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The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif

TitleThe amylase inhibitor montbretin A reveals a new glycosidase inhibition motif
Publication TypeJournal Article
Year of Publication2015
AuthorsWilliams, LK, Zhang, X, Caner, S, Tysoe, C, Nguyen, NT, Wicki, J, Williams, DE, Coleman, J, McNeill, JH, Yuen, V, Andersen, RJ, Withers, SG, Brayer, GD
JournalNATURE CHEMICAL BIOLOGY
Volume11
Pagination691+
Date PublishedSEP
ISSN1552-4450
Abstract

The complex plant flavonol glycoside montbretin A is a potent (K-i = 8 nM) and specific inhibitor of human pancreatic alpha-amylase with potential as a therapeutic for diabetes and obesity. Controlled degradation studies on montbretin A, coupled with inhibition analyses, identified an essential high-affinity core structure comprising the myricetin and caffeic acid moieties linked via a disaccharide. X-ray structural analyses of the montbretin A-human alpha-amylase complex confirmed the importance of this core structure and revealed a novel mode of glycosidase inhibition wherein internal pi-stacking interactions between the myricetin and caffeic acid organize their ring hydroxyls for optimal hydrogen bonding to the alpha-amylase catalytic residues D197 and E233. This novel inhibitory motif can be reproduced in a greatly simplified analog, offering potential for new strategies for glycosidase inhibition and therapeutic development.

DOI10.1038/NCHEMBIO.1865