GLYCOSIDASES AS RELATED TO SPHINGOLIPIDOSES

与鞘脂相关的糖苷酶

• 批准号: 6151522
• 负责人: YU-TEH LI
• 金额: $ 33.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151522
• 关键词: Bivalvia; Tay Sachs disease; X ray crystallography; beta N acetylhexosaminidase; biotransformation; disease /disorder model; enzyme mechanism; enzyme structure; enzyme substrate; exo alpha sialidase; gangliosides; glycoproteins; glycosidases; glycosphingolipids; laboratory mouse; laboratory rat; lipid metabolism; molecular cloning; molecular pathology; protein purification; site directed mutagenesis; sphingolipidosis

DESCRIPTION: 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.

描述：糖缀合物（糖蛋白和糖磷脂）具有 被证明可以携带生物学信息并发挥重要的生物学作用 功能。 糖苷酶是负责的 糖缀合物和糖缀合物异常的分解代谢可能会导致 天生的溶酶体疾病，例如鞘脂。 特定目的我 提案的重点是针对Tay-Sachs疾病的化学病理学研究 由GM2的异常分解代谢引起，GM2是一种糖磷脂。 之前 1970年代，人们认为只有糖苷酶是造成的 糖脂脂的降解。 在过去的二十年中，这个 实验室和其他人已经确定 糖磷脂不仅需要酶，还需要激活剂 蛋白质。 他们计划继续对以下研究进行持续研究：i） 人GM2激活剂的作用，ii）分解代谢之间的差异 GM2中的小鼠和人，以及iii）GM2激活剂的其他生物学功能。 生化和分子生物学方法将用于研究 为什么单独使用β-己糖胺酶不能水解GM2以及激活剂如何 蛋白质促进GM2的水解。 这项研究将提供新的 了解Tay-Sachs疾病的化学病理学。 糖苷酶对于研究的结构和功能是必不可少的 糖缀合物。 本应用程序的具体目标2以研究为中心 在以下新型糖苷酶中，最近在 P.I.的实验室：i）表现出严格的唾液酸酶L neuacalpha2,3gal-linkage特异性并释放2,7-Anhydro-Neuac作为 产品; ii）KDN-sialidase能够从 Sialoglycoconjugates; iii）切割小说的Neugc-GC-Sialidase 通过糖基羟基链接的neugc的sialosyl链接 另一个neugc; iv）α-kdoase能够从内毒素中释放KDO， v）β-半乳糖苷酶S，水解了β连锁半乳糖和 β连锁半乳糖-6-硫酸盐。 这些新颖的糖苷酶可以用作 开放糖生物学生物医学研究新领域的关键。