Potent and Selective Activity-Based Probes for GH27 Human Retaining alpha-Galactosidases

作者：Willems Lianne I; Beenakker Thomas J M; Murray Benjamin; Scheij Saskia; Kallemeijn Wouter W; Boot Rolf G; Verhoek Marri; Donker Koopman Wilma E; Ferraz Maria J; van Rijssel Erwin R; Florea Bogdan I; Codee Jeroen D C; van der Marel Gij**ert A; Aerts Johannes M F G^*; Overkleeft Herman S

来源：Journal of the American Chemical Society, 2014, 136(33): 11622-11625.

DOI：10.1021/ja507040n

Lysosomal degradation of glycosphingolipids is mediated by the consecutive action of several glycosidases. Malfunctioning of one of these hydrolases can lead to a lysosomal storage disorder such as Fabry disease, which is caused by a deficiency in alpha-galactosidase A. Herein we describe the development of potent and selective activity-based probes that target retaining alpha-galactosidases. The fluorescently labeled aziridine-based probes 3 and 4 inhibit the two human retaining alpha-galactosidases alpha Gal A and alpha Gal B covalently and with high affinity. Moreover, they enable the visualization of the endogenous activity of both alpha-galactosidases in cell extracts, thereby providing a means to study the presence and location of active enzyme levels in different cell types, such as healthy cells versus those derived from Fabry patients.

• 出版日期2014-8-20