A Tool for synthetic post-translational modifications of cysteines

首席调查员/项目主任(最后、第一、中间)：ROVIS，Tomislav 半胱氨酸的合成翻译后修饰工具 摘要- 在蛋白质支架内选择性地安装氨基酸残基的能力已经被 在解开生物学的中心教条方面具有不朽的意义。具体地说，引入了不自然 氨基酸(UAA)有助于研究蛋白质内部的机制研究，以及 激励社区开发安装UAA的合成方法。在这一领域内， 能够安装包含翻译后修改(PTM)UAA是有价值的， 尤其是那些原生于生物学的生物。尤其是对蛋白质的理解 由于缺乏对磷酸化的机制了解，磷酸化仍然受到限制。 小路。因此，合成结合磷酸化氨基酸是一种推动力。 变成一种蛋白质支架。我们的目标是创造一种方法来综合安装天然的PTM在一个 采用半胱氨酸硫醇和光氧化还原催化的蛋白质支架。 在此，我们提出一种 利用含半胱氨酸的方法 作为前驱体的多肽 以碳为中心的自由基，它 可以通过以下方式进一步实现功能 镍催化。在这一点上，可以通过半胱硫基的β-裂解来进行脱硫 自由基和磷化氢，生成一个新的C中心自由基。通过选择偶联伙伴， 各种芳基官能团可以选择性地结合在半胱氨酸位置上。此外，芳香 配备了天然PTMS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)开发一种用于半胱氨酸转化为 磷酸酪氨酸 2)将该方法推广到寡肽和蛋白质的半胱氨酸修饰

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