BIOORGANIC APPROACH TO CARBOHYDRATE RECOGNITION

碳水化合物识别的生物有机方法

• 批准号: 6180767
• 负责人: Randall L Halcomb
• 金额: $ 8.98万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180767
• 关键词: N acetylglucosamine; carbohydrate structure; combinatorial chemistry; galactosyltransferases; glycoprotein biosynthesis; glycoprotein structure; glycosylation; peptide chemical synthesis; sialyltransferases

DESCRIPTION: Oligosaccharides, glycoproteins, and other glycoconjugates are involved in a number of biochemical processes, particularly at the cell surface. Additionally, many disease states, such as cancerous and inflammatory conditions, are associated with aberrant glycosylation. The proposed research program would develop novel molecular structures to investigate the molecular recognition of carbohydrates in normal and diseased biochemical systems, and develop novel chemoenzymatic methods for solution- and solid-phase glycoconjugate synthesis to facilitate theses endeavors. Specific research areas to be addressed include: (1) A program to determine the manner in which structural information is conveyed from proteins to their attached carbohydrat chains during O-linked glycoprotein biosynthesis. The general approach is to design and synthesize conformationally constrained variants of the N-acetylglucosaminyl serine glycoprotein linkage point, and substitute these for the parent linkage in oligopeptides. The net effect of these substitutions would be to fix the carbohydrate domain relative to the peptide in defined orientations. These glycopeptides would be evaluated as inhibitors or substrates of the Core 1 galactosyltransferase, and enzyme that catalyzes a glycosylation reaction in the early stages of mucin glycoprotein biosynthesis, and which is known to recognize both peptide and carbohydrate binding determinants within its substrates. The information gained from these investigations would provide a map of the transferase binding site, and would establish a foundation for development of therapeutic strategies based on selective inhibitors of protein glycosylation. (2) The development of novel chemical and enzymatic methods for the synthesis of complex glycoproteins and oligosaccharides to facilitate the study of their biochemical and cellular functions. In particular, a novel method for glycosylation with sialic acid an derivatives thereof, using sialyltransferases as synthetic catalysts, would be developed. Additionally, methods for the solid-phase synthesis of complex glycoproteins using a chemoselective ligation strategy would be developed. These would be suitable for combinatorial library generation, and could used i combination with conformational constraint to synthesize glycoproteins having strictly defined topologies. These molecules would open new avenues to investigate the functional roles of glycoconjugates in normal and disease-associated processes.

描述：寡糖，糖蛋白和其他糖缀合物是 参与许多生化过程，尤其是在细胞中 表面。 此外，许多疾病状态，例如癌变和 炎症条件与异常的糖基化有关。 这 拟议的研究计划将开发新的分子结构 研究正常和 患病的生化系统，并开发新的化学酶方法 溶液和固相糖缀合物合成以促进论文 努力。 要解决的特定研究领域包括：（1） 确定从中传达结构信息的方式 O连接糖蛋白期间，蛋白质与其连接的碳水化合物链 生物合成。 一般方法是设计和合成 N-乙酰葡萄糖胺丝氨酸的构象约束变体 糖蛋白链接点，将其替换为父母链接 寡肽。 这些替代的净效应是修复 碳水化合物域相对于定义方向的肽。 这些 糖肽将作为核心1的抑制剂或底物评估 半乳糖基转移酶和酶催化糖基化反应 粘蛋白糖蛋白生物合成的早期阶段，并且已知 识别其内肽和碳水化合物结合的决定因素 基材。 从这些调查中获得的信息将提供 转移酶结合位点的地图，并为 基于选择性抑制剂的治疗策略的制定 蛋白质糖基化。 （2）新型化学和酶促的发展 复杂的糖蛋白和寡糖合成的方法 促进其生化和细胞功能的研究。 在 特别是一种用唾液酸和衍生物糖基化的新方法 它使用乙酰转移酶作为合成催化剂，将是 发达。 另外，复合物固相合成的方法 将开发使用化学选择性连接策略的糖蛋白。 这些适用于组合图书馆的生成，可以使用 我与合成糖蛋白的构象约束结合 具有严格定义的拓扑结构。 这些分子将开放新的途径 研究糖缀合物在正常和 疾病相关的过程。