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，古生物或原核细胞在其表面显示不同的聚糖阵列。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。分枝杆菌和棒状细菌细胞壁的一个突出特征是一种结构独特的阿拉伯半乳聚糖（AG）聚合物，它作为支架将粘稠的霉菌酸外层与由交联肽聚糖网络组成的基层连接起来。AG的阿拉伯糖段是一种复杂的支链多糖，完全由阿拉伯糖糠糖（Araf）残基组成。在分枝杆菌的情况下，这种阿拉伯多糖是必不可少的生存。阿拉伯糖在维持分枝杆菌活力和孤雌生殖方面的确切功能尚不清楚，也不清楚阿拉伯糖的特定结构特征如何促进其功能。假设Araf供体的合成类似物十烯丙基磷酰-？- d -阿拉伯糖醛酸（DPA）可用于将非天然糖残基引入活菌细胞壁阿拉伯糖。本研究的目的是利用DPA的合成类似物来探索阿拉伯糖在其天然环境中的结构、功能、定位和动力学。

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.