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

描述（由申请人提供）：所有细胞（真核细胞、古细菌或原核细胞）在其表面展示多种聚糖。在原核生物的情况下，这些聚糖作为细胞壁的组成部分存在。细胞壁被认为具有许多功能，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而疏水的细胞壁。分枝杆菌和棒状杆菌细胞壁的突出特征是结构上不同的阿拉伯半乳聚糖（AG）聚合物，其充当将分枝菌酸的厚外层连接到由交联肽聚糖网络组成的基底层的支架。AG的阿拉伯聚糖片段是完全由阿拉伯呋喃糖（Araf）残基制成的复杂的支链多糖。对于分支杆菌来说，这种阿拉伯聚糖多糖对于生存至关重要。阿拉伯聚糖在维持分枝杆菌活力和孤雌生殖中的确切功能尚不清楚，阿拉伯聚糖的特定结构特征如何有助于其功能也不清楚。据推测，合成类似物的Araf供体decaprenylphosphoryl-？D-阿拉伯呋喃糖（DPA）可用于将非天然糖残基引入活细菌的细胞壁阿拉伯聚糖中。拟议的研究的目标是使用DPA的合成类似物来探测阿拉伯聚糖在其天然环境中的结构、功能、定位和动力学。 公共卫生相关性：阿拉伯半乳聚糖是一种结构独特的多糖，其是分枝杆菌细胞壁的突出特征，并且对于结核分枝杆菌的存活是必需的。我们试图阐明阿拉伯半乳聚糖的结构功能关系，并研究其在细胞壁中的定位和动力学。这些研究将有助于确定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的设计。

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.