CONFORMATION/BIOACTIVITY OF HUMAN SALIVARY MUCIN GLYCANS

人类唾液粘蛋白通过提供一种物理的 阻隔环保剂，具有粘弹性 对口腔的润滑和参与调节必不可少 弗洛拉。这些特性在很大程度上依赖于粘蛋白的O- 连接的低聚糖和其周围的多肽 糖肽连接。关于模式的几个核心问题 对O-糖基化的预测尚不清楚。 O-糖基化模式对粘蛋白生物学特性的影响 函数(S)。首先，类似于ASN-xxx-Thr/Ser的共识序列 N-糖基化基序尚未确定，因此该因子(S) 决定哪些丝氨酸和苏氨酸残基是O-糖基化的 为人所知。第二，决定O-的最终结构的因素 连接的单位和它们沿肽骨架的分布不是 明白了。我们的假设是，镁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 以及相邻或侧翼的多肽序列。例如，粘蛋白 与某些细菌的相互作用(例如，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-连接低聚糖和细菌粘附素。我们的远景目标 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 作为唾液替代品的生物活性粘蛋白类似物。要实现 这个目标，我们将使用镁作为模型，因为它的结构已经很好了 这是我们实验室的特点。我们解决这个问题的方法是 本质上是双相的。在第一阶段，我们将合成镁 串联重复序列中存在的糖肽具有不同水平的O- 链接的单位。我们将比较这些糖肽的生物活性。 以评估糖基化模式对生物的作用 功能。在后面的阶段，完全了解 这些生物活性糖肽的构象动力学将被携带 出去。然后，所获得的数据将被用于设计粘蛋白多肽(例如 GlycoMimtics)的构象和生物学特性 生物活性糖肽。

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.