Chemical Tools for the Investigation and Manipulation of Protein Glycosylation

摘要：“研究和操纵蛋白质糖基化的化学工具” 这项提议的广泛目标是开发化学工具，使 鉴定糖蛋白，抑制特定类型的糖基化，并发现糖基化- 中介的生物相互作用。碳水化合物在蛋白质中的添加，或糖基化，是最重要的 常见的翻译后修饰形式，与包括蛋白质在内的各种过程有关 稳定性、大分子相互作用和细胞信号。不幸的是，目前可用的工具 询问这些功能是不够的，这将糖基化的研究限制在几个专家实验室。我们计划 在三个具体目标上解决这一未得到满足的需求。目标1建立在我们的新陈代谢化学开发基础上 记者，重点是使这些化学工具对不同类别的糖基化具有选择性。目标2 建议将选择性化学记者直接转化为特异性的选择性小分子抑制剂 糖基转移酶。Aim 3利用化学酶修饰糖基化的优势安装 将特定的光交联剂连接到活细胞上，重点是识别 由多聚糖调节。

ABSTRACT - “Chemical Tools for the Investigation and Manipulation of Protein Glycosylation” The broad goal of this proposal is the development of chemical tools that will enable the facile and robust identification of glycoproteins, inhibition of specific types of glycosylation, and the discovery of glycosylation- mediated biological interactions. The addition of carbohydrates to proteins, or glycosylation, is one of the most common forms of posttranslational modifications and is associated with various processes, including protein stability, macromolecular interactions, and cellular signaling. Unfortunately, the currently available tools for interrogating these functions fall short, which limits the study of glycosylation to a few expert labs. We plan to tackle this unmet need in three specific aims. Aim 1 builds on our development of metabolic chemical reporters, with a focus on making these chemical tools selective for different classes of glycosylation. Aim 2 proposes to directly transform selective chemical reporters into selective small-molecule inhibitors of specific glycosyltransferases. Aim 3 leverages the advantages of chemoenzymatic modification of glycosylation to install specific photo-cross-linkers onto living cells, with a focus on identifying biological interactions that are mediated by glycans.