Title | In situ extension as an approach for identifying novel alpha-amylase inhibitors |
Publication Type | Journal Article |
Year of Publication | 2004 |
Authors | Numao, S, Damager, I, Li, CM, Wrodnigg, TM, Begum, A, Overall, CM, BRAYER, GD, Withers, SG |
Journal | JOURNAL OF BIOLOGICAL CHEMISTRY |
Volume | 279 |
Pagination | 48282-48291 |
Date Published | NOV 12 |
ISSN | 0021-9258 |
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. |
DOI | 10.1074/jbc.M406804200 |
