GLYCOSIDASES AS RELATED TO SPHINGOLIPIDOSES

与鞘脂相关的糖苷酶

• 批准号: 3393987
• 负责人: YU-TEH LI
• 金额: $ 18.05万
• 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 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3393987
• 关键词: O glycosidase; Primates; Tay Sachs disease; alpha galactosidase; beta N acetylhexosaminidase; beta glucosidases; chromatography; cow; enzyme linked immunosorbent assay; enzyme mechanism; enzyme substrate; enzyme therapy; gangliosidosis GM1; glycosphingolipids; human tissue; hydrolysis; inborn metabolism disorder diagnosis; lipid metabolism; metachromatic leukodystrophy; molecular pathology; radioimmunoassay; sphingolipidosis; swine; urinalysis

Sphingolipidoses are a group of congenital disorders caused by the impaired catabolism of glycosphingolipids. Since the storage of partially degraded glycosphingolipids in the secondary lysosomes of various sphingolipidoses is linked to a deficiency of glycosidases, the enzyme deficiency was once considered to be the sole cause of the pathogenesis of sphingolipidoses. Through the past support of this grant, we have established that activator proteins are requisite for the enzymic hydrolysis of GM1 and GM2. We have also discovered a new variant of Type-AB GM2 gangliosidosis caused by a defect in Beta-hexosaminidase A. Our work, together with that of others, has resulted in the introduction of a new concept that both glycosidases and activator proteins are required for the catabolism of glycosphingolipids. Therefore, according to this new concept, sphingolipidoses can be caused by four different etiologies: a defect in either activator protein or glycosidases or a deficiency in either activator protein or glycosidase. In this grant period we would like to continue investigating the chemical pathology of sphingolipidoses by studying the catabolism of glycosphingolipids. Our specific aims are: a) to improve the isolation techniques for activator proteins which stimulate the hydrolysis of GM1 and Gm2 (GM1- and GM2-activators) and to further study their specificities and subcellular localization; b) to characterize activator proteins in human urine; c) to develop a sensitive method such as enzyme-linked adsorbent assay or radioimmunoassay for the detection of GM1- and GM2- activators and the clinical diagnosis of lipidosis due to the deficiency of activator protein; d) to complete the overall catabolic pathways of GM1 and GbOse4Cer; e) to study inhibitor proteins which inhibit the catabolism of glycosphingolipids, and f) to continue the isolation and characterization of glycosidases pertinent to sphingolipidoses. Our long term objective is to completely understand the role of activator proteins, inhibitor proteins, and their interaction with glycosidases and glycolipid substrates. This information will lead to the better understanding of the catabolism of glycosphingolipids and the molecular basis of sphingolipidoses.

鞘脂脂是由受损引起的一组先天性疾病 糖脂果脂的分解代谢。 由于存储部分退化 各种鞘脂的二级溶酶体中的糖脂脂 与糖苷酶的缺乏有关，酶缺乏症一次 被认为是鞘脂发病机理的唯一原因。 通过这笔赠款的过去支持，我们已经确定了激活者 蛋白质是GM1和GM2的酶水解所必需的。 我们有 还发现 β-己糖胺酶A中的缺陷A。我们的工作以及其他工作， 导致引入了两个糖苷酶的新概念 激活蛋白是需要的 糖磷脂。 因此，根据这个新概念 鞘脂可以由四种不同的病因引起： 激活剂蛋白或糖苷酶或任何一种 激活蛋白或糖苷酶。 在这个赠款期间，我们想 继续研究鞘脂的化学病理学 研究糖磷脂脂的分解代谢。 我们的具体目的是：a） 改善激活蛋白的隔离技术的刺激蛋白 GM1和GM2（GM1-和GM2激活剂）的水解，并进一步 研究他们的特殊性和亚细胞定位； b）表征 人尿中的激活蛋白； c）开发一种敏感方法，例如 酶联的吸附剂测定或放射免疫测定法检测GM1- GM2-激活剂以及由于 激活蛋白的缺乏； d）完成整体分解代谢 GM1和Gbose4cer的途径； e）研究抑制抑制剂的抑制剂 糖磷脂脂的分解代谢，以及f）继续隔离和 与鞘脂有关的糖苷酶的表征。 我们的漫长 术语目标是完全了解激活蛋白的作用， 抑制剂蛋白质及其与糖苷酶和糖脂的相互作用 基材。 这些信息将导致对 糖磷脂的分解代谢和分子基础 鞘脂。