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CELLULAR ACTION OF ALKYLGLYCOSIDES AS GLYCOGEN PRIMERS

烷基糖苷作为糖原引物的细胞作用

基本信息

批准号：
6177757
负责人：
ELIAS MEEZAN
金额：
$ 17.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-05 至 2002-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6177757
关键词：
enzyme mechanism enzyme substrate glucose transport glycogen synthase glycogenesis glycosides glycosylation hexosyltransferase insulin laboratory mouse noninsulin dependent diabetes mellitus obesity oligosaccharides tissue /cell culture

项目摘要

The regulation of glycogen metabolism is deranged in both Type I and Type II diabetes mellitus. Glycogen metabolism is impaired in insulin- sensitive tissues, primarily in skeletal muscle and liver, so that the synthesis of this glucose storage compound is inadequate to meet the demands of hyperglycemia. Glycogenin is a self-glycosylating enzyme which has recently been shown to serve as the core protein for glycogen synthesis by transferring glucose to itself to form a protein-linked oligosaccharide chain which serves as a primer for glycogen synthase to assemble the glycogen molecule. We have recently demonstrated that several alkylglycosides serve as acceptors for glucose transfer mediated by enzyme preparations of both glycogenin and glycogen synthase and have shown that these compounds increase glucose incorporation in liver and diaphragm of mice. They therefore have the potential to serve as artificial primers for the synthesis of glycogen. The principal objective of this proposal is to demonstrate that alkylglucosides and alkylmaltosides can initiate the synthesis of alpha 1 greater than 4 linked maltooligosaccharide chains in cultured skeletal muscle (L6) and liver (HEP-G2) cells and thereby modulate the synthesis of glycogen in these cells.We propose to determine the activities of glycogenin and glycogen synthesis in cell-free extracts of these cells and demonstrate that the alkylglycosides will serve as substrates for glucose transfer by these enzymes. We will then establish that the alkylglycosides will serve as acceptor substrates for glucose addition in intact cells and characterize the alkylmaltooligosaccharide products produced as a result of such addition. The effects of alkylglycosides on glycogenin and glycogen synthase activities and on glycogen synthesis will also be determined as will the effects on glucose transport and the influence of ambient glucose concentrations and insulin on the glucosylation of alkylglycosides and on glycogen synthesis in these cells. Any effects of the alkylglycosides on the molecular size and structure of glycogen synthesized will also be investigated. Significant findings in cultured cells will be correlated with the effects of the compounds in vivo in the ob/ob mouse model of NIDDM. The goal of these studies will be to elucidate how the alkylglycosides serve as exogenous acceptors for glucose transfer mediated by glycogenin and glycogen synthase in intact cells and therefore initiate and/or modulate the biosynthesis of glycogen. These studies may have therapeutic implications for modulating the disposal of glucose in diabetes.

糖原代谢的调节在I型和II型糖尿病中均紊乱。 2型糖尿病糖原代谢受损胰岛素- 敏感组织，主要是骨骼肌和肝脏，这种葡萄糖储存化合物的合成不足以满足高血糖症的要求。糖原是一种自身糖基化酶它最近被证明是糖原的核心蛋白通过将葡萄糖转移到自身以形成蛋白质连接的寡糖链，其作为糖原合酶的引物，组装糖原分子。我们最近已经证明，几种烷基糖苷作为葡萄糖转移介导的受体通过糖原和糖原合酶的酶制剂，显示这些化合物增加肝脏中的葡萄糖掺入，小鼠横膈膜。因此，它们有可能成为合成糖原的人工引物。校长本提案的目的是证明烷基葡糖苷和烷基麦芽糖苷可以引发大于4的α 1的合成在培养的骨骼肌中连接的麦芽寡糖链（L6），肝（HEP-G2）细胞，从而调节糖原的合成，这些细胞。我们建议，以确定活动的糖原和这些细胞的无细胞提取物中的糖原合成，烷基糖苷将作为葡萄糖转移的底物这些酶。然后我们将确定烷基糖苷将作为完整细胞中葡萄糖添加的受体底物，表征由此产生的烷基麦芽低聚糖产品这样的添加。烷基糖苷类化合物对糖原合成和糖原合成酶活性和对糖原合成的影响也将被确定对葡萄糖转运的影响以及环境葡萄糖浓度和胰岛素对烷基糖苷和糖原合成在这些细胞。任何影响烷基糖苷对糖原分子大小和结构的影响合成的也将进行研究。培养的重要发现细胞将与化合物在体内的作用相关， NIDDM的ob/ob小鼠模型。这些研究的目标是阐明烷基糖苷如何作为外源受体，糖原合成酶介导的葡萄糖转移细胞，并因此启动和/或调节糖原这些研究可能具有治疗意义，糖尿病中葡萄糖的处理。