BACTERIAL CHITOBIASE STRUCTURE PROVIDES INSIGHT INTO CATALYTIC MECHANISM AND THE BASIS OF TAY-SACHS-DISEASE

Chitin, the second most abundant polysaccharide on earth, is degraded by chitinases and chitobiases. The structure of Serratia marcescens ch itobiase has been refined at 1.9 Angstrom resolution. The mature prote in is folded into four domains and its active site is situated at the C-terminal end of the central (beta alpha)(8)-barrel. Based on the str ucture of the complex with the substrate disaccharide chitobiose, we p ropose an acid-base reaction mechanism, in which only one protein carb oxylate acts as catalytic acid, while the nucleophile is the polar ace tamido group of the sugar in a substrate-assisted reaction. The struct ural data lead to the hypothesis that the reaction proceeds with reten tion of anomeric configuration. The structure allows us to model the c atalytic domain of the homologous hexosaminidases to give a structural rationale to pathogenic mutations that underlie Tay-Sachs and Sandhof f disease.