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

首席调查员/计划总监（最后，第一，中间）：Rovis，Tomislav 半胱氨酸的合成后翻译后修饰工具 抽象的- 选择性安装氨基酸保留在蛋白质支架中的能力已经 纪念性涉及生物学的中心教条。具体来说，引入了不自然的 氨基酸（UAA）有助于研究蛋白质内的机械研究， 激励社区开发安装UAA的合成方法。在此字段中， 能够安装包含翻译后修改（PTMS）的UAA是有价值的 特别是那些原生生物学的人。特别是对蛋白质的理解 磷酸化仍然受到对磷酸化的机械理解的限制 途径。因此，合成掺入磷酸化氨基酸的动力 进入蛋白质支架。我们旨在创建一种方法，以合成在 蛋白质支架使用Cys硫醇和光毒素催化。 在这里，我们提出了一个 利用含Cys的方法 肽作为前体 以碳为中心的自由基 可以通过 镍催化。在这方面，可以通过Cys硫基的β-SCISS进行脱硫 自由基和磷酸，产生新的以C为中心的自由基。通过选择耦合伙伴， 可以在CYS位置选择性地合并各种芳基功能。另外，芳基 与天然PTM相当的功能可以直接合并到蛋白质支架中。 这项研究的具体目标如下： 1）开发一种现场选择性芳基化方案，以将半胱氨酸转化为 磷酸酪氨酸 2）将此方法扩展到寡肽和蛋白质中的CYS修饰