TY - JOUR
T1 - Characterizing the selectivity of ER α-glucosidase inhibitors
AU - O'Keefe, Sarah
AU - Roebuck, Quentin P.
AU - Nakagome, Izumi
AU - Hirono, Shuichi
AU - Kato, Atsushi
AU - Nash, Robert
AU - High, Stephen
N1 - Funding Information:
This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Programme Award BB/J014478/ 1 (S.O’K.), a Welcome Trust Investigator Award in Science 204957/Z/16/Z (S. H.) and a Grant-in-Aid for Scientific Research (C) from the Japanese Society for the Promotion of Science (JSPS KAKENHI) JP17K08362 (A.K.).
Publisher Copyright:
© 2019 The Author(s). Published by Oxford University Press.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - The endoplasmic reticulum (ER) contains both α-glucosidases and α-mannosidases which process the N-linked oligosaccharides of newly synthesized glycoproteins and thereby facilitate polypeptide folding and glycoprotein quality control. By acting as structural mimetics, iminosugars can selectively inhibit these ER localized α-glycosidases, preventing N-glycan trimming and providing a molecular basis for their therapeutic applications. In this study, we investigate the effects of a panel of nine iminosugars on the actions of ER luminal α-glucosidase I and α-glucosidase II. Using ER microsomes to recapitulate authentic protein N-glycosylation and oligosaccharide processing, we identify five iminosugars that selectively inhibit N-glycan trimming. Comparison of their inhibitory activities in ER microsomes against their effects on purified ER α-glucosidase II, suggests that 3,7a-diepi-alexine acts as a selective inhibitor of ER α-glucosidase I. The other active iminosugars all inhibit α-glucosidase II and, having identified 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) as the most effective of these compounds, we use in silico modeling to understand the molecular basis for this enhanced activity. Taken together, our work identifies the C-3 substituted pyrrolizidines casuarine and 3,7a-diepi-alexine as promising "second-generation" iminosugar inhibitors.
AB - The endoplasmic reticulum (ER) contains both α-glucosidases and α-mannosidases which process the N-linked oligosaccharides of newly synthesized glycoproteins and thereby facilitate polypeptide folding and glycoprotein quality control. By acting as structural mimetics, iminosugars can selectively inhibit these ER localized α-glycosidases, preventing N-glycan trimming and providing a molecular basis for their therapeutic applications. In this study, we investigate the effects of a panel of nine iminosugars on the actions of ER luminal α-glucosidase I and α-glucosidase II. Using ER microsomes to recapitulate authentic protein N-glycosylation and oligosaccharide processing, we identify five iminosugars that selectively inhibit N-glycan trimming. Comparison of their inhibitory activities in ER microsomes against their effects on purified ER α-glucosidase II, suggests that 3,7a-diepi-alexine acts as a selective inhibitor of ER α-glucosidase I. The other active iminosugars all inhibit α-glucosidase II and, having identified 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) as the most effective of these compounds, we use in silico modeling to understand the molecular basis for this enhanced activity. Taken together, our work identifies the C-3 substituted pyrrolizidines casuarine and 3,7a-diepi-alexine as promising "second-generation" iminosugar inhibitors.
KW - endoplasmic reticulum
KW - glucose trimming
KW - iminosugar inhibitors
KW - N-linked glycosylation
UR - http://www.scopus.com/inward/record.url?scp=85068488177&partnerID=8YFLogxK
U2 - 10.1093/glycob/cwz029
DO - 10.1093/glycob/cwz029
M3 - Article
SN - 0959-6658
VL - 29
SP - 530
EP - 542
JO - Glycobiology
JF - Glycobiology
IS - 7
ER -