A Tool for synthetic post-translational modifications of cysteines

半胱氨酸合成翻译后修饰的工具

• 批准号: 10378706
• 负责人: Tomislav Rovis
• 金额: $ 19.63万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378706
• 关键词: Amino Acids; Biology; Carbon; Catalysis; Communities; Complex; Coupling; Cysteine; Goals; Health; Incentives; Investigation; Methods; Modification; Nickel; Oligopeptides; Pathway interactions; Peptides; Phosphines; Phosphorylation; Phosphotyrosine; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Proteins; Protocols documentation; Research; Scaffolding Protein; Site; Sulfhydryl Compounds; Therapeutic Agents; desulfurization; programs; small molecule; tool; unnatural amino acids

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav A tool for synthetic post-translational modifications of cysteines Abstract- The ability to selectively install amino acid residues within a protein scaffold has been monumental in deconvoluting the central dogma of biology. Specifically, introducing unnatural amino acids (UAAs) have aided in the investigation of mechanistic studies within proteins, and has incentivized the community to develop synthetic methods for installing UAAs. Within this field, it is valuable to be able to install UAAs that contain post-translational modifications (PTMs), especially those that are native to biology. In particular, the understanding of protein phosphorylation is still limited by the lack of mechanistic understanding of phosphorylation pathways. Therefore, there is an impetus to synthetically incorporate phosphorylated amino acids into a protein scaffold. We aim to create a method to synthetically install natural PTMs within a protein scaffold using Cys thiols and photoredox catalysis. Herein, we propose a method to utilize Cys-containing peptides as a precursor for carbon-centered radicals, which can be further functionalized via nickel catalysis. In this regard, desulfurization can occur through the β-scission of the Cys thiyl radical and a phosphine, generating a new C-centered radical. By choosing the coupling partner, a variety of aryl functionality can be incorporated selectively at the Cys position. In addition, aryl functionality equipped with natural PTMs can be directly incorporated into a protein scaffold. The specific goals of this research are as follows: 1) Develop a site-selective arylation protocol for conversion of cysteine to phosphotyrosine 2) Extend this method to Cys modification in oligopeptides and proteins

首席研究员/项目总监（最后、第一、中间）：Rovis、Tomislav 半胱氨酸合成翻译后修饰的工具 抽象的- 在蛋白质支架内选择性安装氨基酸残基的能力 特别是在消除生物学中心法则方面具有里程碑意义，引入了非自然现象。 氨基酸（UAA）有助于蛋白质内部的机制研究，以及 激励社区开发在该领域安装 UAA 的合成方法， 能够安装包含翻译后修饰 (PTM) 的 UAA 非常有价值， 尤其是那些与生俱来的生物。 由于缺乏对磷酸化机制的理解，磷酸化仍然受到限制 因此，有动力合成磷酸化氨基酸 我们的目标是创建一种在蛋白质支架中合成安装天然 PTM 的方法。 使用Cys硫醇和光氧化还原催化的蛋白质支架。 在此，我们提出一个 含Cys的利用方法 肽作为前体 以碳为中心的自由基， 可以通过进一步功能化 在这方面，脱硫可以通过Cys硫基的β-断裂发生。 自由基和膦，生成新的以 C 为中心的自由基，通过选择偶联伙伴， 多种芳基官能团可以选择性地并入Cys位置。 具有天然 PTM 的功能，可以直接整合到蛋白质支架中。 本研究的具体目标如下： 1) 开发位点选择性芳基化方案，将半胱氨酸转化为 磷酸酪氨酸 2)将该方法扩展到寡肽和蛋白质中的Cys修饰