Mixed-Linkage Cellooligosaccharides: A New Class of Glycoside Hydrolase Inhibitors
✍ Scribed by Sébastien Fort; Annabelle Varrot; Martin Schülein; Sylvain Cottaz; Hugues Driguez; Gideon J. Davies
- Publisher
- John Wiley and Sons
- Year
- 2001
- Tongue
- English
- Weight
- 161 KB
- Volume
- 2
- Category
- Article
- ISSN
- 1439-4227
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✦ Synopsis
A new class of inhibitors for b-D-glycoside hydrolases, in which a single a-(1 34)-glycosidic bond is incorporated into an otherwise all-b-(1 34)-linked oligosaccharide, is described. Such mixed b/alinkage cellooligosaccharides are not transition-state mimics, but instead are capable of utilising binding energy from numerous subsites, spanning either side of the catalytic centre, without the need for substrate distortion. This binding is significant; a mixed a/b-D-tetrasaccharide acts competitively on a number of cellulases, displaying inhibition constants in the range of 40 ± 300 mM. Using the Bacillus agaradhaerens enzyme Cel5A as a model system, one such mixed b/a-cellooligosaccharide, methyl 4 II ,4 III -dithio-a-cellobiosyl-(1 34)-b-cellobioside, displays a K i value of 100 mM, an inhibition at least 150 times better than is observed with an equivalent all-b-linked compound. The three-dimensional structure of B. agaradhaerens Cel5A in complex with methyl 4 II ,4 III -dithio-acellobiosyl-(1 34)-b-cellobioside has been determined at 1.8 resolution. This confirms the expected mode of binding in which the ligand, with all four pyranosides in the 4 C 1 chair conformation, occupies the À 3, À 2 and 1 subsites whilst evading the catalytic (À 1) subsite. Such ªby-passº compounds offer great scope for the development of a new class of b-D-glycoside hydrolase inhibitors.