PUBLICATION
Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase
- Authors
- Su, Q., Schröder, S.P., Lelieveld, L.T., Ferraz, M.J., Verhoek, M., Boot, R.G., Overkleeft, H.S., Aerts, J.M.F.G., Artola, M., Kuo, C.L.
- ID
- ZDB-PUB-210831-12
- Date
- 2021
- Source
- Chembiochem : a European journal of chemical biology 22(21): 3090-3098 (Journal)
- Registered Authors
- Keywords
- Glucocerebrosidase (GBA), β-D-xylose-configured cyclophellitol, selective GBA inhibitor, Gaucher disease, chemical-knockout model
- MeSH Terms
-
- Animals
- Cells, Cultured
- Cyclohexanols/chemistry
- Cyclohexanols/pharmacology*
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology*
- Glucosylceramidase/antagonists & inhibitors*
- Glucosylceramidase/genetics
- Glucosylceramidase/metabolism
- HEK293 Cells
- Humans
- Molecular Conformation
- Xylose/chemistry
- Xylose/pharmacology*
- Zebrafish
- PubMed
- 34459538 Full text @ Chembiochem
Citation
Su, Q., Schröder, S.P., Lelieveld, L.T., Ferraz, M.J., Verhoek, M., Boot, R.G., Overkleeft, H.S., Aerts, J.M.F.G., Artola, M., Kuo, C.L. (2021) Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase. Chembiochem : a European journal of chemical biology. 22(21):3090-3098.
Abstract
Glucocerebrosidase (GBA), a lysosomal retaining β-D-glucosidase, has recently shown to hydrolyze β-D-xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the lysosomal storage disorder Gaucher disease (GD), and also constitute a risk factor for developing Parkinson's disease. GBA and other retaining glycosidases can be selectively visualized by activity-based protein profiling (ABPP) using fluorescent probes composed of a cyclophellitol scaffold having a configuration tailored to the targeted glycosidase family. GBA processes β-Dxylosides in addition to β-D-glucosides, this in contrast to the other two mammalian cellular retaining β-D-glucosidases, GBA2 and GBA3. Here we show that the xylopyranose preference also holds up for covalent inhibitors: xylose-configured cyclophellitol and cyclophellitol aziridines selectively react with GBA over GBA2 and GBA3 in vitro and in vivo , and that the xylose-configured cyclophellitol is more potent and more selective for GBA than the classical GBA inhibitor, conduritol B-epoxide (CBE). Both xyloseconfigured cyclophellitol and cyclophellitol aziridine cause accumulation of glucosylsphingosine in zebrafish embryo, a characteristic hallmark of GD, and we conclude that these compounds are well suited for creating such chemically induced GD models.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping