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J. Biol. Chem., Vol. 279, Issue 46, 48282-48291, November 12, 2004

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In Situ Extension as an Approach for Identifying Novel -Amylase Inhibitors^*

Shin Numao, Iben Damager¶||, Chunmin Li¶**, Tanja M. Wrodnigg, Anjuman Begum**, Christopher M. Overall**, Gary D. Brayer**, and Stephen G. Withers**¶¶

From the Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada and the Departments of ^**Biochemistry and Molecular Biology and Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of -amylases based upon autoglucosylation of known -glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized to occur with acarbose, is demonstrated with the known -glucosidase inhibitor, D-gluconohydroximino-1,5-lactam. This was transformed from an inhibitor of human pancreatic -amylase with a K_i value of 18 mM to a trisaccharide analogue with a K_i value of 25 µM. 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 -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.

Received for publication, June 17, 2004 , and in revised form, August 9, 2004.

^* This work was supported by the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Canadian Institutes of Health Research Studentship. Present address: Institut für Mikrobiologie, ETH Zürich, CH-8092 Zürich, Switzerland.

^¶ These authors contributed equally to this work.

^|| Supported by Carlsbergfondet in Denmark.

Supported by Erwin Schrödinger Post Doctoral Stipend J2092 by the Austrian Fonds zur Förderung der wissenschaftlichen Forschung. Present address: Institut für Organische Chemie der Technischen Universität Graz, Stremayrgasse 16, S-8010 Graz, Austria.

^¶¶ To whom correspondence should be addressed: Dept. of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. Tel.: 604-822-3402; Fax: 604-822-8869; E-mail: withers{at}chem.ubc.ca.

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