Xylose-Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase.

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. © 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.

Citation

Qin Su, Sybrin P Schröder, Lindsey T Lelieveld, Maria J Ferraz, Marri Verhoek, Rolf G Boot, Herman S Overkleeft, Johannes M F G Aerts, Marta Artola, Chi-Lin Kuo. Xylose-Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase. Chembiochem : a European journal of chemical biology. 2021 Nov 03;22(21):3090-3098

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PMID: 34459538

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