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Titolo:
Mixed-linkage cellooligosaccharides: A new class of glycoside hydrolase inhibitors
Autore:
Fort, S; Varrot, A; Schulein, M; Cottaz, S; Driguez, H; Davies, GJ;
Indirizzi:
Univ York, Dept Chem, Struct Biol Lab, York YO10 5DD, N Yorkshire, EnglandUniv York York N Yorkshire England YO10 5DD O10 5DD, N Yorkshire, England Univ Grenoble 1, CNRS, CERMAV, F-38041 Grenoble 9, France Univ Grenoble 1Grenoble France 9 RS, CERMAV, F-38041 Grenoble 9, France Novozymes AS, DK-2880 Bagsvaerd, Denmark Novozymes AS Bagsvaerd Denmark DK-2880 es AS, DK-2880 Bagsvaerd, Denmark
Titolo Testata:
CHEMBIOCHEM
fascicolo: 5, volume: 2, anno: 2001,
pagine: 319 - 325
SICI:
1439-4227(20010504)2:5<319:MCANCO>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
SEQUENCE-BASED CLASSIFICATION; ANGSTROM RESOLUTION; HUMICOLA-INSOLENS; ENDOGLUCANASE-I; CYCLODEXTRIN GLYCOSYLTRANSFERASE; MACROMOLECULAR STRUCTURES; FUSARIUM-OXYSPORUM; CRYSTAL-STRUCTURE; ALPHA-AMYLASE; MECHANISMS;
Keywords:
carbohydrates; hydrolases; inhibitors; protein structures; thiooligosaccharides;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
61
Recensione:
Indirizzi per estratti:
Indirizzo: Davies, GJ Univ York, Dept Chem, Struct Biol Lab, York YO10 5DD, N Yorkshire, England Univ York York N Yorkshire England YO10 5DD Yorkshire, England
Citazione:
S. Fort et al., "Mixed-linkage cellooligosaccharides: A new class of glycoside hydrolase inhibitors", CHEMBIOCHEM, 2(5), 2001, pp. 319-325

Abstract

A new class of inhibitors for beta -D-glycoside hydrolases, in which a single alpha-(1 -->4)-glycosidic bond is incorporated into an otherwise all-beta-(1 -->4)-linked oligosaccharide, is described. Such mixed beta/alpha -linkage 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 alpha/beta -D-tetrasaccharide acts competitively on a number of cellulases, displaying inhibition constants in the range of 40-300 muM. Using the Bacillus agaradhaerens enzyme Cel5A as a model system, one such mixed beta/alpha -cellooligosaccharide, methyl 4'',4'''-dithio-alpha -cellobiosyl-(1 -->4)-beta -cellobioside, displays a K-i value of 100 muM, an inhibition at least 150 times better than is observed with an equivalent all-beta -linked compound. the three-dimensional structure of B. agaradhaerens Cel5A in complex with methyl 4'',4'''-dithio-alpha -cellobiosyl-(1 -->4)-beta -cellobioside has been determined at 1.8 Angstrom resolution. This confirms the expected mode of binding in which the ligand,with all four pyranosides in the C-4(1) chair conformation, occupies the -3, -2 and +1 subsites whilst evading the catalytic (-1) subsite. Such "by-pass" compounds offer great scope for the development of a new class of beta-D-glycoside hydrolase inhibitors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/09/20 alle ore 18:43:05