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

Abstract

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.

• Authors: 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 Codée, Gijsbert A van der Marel, Johannes M F G Aerts, Herman S Overkleeft
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 136 Issue 33 Pg. 11622-5 (Aug 20 2014) ISSN: 1520-5126 [Electronic] United States
• PMID: 25105979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aziridines
• Fluorescent Dyes
• aziridine
• alpha-Galactosidase

Topics

• Aziridines (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Fluorescent Dyes (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Structure-Activity Relationship
• alpha-Galactosidase (antagonists & inhibitors, metabolism)