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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS009626-29
Application #
2873123
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Spinella, Giovanna M
Project Start
1979-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
29
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Tulane University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Nakagawa, Tetsuto; Shimada, Yoshimi; Pavlova, Nadejda V et al. (2015) Cloning and expression of 3-deoxy-d-manno-oct-2-ulosonic acid ?-ketoside hydrolase from oyster hepatopancreas†. Glycobiology 25:1431-40
Li, Su-Chen; Anderson, Kimberly M; Li, Yu-Teh (2011) A unique endo-?-galactosidase that cleaves both blood group A and B glycotopes. Adv Exp Med Biol 705:81-95
Li, Yu-Teh; Li, Su-Chen; Buck, Wayne R et al. (2011) Selective extraction and effective separation of galactosylsphingosine (psychosine) and glucosylsphingosine from other glycosphingolipids in pathological tissue samples. Neurochem Res 36:1612-22
Kobayashi, Takaaki; Liu, Dage; Ogawa, Haruko et al. (2009) Removal of blood group A/B antigen in organs by ex vivo and in vivo administration of endo-beta-galactosidase (ABase) for ABO-incompatible transplantation. Transpl Immunol 20:132-8
Li, Yu-Teh; Chou, Chau-Wen; Li, Su-Chen et al. (2009) Preparation of homogenous oligosaccharide chains from glycosphingolipids. Glycoconj J 26:929-33
Komori, Tatsuya; Ando, Takayuki; Imamura, Akihiro et al. (2008) Design and efficient synthesis of novel GM2 analogues with respect to the elucidation of the function of GM2 activator. Glycoconj J 25:647-61
Goto-Inoue, Naoko; Hayasaka, Takahiro; Sugiura, Yuki et al. (2008) High-sensitivity analysis of glycosphingolipids by matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight imaging mass spectrometry on transfer membranes. J Chromatogr B Analyt Technol Biomed Life Sci 870:74-83
Li, Yu-Teh; Li, Su-Chen; Kiso, Makoto et al. (2008) Effect of structural modifications of ganglioside GM2 on intra-molecular carbohydrate-to-carbohydrate interaction and enzymatic susceptibility. Biochim Biophys Acta 1780:353-61
Ginzburg, Luba; Li, Su-Chen; Li, Yu-Teh et al. (2008) An exposed carboxyl group on sialic acid is essential for gangliosides to inhibit calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase: relevance to gangliosidoses. J Neurochem 104:140-6
Zhang, Xian-Yang; Dinh, Annie; Cronin, James et al. (2008) Cellular uptake and lysosomal delivery of galactocerebrosidase tagged with the HIV Tat protein transduction domain. J Neurochem 104:1055-64

Showing the most recent 10 out of 87 publications