INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

复杂碳水化合物生物合成的抑制

• 批准号: 3288781
• 负责人: BRUCE GANEM
• 金额: $ 11.03万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3288781
• 关键词: O glycosidase; affinity chromatography; alkylation; alpha glucosidase; amylases; carbohydrate biosynthesis; chemical conjugate; chemical structure function; chemical synthesis; cyclic amine; cyclization; enzyme inhibitors; enzyme mechanism; gangliosides; gel filtration chromatography; mannosidase; oligosaccharides; stereoisomer

This proposal describes the synthesis of several classes of new structures designed specifically to inhibit biologically important glycosidases (glycosyl hydrolases). A rationale for predicting sugar and anomer specificity is presented based on (1) a working hypothesis of enzyme mechanism and (2) results with previously known inhibitors. Target structures are typically polyhydroxylated cyclic amines, which will be prepared in enantiomerically pure form by a new method from D-hexoses. Glycosidases are ubiquitous in nature, being essential for the normal growth and development of all organisms. Glycosidases are involved in a variety of important cellular functions including the breakdown of carbohydrate foodstuffs, the processing of eucaryotic glycoproteins, and the catabolism of polysaccharides and glycoconjugates. One family of glycosidases functions in the biosynthesis and breakdown of complex brain and nervous system sphingolipids known as gangliosides. Disorders of ganglioside breakdown such as Tay-Sachs, Sandhoff's, Gaucher's, Fabry's and Krabbe's diseases are genetically inherited and result from deficiencies of specific glycosidases. Inhibitors of these enzymes could be used to induce disease symptoms in experimental animals, thus facilitating clinical study. In general, glycosidase inhibitors would be useful in studying the biosynthesis of polysaccharides and glycoconjugates. They should find wide application in microbiology, virology, cell biology, immunology, developmental biology and medicine.

该建议描述了几类新结构的综合 专门设计用于抑制生物学上重要的糖苷酶 （糖基水解酶）。 预测糖和厌氧剂的理由 根据（1）酶的工作假设提出了特异性 机理和（2）先前已知的抑制剂的结果。 目标 结构通常是多羟基化的环化胺，这将是 通过D-Hexoses的新方法以对映体纯正形式制备。 糖苷酶本质上是普遍的，对于正常 所有生物的生长和发育。 糖苷酶参与 各种重要的蜂窝功能，包括分解 碳水化合物食品，桉树糖蛋白的加工和 多糖和糖缀合物的分解代谢。 一个家庭 糖苷酶在复杂大脑的生物合成和分解中起作用 和神经系统鞘脂被称为神经脂化。 的疾病 神经节的崩溃，例如Tay-Sachs，Sandhoff's，Gaucher's，Fabry's和 克拉布的疾病是遗传遗传的，并由 特定的糖苷酶。 这些酶的抑制剂可用于诱导 实验动物的疾病症状，从而促进临床研究。 通常，糖苷酶抑制剂对研究 多糖和糖缀合物的生物合成。 他们应该找到宽阔的 在微生物学，病毒学，细胞生物学，免疫学中的应用， 发展生物学和医学。