Potent and selective activity-based probes for GH27 human retaining α-galactosidases

Lianne I. Willems, Thomas J. M. Beenakker, Benjamin S. 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 Codée, Gijsbert A. Van Der Marel, Johannes M F G Aerts, Herman S. Overkleeft*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 α-galactosidase A. Herein we describe the development of potent and selective activity-based probes that target retaining α-galactosidases. The fluorescently labeled aziridine-based probes 3 and 4 inhibit the two human retaining α-galactosidases αGal A and αGal B covalently and with high affinity. Moreover, they enable the visualization of the endogenous activity of both α-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.

Original languageEnglish
Pages (from-to)11622-11625
Number of pages4
JournalJournal of the American Chemical Society
Issue number33
Publication statusE-pub ahead of print - 8 Aug 2014

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