BIOORGANIC APPROACH TO CARBOHYDRATE RECOGNITION

碳水化合物识别的生物有机方法

• 批准号: 2629054
• 负责人: Randall L Halcomb
• 金额: $ 10.23万
• 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/2629054
• 关键词: N acetylglucosamine; carbohydrate structure; chemical synthesis; 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：低聚糖、糖蛋白和其他糖复合物 参与许多生化过程，特别是在细胞中 表面。 此外，许多疾病状态，例如癌症和 炎症状况与异常糖基化有关。 这 拟议的研究计划将开发新颖的分子结构 研究正常和中碳水化合物的分子识别 患病的生化系统，并开发新的化学酶方法 溶液和固相糖复合物合成以促进这些研究 努力。 具体研究领域包括： (1) 计划 确定结构信息的传递方式 O-连接糖蛋白过程中蛋白质与其附着的碳水化合物链 生物合成。 一般方法是设计和综合 N-乙酰氨基葡萄糖丝氨酸的构象受限变体 糖蛋白连接点，并将其替换为亲本连接 寡肽。 这些替代的最终效果将是修复 碳水化合物结构域相对于肽在确定的方向上。 这些 糖肽将被评估为核心 1 的抑制剂或底物 半乳糖基转移酶和催化糖基化反应的酶 粘蛋白糖蛋白生物合成的早期阶段，已知 识别其内的肽和碳水化合物结合决定簇 基材。 从这些调查中获得的信息将提供 转移酶结合位点的图谱，并将为以下方面奠定基础 开发基于选择性抑制剂的治疗策略 蛋白质糖基化。 (2)新型化学和酶学的发展 复合糖蛋白和寡糖的合成方法 促进其生化和细胞功能的研究。 在 特别是，一种用唾液酸及其衍生物进行糖基化的新方法 其中，使用唾液酸转移酶作为合成催化剂，将是 发达。 此外，复杂的固相合成方法 将开发使用化学选择性连接策略的糖蛋白。 这些将适合组合文库生成，并且可以使用 i 结合构象约束合成糖蛋白 具有严格定义的拓扑。 这些分子将开辟新途径 研究糖复合物在正常和 疾病相关过程。