H/D‐Ex data indicate that the binding of IFG not only restricts the local protein dynamics of the active site, but also propagates this effect into surrounding regions.