Multiscale chemical approaches to map oxidative stress

绘制氧化应激图谱的多尺度化学方法

基本信息

项目摘要

DESCRIPTION (provided by applicant): Radical species are an unavoidable consequence of respiration and the environment, and are tightly buffered by small molecule antioxidants and redo detoxifying enzymes. Oxidative stress emerges when an imbalance develops between the levels of reactive oxygen species and the cell's ability to readily eliminate the reactive intermediates or to repair the resulting damage. Aberrant oxidative signaling is perhaps one of the most important factors contributing to aging, neurodegeneration, heart disease, diabetes, and cancer. In order to induce a phenotypic change, oxidative stress must induce biochemical alterations to the genome, proteome and/or metabolome. Crystallographic analysis revealed that DJ-1 harbors a stabile sulfinic acid, and this oxidative modification is required for the suppression of mitochondrial oxidative stress. We have now shown that this sulfinic acid can react with nitrosothiols to form a thiosulfonate linkage, which can then be reduced by cellular thiols. Amazingly, sulfinates react with nitrosothiols faster than thiolates in standard physiological buffers. This provides a potential mechanism for DJ-1 function, which will be further explored with this award. We extended this approach to develop biotin-linked sulfinates for the direct detection and enrichment of endogenous nitrosylated proteins. In preliminary experiments, this method led to the identification of >1500 endogenous nitrosylated proteins, and establishes a robust new platform to functionally interrogate the dynamics of S-nitrosylation. In addition, we describe a new methodology for the selective enrichment of sulfinic acids based on orthogonal alkylation reagents, and propose to identify novel functional sulfinates in the proteome. Finally, we present a new class of ratiometric fluorescent probes for live-cell imaging and 19F-NMR of protein sulfenylation in vivo. Despite the central role of oxidative stress in human health, our ability to study the precise mechanisms of such modifications is hampered by a lack of selective chemical and analytical methods. In this proposal, we present a series of innovative chemical approaches to study oxidative damage across experimental scales, from live-cell imaging to in vivo imaging, in addition to proteome-wide annotation of oxidative post-translational modifications. Furthermore, we present a likely mechanism for the Parkinson's disease-linked redox chaperone DJ-1, and present new mechanism-based probes to functionally annotate and profile S-nitrosylation (R-SNO), S-sulfenylation (R-SOH), and S-sulfinylation (R-SO2H).
描述(由申请人提供):自由基物质是呼吸和环境的不可避免的结果,并通过小分子抗氧化剂和重做解毒酶紧密缓冲。当活性氧水平与细胞清除活性中间体或修复损伤的能力之间出现不平衡时,就会出现氧化应激。异常的氧化信号传导可能是导致衰老、神经退行性变、心脏病、糖尿病和癌症的最重要因素之一。为了诱导表型变化,氧化应激必须诱导基因组、蛋白质组和/或代谢组的生化改变。晶体学分析显示,DJ-1含有一个稳定的亚磺酸,这种氧化修饰是抑制线粒体氧化应激所必需的。我们现在已经表明,这种亚磺酸可以与亚硝基硫醇反应形成硫代磺酸酯键,然后可以被细胞硫醇还原。令人惊讶的是,在标准生理缓冲液中,亚磺酸盐与亚硝基硫醇的反应速度比硫醇盐更快。这为DJ-1功能提供了一种潜在的机制,将通过该奖项进一步探索。我们扩展了这种方法,以开发生物素连接的亚磺酸盐,用于直接检测和富集内源性亚硝基化蛋白。在初步实验中,该方法鉴定了>1500种内源性亚硝基化蛋白,并建立了一个强大的新平台来功能性地询问S-亚硝基化的动力学。此外,我们描述了一种新的方法,用于选择性富集的亚磺酸的基础上正交烷基化试剂,并建议确定新的功能亚磺酸酯的蛋白质组。最后,我们提出了一类新的比率荧光探针的活细胞成像和19 F-NMR的蛋白质磺酰化在体内。尽管氧化应激在人类健康中起着核心作用,但由于缺乏选择性的化学和分析方法,我们研究这种修饰的精确机制的能力受到阻碍。在这项提案中,我们提出了一系列创新的化学方法来研究氧化损伤的实验规模,从活细胞成像在体内成像,除了蛋白质组范围的注释氧化翻译后修饰。此外,我们提出了帕金森病相关的氧化还原伴侣DJ-1的可能机制,并提出了新的基于机制的探针功能注释和配置文件S-亚硝基化(R-SNO),S-亚磺酰化(R-SOH)和S-亚磺酰化(R-SO2 H)。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation.
  • DOI:
    10.1016/j.chembiol.2021.02.019
  • 发表时间:
    2021-03
  • 期刊:
  • 影响因子:
    8.6
  • 作者:
    Dongyu Zhao;Zhangyuan Yin;M. Soellner;Brent R. Martin
  • 通讯作者:
    Dongyu Zhao;Zhangyuan Yin;M. Soellner;Brent R. Martin
Temporal Profiling Establishes a Dynamic S-Palmitoylation Cycle.
时间分析建立动态的S-膜酰化周期。
  • DOI:
    10.1021/acschembio.8b00157
  • 发表时间:
    2018-06-15
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Won SJ;Martin BR
  • 通讯作者:
    Martin BR
Protein depalmitoylases.
Enrichment of S-Palmitoylated Proteins for Mass Spectrometry Analysis.
用于质谱分析的 S-棕榈酰化蛋白质的富集。
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Brent Randall Martin其他文献

Brent Randall Martin的其他文献

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{{ truncateString('Brent Randall Martin', 18)}}的其他基金

Quantitative chemical proteomics of dynamic palmitoylation in cells
细胞中动态棕榈酰化的定量化学蛋白质组学
  • 批准号:
    8516469
  • 财政年份:
    2011
  • 资助金额:
    $ 222.21万
  • 项目类别:
Quantitative chemical proteomics of dynamic palmitoylation in cells
细胞中动态棕榈酰化的定量化学蛋白质组学
  • 批准号:
    8335370
  • 财政年份:
    2011
  • 资助金额:
    $ 222.21万
  • 项目类别:
Quantitative chemical proteomics of dynamic palmitoylation in cells
细胞中动态棕榈酰化的定量化学蛋白质组学
  • 批准号:
    8318448
  • 财政年份:
    2011
  • 资助金额:
    $ 222.21万
  • 项目类别:
Quantitative chemical proteomics of dynamic palmitoylation in cells
细胞中动态棕榈酰化的定量化学蛋白质组学
  • 批准号:
    7952795
  • 财政年份:
    2010
  • 资助金额:
    $ 222.21万
  • 项目类别:
Metaobolomics of Neurodegenerative Disorders Caused by Hydrolase Deficiencies
水解酶缺陷引起的神经退行性疾病的代谢组学
  • 批准号:
    7741199
  • 财政年份:
    2007
  • 资助金额:
    $ 222.21万
  • 项目类别:
Metaobolomics of Neurodegenerative Disorders Caused by Hydrolase Deficiencies
水解酶缺陷引起的神经退行性疾病的代谢组学
  • 批准号:
    7506262
  • 财政年份:
    2007
  • 资助金额:
    $ 222.21万
  • 项目类别:
Metaobolomics of Neurodegenerative Disorders Caused by Hydrolase Deficiencies
水解酶缺陷引起的神经退行性疾病的代谢组学
  • 批准号:
    7406969
  • 财政年份:
    2007
  • 资助金额:
    $ 222.21万
  • 项目类别:

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