β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Abstract

Background: GBA2 and GBA are both ␤-glucosidases that degrade glucosylceramide. Results: Conduritol B epoxide inactivates both GBA and GBA2, whereas the imino sugar NB-DGJ selectively inhibits GBA2. Conclusion: NB-DGJ is a suitable reagent to distinguish GBA2 from GBA. Significance: This study redefines GBA2 activity, which is relevant for clinical GBA2 measurements and imino sugar pharmacology.

Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46)

“…Mutations in the GBA2 gene have been identified in patients presenting with the combination of cerebellar ataxia and spastic paraplegia (SPG46). Further, GBA2 is sensitive to inhibition by the smallmolecular compounds miglustat (N-butyldeoxynojirimycin, NB-DNJ) and N-butyldeoxygalactonojirimycin (NB-DGJ) [14,19,20]. Table 1 List of mutations found in the GBA2 gene in patients diagnosed with a combination of spastic paraplegia and cerebellar ataxia (SPG46).…”

“…GBA2 b-glucosidase activity was determined as the b-glucosidase activity that is sensitive to inhibition by N-butyldeoxygalactonojirimycin (NB-DGJ) as described [14]. Samples were incubated with the substrate 4-methylumbelliferyl-b-D-glucoside (Glycosynth, Warrington, UK) in the absence or presence of 0.3 mM NB-DGJ (Toronto Research Chemicals/Actelion Pharmaceuticals Ltd) at pH 5.8 and 37 C. Protein concentrations were assayed with the bicinchoninic acid reagent using BSA as standard (Thermo Scientific).…”

The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases

“…The basis for these observations may be the inhibition of GBA2 by miglustat ( 33 ). Miglustat is 60 times more potent as an inhibitor of this enzyme than of glucosylceramide synthase.…”

Development of targeted therapies for Parkinson's disease and related synucleinopathies

“…Anecdotal observations suggest that miglustat may be of some benefi t in treatment of patients with Sandhoff disease; however, no controlled clinical trials have been performed several glycosidases, including the lysosomal glucocerebrosidase, GBA1, and the non-lysosomal glucocerebrosidase, GBA2 ( 35 ). Miglustat can also display chaperone-like activity, facilitating the translocation of glucocerebrosidase from the endoplasmic reticulum (ER) to the lysosome ( 36,37 ).…”

“…Miglustat is an iminosugar that inhibits GlcCer biosynthesis ( 35 ) and has been studied extensively. It displays modest selectivity toward GlcCer synthase and also inhibits…”