CONFORMATION/BIOACTIVITY OF HUMAN SALIVARY MUCIN GLYCANS

人唾液粘蛋白​​聚糖的构象/生物活性

• 批准号: 6104711
• 负责人: MICHAEL J LEVINE
• 金额: $ 15.07万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104711
• 关键词: chemical models; circular dichroism; computer simulation; conformation; glycopeptides; glycosylation; human subject; mucins; nuclear magnetic resonance spectroscopy; peptide analog; peptide chemical synthesis; protein structure function; saliva

Human salivary mucins protect the oral tissues by providing a physical barrier to environmental agents, possessing viscoelastic properties essential for lubrication and participating in the modulation of the oral flora. These properties are dependent, in large part, on the mucin's O- linked oligosaccharides and the peptide moieties surrounding the glycopeptide linkage. Several central questions regarding the patterns of O-glycosylation remain to be understood for the prediction of the influence of O-glycosylation patterns on the mucin's biological function(s). First, a consensus sequence akin to the Asn-Xxx-Thr/Ser motif for N-glycosylation has not been identified and hence the factor(s) that determine which Ser and Thr residues are O-glycosylated are not known. Second, factors that determine the final structure of the O- linked units and their distribution along the peptide backbone are not understood. Our hypothesis is that the patterns of MG2 O-glycosylation are important determinants in biological activity. Importantly, these patterns are influenced by the conformation adopted by O-linked units and adjacent or flanking peptide sequences. For example, mucin's interaction with certain bacteria (e.g. viridans streptococci and Actinomyces viscosus) involves stereochemical recognition between mucin's O-linked oligosaccharides and bacterial adhesins. Our long range goal is to obtain a detailed understanding of human salivary mucin O- glycosylation patterns for the eventual production by design and mimicry of bioactive mucin analogs to be used as saliva substitutes. To achieve this goal, we will use MG2 as a model since its structure has been well characterized in our laboratory. Our approach to this problem is biphasic in nature. In the first phase, we will synthesize MG2 glycopeptides present in the tandem repeat with varying levels of O- linked units. The bioactivity of these glycopeptides will be compared to native MG2 to assess the role of glycosylation patterns on biological function. In the later phase, a complete understanding of the conformational dynamics of these bioactive glycopeptides will be carried out. The data obtained will then be used to design mucin peptides (e.g. glycomimetics) that mimic the conformation and biological properties of bioactive glycopeptides.

人唾液粘蛋白通过提供一种物理保护来保护口腔组织。 对环境物质的阻隔，具有粘弹性 对于润滑和参与口腔的调节至关重要 植物群。 这些特性在很大程度上取决于粘蛋白的O- 连接的寡糖和围绕寡糖的肽部分 糖肽连接。 关于模式的几个核心问题 O-糖基化的预测仍有待理解。 O-糖基化模式对粘蛋白生物活性的影响 function（s）. 首先，类似于Asn-Xxx-Thr/Ser的共有序列 N-糖基化基序尚未鉴定，因此因子 确定哪些Ser和Thr残基是O-糖基化的， 知道的 第二，决定O- 连接的单元和它们沿肽骨架的沿着分布不是 明白 我们的假设是MG 2 O-糖基化的模式 是生物活性的重要决定因素。 重要的是这些 模式受O-连接单元所采用的构象的影响 和相邻或侧翼的肽序列。 例如，粘蛋白 与某些细菌（例如草绿色链球菌和 粘性放线菌）涉及粘蛋白之间的立体化学识别 O-连接寡糖与细菌粘附素。 我们的长期目标 是为了详细了解人类唾液粘蛋白O- 通过设计和模仿最终生产的糖基化模式 作为唾液替代物的生物活性粘蛋白类似物。 实现 为了实现这一目标，我们将使用MG 2作为模型，因为它的结构已经很好地 在我们的实验室里。 我们解决这个问题的方法是 是双相的 在第一阶段，我们将合成MG 2 存在于串联重复序列中的糖肽，具有不同水平的O- 链接单位 比较了这些糖肽的生物活性 以评估糖基化模式对生物学特性的作用。 功能 在后期阶段， 这些生物活性糖肽的构象动力学将进行 出去 然后将获得的数据用于设计粘蛋白肽（例如， 糖模拟物），其模拟糖的构象和生物学性质。 生物活性糖肽。