Characterizing the selectivity of ER α-glucosidase inhibitors.
Glycobiology
; 29(7): 530-542, 2019 07 01.
Article
en En
| MEDLINE
| ID: mdl-30976784
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arabinosa
/
Alcaloides de Pirrolicidina
/
Alcoholes del Azúcar
/
Retículo Endoplásmico
/
Iminofuranosas
/
Alfa-Glucosidasas
/
Inhibidores de Glicósido Hidrolasas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Glycobiology
Asunto de la revista:
BIOQUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido