Synthetic Sugar Analogues to Probe the Function and Dynamics of Cell Wall Glycans

描述(申请人提供)：所有细胞，真核细胞，古细胞，或原核生物在其表面显示不同的多聚糖阵列。在原核生物的情况下，这些多糖作为细胞壁的组成部分存在。细胞壁被认为具有多种功能，但其最重要的作用之一是为细胞提供形状和保护。分枝杆菌和棒状杆菌具有独特的厚壁和疏水性细胞壁。分枝杆菌和棒状杆菌细胞壁的一个显著特征是结构上不同的阿拉伯半乳糖(AG)聚合物，它充当连接厚厚的分枝杆菌酸外层和由交联肽聚糖网络组成的基层的支架。AG的阿拉伯糖段是一种复杂的分枝多糖，完全由阿拉伯呋喃糖(Araf)残基组成。对于分枝杆菌来说，这种阿拉伯多糖是生存所必需的。阿拉伯聚糖在维持分枝杆菌活性和孤雌生殖方面的确切功能尚不清楚，也不清楚阿拉伯聚糖的特定结构特征如何影响其功能。假设合成的阿拉伯糖供体十碳烯基磷酰基-D-阿拉伯呋喃糖(DPA)类似物可用于将非天然糖残基引入活细菌的细胞壁阿拉伯糖中。这项研究的目的是使用合成的DPA类似物来探索阿拉伯聚糖在其自然环境中的结构、功能、定位和动力学。 公共卫生相关性：阿拉伯半乳糖是一种结构独特的多糖，是分枝杆菌细胞壁的显著特征，对结核分枝杆菌的生存至关重要。我们试图阐明阿拉伯半乳糖的结构和功能关系，并研究其在细胞壁中的定位和动力学。这些研究将有助于识别分枝杆菌细胞壁的脆弱性，并指导治疗分枝杆菌感染的新药设计。

DESCRIPTION (provided by applicant): All cells, eukaryotic, archael, or prokaryotic display a diverse array of glycans at their surface. In the case of prokaryotes, these glycans exist as an integral part of a cell wall. The cell wall is thought to have many functions, but one on its most important roles is to provide shape and protection to the cell. Mycobacteria and corynebacteria possess a uniquely thick and hydrophobic cell wall. A prominent feature of the mycobacterial and corynebacterial cell wall is a structurally distinct arabinogalactan (AG) polymer that acts as a scaffold connecting a thick outer layer of mycolic acids to a base layer composed of a cross-linked peptidoglycan network. The arabinan segment of the AG is a complex, branched polysaccharide made entirely of arabinofuranose (Araf) residues. In the case of mycobacteria, this arabinan polysaccharide is essential for survival. The exact function of the arabinan in maintaining mycobacterial viability and parthenogenesis is not known, nor is how the specific structural characteristics of the arabinan contribute to its function. It is hypothesized that synthetic analogues of the Araf donor decaprenylphosphoryl-?-D-arabinofuranose (DPA) could be used to introduce non-natural sugar residues into the cell wall arabinan of living bacteria. The goal of the proposed research is to use synthetic analogues of DPA to probe the structure, function, localization, and dynamics of the arabinan in its native environment. PUBLIC HEALTH RELEVANCE: The arabinogalactan is a structurally distinct polysaccharide that is a prominent feature of the mycobacterial cell wall and is essential for the survival of Mycobacterium tuberculosis. We seek to elucidate the structure function relationships of the arabinogalactan and study its localization and dynamics in the cell wall. These studies will help identify vulnerabilities in the mycobacterial cell wall and guide the design of new drugs to treat mycobacterial infections.