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: 10194719
• 负责人: Tomislav Rovis
• 金额: $ 23.61万
• 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/10194719
• 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; c new; 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

主要研究者/项目负责人（最后，第一，中间）：Rovis，Tomislav 半胱氨酸翻译后修饰的合成工具 摘要-- 选择性地将氨基酸残基安装在蛋白质支架内的能力已经被证实。 在生物学中心法则的解卷积方面具有里程碑意义。具体来说，引入非自然的 氨基酸（UAA）有助于蛋白质内机制研究的调查， 激励了社区开发安装UAA的合成方法。在这一领域内， 能够安装包含翻译后修饰（PTM）UAA是有价值的， 尤其是那些生物体中的原生物种尤其是对蛋白质的理解 由于缺乏对磷酸化机制的理解， 途径。因此，有一个动力，合成纳入磷酸化氨基酸 into a protein蛋白scaffold支架.我们的目标是创造一种方法，在一个 蛋白质支架使用半胱氨酸硫醇和光氧化还原催化。 在此，我们提出一个 利用含半胱氨酸的方法 肽作为前体， 碳中心的自由基， 可以通过以下方式进一步官能化： 镍催化在这方面，脱硫可以通过Cys硫基的β-断裂发生， 自由基和膦，产生一个新的C中心的自由基。通过选择耦合伙伴， 可以在Cys位置选择性地引入各种芳基官能团。此外，芳基 具有天然PTM功能的蛋白质可以直接掺入蛋白质支架中。 本研究的具体目标如下： 1)开发一种位点选择性芳基化方案，用于将半胱氨酸转化为 磷酸酪氨酸 2)将该方法扩展到寡肽和蛋白质中的Cys修饰