Glycoconjugates (glycoproteins and glycosphingolipids) have been shown to carry biological messages and play important biological functions. Glycosidases are responsible for the catabolism of glycoconjugates and abnormal catabolism of glycoconjugates can lead to inborn lysosomal diseases such as sphingolipidoses.
Specific Aim I of this proposal focuses on the studies of chemical pathology to Tay-Sachs disease caused by the abnormal catabolism of GM2, a glycosphingolipid. Before the 1970s, it was believed that only glycosidases are responsible for the degradation of glycosphingolipids. During the past two decades, this laboratory and others have established that the catabolism of glycosphingolipids requires not only the enzyme but also the activator proteins. They plan to continue ongoing studies on: I) the mechanism of action of human GM2 activator, ii) the differences between the catabolism of GM2 in mouse and man, and iii) other biological functions of GM2 activator. Biochemical and molecular biological approaches will be used to investigate why beta-hexosaminidase A alone can not hydrolyze GM2 and how the activator protein promotes the hydrolysis of GM2. This study will provide new understanding on the chemical pathology of Tay-Sachs disease. Glycosidases are indispensable for studying the structure and function of glycoconjugates.
Specific Aim 2 of this application centers on the studies of the following novel glycosidases that are recently discovered in the P.I.'s laboratory: I) sialidase L which exhibits strict NeuAcalpha2,3Gal-linkage specificity and releases 2,7-anhydro-NeuAc as the product; ii) KDN-sialidase capable of releasing both KDN and NeuAc from sialoglycoconjugates; iii) NeuGc-Gc-sialidase which cleaves the novel sialosyl linkage of a NeuGc linked through the glycolyl hydroxyl group of another NeuGc; iv) alpha-KDOase capable of releasing KDO from endotoxins, and v) beta- galactosidase S which hydrolyzes both beta-linked galactose and beta-linked galactose-6-sulfate. These novel glycosidases can serve as the keys to open new frontiers of biomedical research in glycobiology.
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