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In situ extension as an approach for identifying novel alpha-amylase inhibitors

TitleIn situ extension as an approach for identifying novel alpha-amylase inhibitors
Publication TypeJournal Article
Year of Publication2004
AuthorsNumao, S, Damager, I, Li, CM, Wrodnigg, TM, Begum, A, Overall, CM, BRAYER, GD, Withers, SG
JournalJOURNAL OF BIOLOGICAL CHEMISTRY
Volume279
Pagination48282-48291
Date PublishedNOV 12
ISSN0021-9258
Abstract

A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of alpha-amylases based upon autoglucosylation of known alpha-glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized to occur with acarbose, is demonstrated with the known alpha-glucosidase inhibitor, D-gluconohydroximino-1,5-lactam. This was transformed from an inhibitor of human pancreatic alpha-amylase with a K-i value of 18 mM to a trisaccharide analogue with a K-i value of 25 muM. The three-dimensional structure of this complex was determined by x-ray crystallography and represents the first such structure determined with this class of inhibitors in any alpha-glycosidase. This approach to the discovery and structural analysis of amylase inhibitors should be generally applicable to other endoglucosidases and readily adaptable to a high throughput format.

DOI10.1074/jbc.M406804200