Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase
| العنوان: | Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase |
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| المؤلفون: | Chi-Lin Kuo, Rolf G. Boot, Marta Artola, Qin Su, Lindsey T. Lelieveld, Marri Verhoek, Sybrin P. Schröder, Maria J. Ferraz, Herman S. Overkleeft, Johannes M. F. G. Aerts |
| المصدر: | Chembiochem Chembiochem, 22, 1-10. WILEY-V C H VERLAG GMBH |
| بيانات النشر: | John Wiley and Sons Inc., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Molecular Conformation, Gaucher disease, Xylose, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, GBA3, activity-based probe, Animals, Humans, Glycoside hydrolase, Enzyme Inhibitors, Molecular Biology, Cells, Cultured, Zebrafish, 030304 developmental biology, 0303 health sciences, Full Paper, Chemistry, glucocerebrosidase, Organic Chemistry, Full Papers, Cyclohexanols, In vitro, 3. Good health, Cyclophellitol, HEK293 Cells, cyclophellitol, Molecular Medicine, Glucosylceramidase, Glucocerebrosidase, 030217 neurology & neurosurgery, Conduritol, conduritol B-epoxide |
| الوصف: | Glucocerebrosidase (GBA), a lysosomal retaining β‐d‐glucosidase, has recently been 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‐d‐xylosides 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 xylose‐configured 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. New selective GBA inhibitor: We show that the β‐d‐xylose configured epoxide and aziridine are potent selective inhibitors towards GBA in vitro and in vivo, and their selectivity and inhibitory effect towards GBA are superior to the widely used GBA inhibitor Conduritol B‐epoxide (CBE). |
| اللغة: | English |
| تدمد: | 1439-7633 1439-4227 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::051ee41c7214160b3f631d67d2be9f0eTest http://europepmc.org/articles/PMC8596838Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....051ee41c7214160b3f631d67d2be9f0e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14397633 14394227 |
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