Modular Synthesis of N-Glycans and Homogeneous Glycoproteins

美国国家科学基金会化学部化学合成项目通过这一奖项支持斯克里普斯研究所黄志辉教授的研究。黄教授和他的研究小组正在开发利用化学和酶的工具连接糖分子形成低聚糖（相对较小的碳水化合物）的新方法。这些构建低聚糖的新方法随后被用于组装糖蛋白（附着糖的蛋白质），并了解低聚糖片段如何影响蛋白质功能。糖蛋白具有许多重要的生物学功能，例如对免疫系统、消化系统和生殖系统至关重要。由于高等生物中的大多数蛋白质都是用不同序列、长度和分支的低聚糖修饰的，在多个位点上，任何给定的糖蛋白都存在相当大的微观异质性。这使得很难建立糖蛋白清晰的结构/功能关系。低聚糖的合成方法的发展及其在均质糖蛋白组装中的应用对此类研究至关重要。Wong小组所做的工作还为研究生和本科生以及博士后研究人员提供了化学、化学生物学、分子生物学和生物化学方面的跨学科培训。了解糖基化对蛋白质折叠、结构和功能的影响在生物学和医学中至关重要，需要大量复杂的结构明确的天冬酰胺连接的n -聚糖。黄教授和他的研究小组正在通过设计模块化的化学酶方法来组装低聚糖来解决这一挑战。更具体地说，他们正在开发制备具有氟化唾液酸和集中功能的多天线n链聚糖的方法，以及优化酶以实现三和四烯十烷低聚糖的转移。在这些研究中制备的n -聚糖的重要阵列可用于生成均匀的糖蛋白，如单克隆抗体，用于研究其活性。所有被发现的模块、酶和试剂也将提供给社区，以提供有用的混合合成/酶工具箱，以促进更好地理解蛋白质糖基化的关键需求，并推进糖科学的研究。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Chi-Huey Wong at The Scripps Research Institute. Professor Wong and his research team are developing new ways to link sugar molecules to form oligosaccharides (relatively small carbohydrates) using chemical and enzymatic tools. These new methods for the construction of oligosaccharides are then being used to assemble glycoproteins (proteins that have sugars attached to them) and to understand how the oligosaccharide fragments affect protein function. Glycoproteins perform many important biological functions that are central to the immune, digestive, and reproductive systems, for example. Since most proteins in higher organisms are modified with oligosaccharides of varying sequence, length and branching, at multiple loci, there is considerable microheterogeneity for any given glycoprotein. This makes it difficult to establish clear structure/function relationships for glycoproteins. The development of methods for the defined synthesis of oligosaccharides and their use for the assembly of homogeneous glycoproteins is critically important for such studies. The work being done in the Wong group is also providing graduate and undergraduate students, as well as postdoctoral researchers, with interdisciplinary training in chemistry, chemical biology, molecular biology, and biochemistry.Understanding the effect of glycosylation on protein folding, structure and function is vitally important in biology and medicine and requires access to a large number of complex structurally-defined asparagine-linked N-glycans. Professor Wong and his research group are addressing this challenge by designing modular chemoenzymatic methods for assembling oligosaccharides. More specifically, they are developing methods to prepare multi-antennary N-linked glycans with fluorinated sialic acid and fucosylated functionalities, as well as optimizing enzymes to achieve transfers of tri-and tetrantennary oligosaccharides. The significant array of N-glycans being prepared in these studies is then available to generate homogeneous glycoproteins, such as monoclonal antibodies, for the study of their activities. All modules, enzymes, and reagents being discovered are also being made available to the community to provide a useful hybrid synthetic/enzymatic toolbox to facilitate the critical need for better understanding of protein glycosylation and to advance research in glycoscience.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.