Potent and Selective Activity-Based Probes for GH27 Human Retaining 伪-Galactosidases
详细信息 查看全文
- 作者：Lianne I. Willems ; Thomas J. M. Beenakker ; Benjamin Murray ; Saskia Scheij ; Wouter W. Kallemeijn ; Rolf G. Boot ; Marri Verhoek ; Wilma E. Donker-Koopman ; Maria J. Ferraz ; Erwin R. van Rijssel ; Bogdan I. Florea ; Jeroen D. C. Cod茅e ; Gijsbert A. van der Marel ; Johannes M. F. G. Aerts ; Herman S. Overkleeft
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：August 20, 2014
- 年：2014
- 卷：136
- 期：33
- 页码：11622-11625
- 全文大小：291K
- ISSN：1520-5126
文摘
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 伪-galactosidase A. Herein we describe the development of potent and selective activity-based probes that target retaining 伪-galactosidases. The fluorescently labeled aziridine-based probes 3 and 4 inhibit the two human retaining 伪-galactosidases 伪Gal A and 伪Gal B covalently and with high affinity. Moreover, they enable the visualization of the endogenous activity of both 伪-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.