title: Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2.
abstract: The primary catabolic pathway for glucosylceramide is catalyzed by the lysosomal enzyme glucocerebrosidase that is defective in Gaucher disease patients. A distinct non-lysosomal glucosylceramidase has been described but its identity remained enigmatic for years. We here report that the non-lysosomal glucosylceramidase is identical to the earlier described bile acid beta-glucosidase, being beta-glucosidase 2 (GBA2). Expressed GBA2 is identical to the native non-lysosomal glucosylceramidase in various enzymatic features such as substrate specificity and inhibitor sensitivity. Expression of GBA2 coincides with increased non-lysosomal glucosylceramidase activity, and GBA2-targeted RNA interference reduces endogenous non-lysosomal glucosylceramidase activity in cells. GBA2 is found to be located at or close to the cell surface, and its activity is linked to sphingomyelin generation. Hydrophobic deoxynojirimycins are extremely potent inhibitors for GBA2. In mice pharmacological inhibition of GBA2 activity is associated with impaired spermatogenesis, a phenomenon also very recently reported for GBA2 knock-out mice (Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M., Hammer, R. E., Hamra, F. K., Matern, S., and Russell, D. W. (2006) J. Clin. Invest. 116, 2985-2994). In conclusion, GBA2 plays a role in cellular glucosylceramide metabolism.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands. r.g.boot@amc.uva.nl
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Marri
authors.initials: M
authors.lastname: Verhoek
authors.forename: Wilma
authors.initials: W
authors.lastname: Donker-Koopman
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.forename: Jan
authors.initials: J
authors.lastname: van Marle
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003902:Detergents; D005776:Gaucher Disease / Q000378:metabolism; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D021962:Membrane Microdomains / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D013091:Spermatogenesis / Q000502:physiology; D014162:Transfection; D001617:beta-Glucosidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D003902:Detergents; D005963:Glucosylceramides; D001617:beta-Glucosidase; C517538:beta-glucosidase 2, mouse; C517537:GBA2 protein, human; D005962:Glucosylceramidase