TY - JOUR
T1 - Potent and selective activity-based probes for GH27 human retaining α-galactosidases
AU - Willems, Lianne I.
AU - Beenakker, Thomas J. M.
AU - Murray, Benjamin S.
AU - Scheij, Saskia
AU - Kallemeijn, Wouter W.
AU - Boot, Rolf G.
AU - Verhoek, Marri
AU - Donker-Koopman, Wilma E.
AU - Ferraz, Maria J.
AU - Rijssel, Erwin R. van
AU - Florea, Bogdan I.
AU - Codée, Jeroen D C
AU - Van Der Marel, Gijsbert A.
AU - Aerts, Johannes M F G
AU - Overkleeft, Herman S.
PY - 2014/8/8
Y1 - 2014/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84906351443&partnerID=8YFLogxK
U2 - 10.1021/ja507040n
DO - 10.1021/ja507040n
M3 - Article
C2 - 25105979
AN - SCOPUS:84906351443
SN - 0002-7863
VL - 136
SP - 11622
EP - 11625
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 33
ER -