Our long-term objectives continue to be the study of glycoconjugate catabolism toward the understanding of the molecular mechanism and pathogenesis of sphingolipidoses and allied disorders. Our knowledge of glycoconjugate catabolism has undergone several stages of evolution. Before the 1970s, it was believed that only exo- and endo-glycosidases were responsible for the degradation of complex carbohydrates. Today, we know that, in addition to glycosidases, activator proteins (protein cofactors) are also required for the degradation of sugar chains in glycosphingolipids (GSLs). The recent discovery of a ceramide glycanase which cleaves the linkage between the sugar chain and the lipid moiety of GSLs has further changed our concept on the catabolism of GSLs. For two decades, our laboratory has contributed to these developments.
Our specific aims i n this grant period can be divided into the following three categories. I. Catabolism of GSLs. In this series of investigation, we will focus on: (a) the isolation of GM2-activator from human placenta, cloning the gene encoding GM2-activator and studying the structure and the activation mechanism of this activator protein; (b) the study of the catabolism of GalCer, which includes the identification of the activator protein for the enzymatic hydrolysis of GalCer and development of an animal model for Krabbe's disease in rhesus monkeys. II. The study of two novel glycosidases. This work will focus on: (a) the studies of the specificity and biological significance of ceramide glycanase and its distribution in higher animals; (b) the investigation of the specificity, function and distribution of a novel sialidase which releases 2,7-anhydro-NeuAc from sialo-glycoconjugates; (c) the study of the biological function of 2,7-anhydro-NeuAc. III. A continuing search for new glycosidases and the exploration of better sources for glycosidases, activator proteins and glycoconjugate substrates. We believe that this research will contribute to a better understanding of the chemical pathology of storage diseases caused by the impaired degradation of glycoconjugates.
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