Polysaccharides are a group of bio-macromolecules which play vital roles in organisms. However, due to the complex structural nature of polysaccharides, their synthesis has proven to be a challenging task for chemists, thus hindering the understanding of their biological functions and their applications in the improvement of life quality.
A team led by Prof. Xin-Shan Ye (the associate editor of this journal) at Peking University, after many years of research, has recently achieved a major breakthrough in the field of polysaccharide synthesis. Arabinogalactan was chosen as the target molecule for their research. This polysaccharide molecule is composed of a linear galactan chain (chain A) linked with two arabinan chains (chain B), forming a highly branched structure. Using simple monosaccharides as starting materials, researchers were able to produce oligosaccharide chains on the gram scale by the glycosyl donor preactivation-based one-pot oligosaccharide synthesis strategy they previously developed. The cis-1,2-glycosidic bonds were built in a highly stereoselective manner through the conformationally-constrained glycosyl donor. The one-pot protocol was used again for the rapid construction of the two chains (chain A and chain B). Finally, these chains were brought together with a [31+31+30] coupling reaction via the glycosylation promoter they developed previously, thus achieving the total synthesis of the highly branched 92-mer arabinogalactan for the first time.
Arabinogalactan is an important polysaccharide constituent of the cell wall of Mycobacterium tuberculosis, relevant to the bacteria's viability and pathogenicity. The artificial synthesis of arabinogalactan will not only shed light upon the mechanism of Mycobacterium tuberculosis cell wall biosynthesis but also benefit the development of novel tuberculosis vaccines. This work represents the synthesis of the largest and even most complicated polysaccharide with a well-defined structure up to date. It is a milestone in the field of carbohydrate synthesis, and will open the gates to further complex polysaccharide synthesis.
The aforementioned results have been published on Nature Communications (2017, 8, 14851). Graduate student Yong Wu from the School of Pharmaceutical Sciences is the first author of this paper. This work was financially supported by the grants from the National Natural Science Foundation of China and the Ministry of Science and Technology of China.
多糖是一类在生命体中发挥着重要作用的生物大分子, 但多糖的结构却非常复杂, 使多糖的合成难题长期以来一直困扰着合成化学家, 令化学家望而却步, 严重地制约着人们对多糖的生物学功能的认识以及实现它在改善人民生活质量方面的用途。
我院叶新山教授研究团队经过多年的研究积累, 近期在多糖人工合成的难题上取得了突破性进展。他们选取阿拉伯半乳聚糖这个多糖为目标分子。该分子由一条半乳聚糖链(A链)和两条紧密靠近的阿拉伯聚糖链(B链)所组成, 具有高度分支的结构。研究人员从简单的单糖原料出发, 采用他们前期所发展的基于糖基供体“预活化”的一釜寡糖合成策略, 以克级规模实现了寡糖链的大量 制备; 并且利用构象受限的糖基供体高立体选择性地构建1,2-顺式糖苷键; 随后再次使用“预活化”一釜寡糖合成策略分别完成了两条多糖链(A链和B链)的快速组装; 最后采用他们自己发展的糖基化反应偶联剂, 经[31+31+30]糖基化反应, 顺利实现了高度分支化、由92个单糖单元所组成的阿拉伯半乳聚糖的首次全合成。
阿拉伯半乳聚糖(Arabinogalactan)是一种重要的多糖, 它是结核分枝杆菌细胞壁的重要组成成分, 与细菌的存活力和致病力相关。该多糖的化学合成不仅为结核分枝杆菌细胞壁生物合成的机制的阐释提供基础, 而且有助于开发预防结核病的新型糖疫苗。这是迄今为止人类所合成的最大、最复杂的均一结构的多糖分子, 在糖合成领域具有里程碑式的意义。该研究必将为复杂多糖的合成开启新的篇章。
上述研究结果发表在《自然-通讯》(Nature Communications, 2017, 8, 14851)杂志上。药学院2013级直博生吴勇是这项工作的第一作者。该工作得到了国家自然科学基金重点项目、国家科技部“973”计划项目的资助。