Metalloprotein Mechanisms of Redox Regulation and Catalysis

氧化还原调节和催化的金属蛋白机制

基本信息

项目摘要

Abstract for Metalloprotein Mechanisms of Redox Regulation and Catalysis This proposal covers the three R01 grants funding my laboratory and aims to fill gaps in understanding the mechanisms of crucial aspects of redox regulation and catalysis by metalloproteins from microbes to humans. Successful completion of this work will reveal novel mechanisms with broad significance to human health, the environment, and biotechnology. Our research integrates a wide variety of biological, biophysical, biochemical and computational approaches. In Project Area 1, we will extend recent discoveries of novel bioinorganic and enzymatic mechanisms of anaerobic microbial CO and CO2 fixation in the Wood-Ljungdahl pathway (WLP), proposed to have fueled the origin of live on earth. We will reveal the mechanisms of these ancient enzymes: their generation and use of CO as a substrate, formation of bioorganometallic catalytic intermediates, utilization of nucleophilic and paramagnetic metal centers as catalysts, requirement of large domain movements and an interprotein CO channel and recently identified alcove for CO binding and CO2 fixation. We will define how these unique features choreograph redox activation, substrate and partner protein binding, leading to biological transformation that chemists are trying to mimic to more rapidly and efficiently accomplish chemically challenging reactions, e.g., to sequester, activate and convert CO2, methane and syngas into industrially important chemical feedstocks and fuels. While I started my career studying the WLP, I have applied the same expertise to other important evolving problems of metabolic regulation in humans by CO and metals and of mercury toxicity. In Project Area 2, we propose to deliver important discoveries on how human metabolism, metal homeostasis and the circadian clock are regulated by heme regulatory motifs (HRMs), signaling molecules (CO and NO), and cellular heme levels and redox poise. Focusing on heme oxygenase-2 (HO2), we will explore crucial conformational changes between the core and tail of HO2 and how these movements control protein turnover, protein-protein interactions, and heme conversion to CO, biliverdin and Fe. We will explore the hypothesis that HO2 serves a dual function in the cell in controlling heme trafficking and turnover. We will monitor the dynamics and interactions of full length HO2 with its redox partner cytochrome P450 reductase and with its heme donor GAPDH and define mechanisms that regulate heme-controlled HO2 turnover. Following up on our finding that the nuclear receptor Rev-Erbb uses a novel mechanism of redox- chemical coupling to serve as a CO/NO sensor, we will address how redox and gas binding affect its structure, function, activity and its interactions with partners like NCoR1 and its heme chaperone. In Project Area 3, recent successes in purifying and crystallizing the active HgcAB complex and defining its unusual thiolate- coordinated B12 cofactor, enable our proposed studies of the mechanism of microbial mercury methylation. We will determine the HgcAB structure, the redox and ligation states of the metal centers during catalysis, and whether a methyl radical or anion is used by these B12 and iron-sulfur clusters during catalysis.
金属蛋白氧化还原调控与催化机制研究

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Stephen Wiley Ragsdale其他文献

Stephen Wiley Ragsdale的其他文献

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{{ truncateString('Stephen Wiley Ragsdale', 18)}}的其他基金

Heme-, Redox-, and CO-dependent Regulation of Heme Homeostasis
血红素稳态的血红素、氧化还原和CO依赖性调节
  • 批准号:
    10660290
  • 财政年份:
    2023
  • 资助金额:
    $ 65.29万
  • 项目类别:
Metalloprotein Mechanisms of Redox Regulation and Catalysis
氧化还原调节和催化的金属蛋白机制
  • 批准号:
    10643866
  • 财政年份:
    2021
  • 资助金额:
    $ 65.29万
  • 项目类别:
Metalloprotein Mechanisms of Redox Regulation and Catalysis
氧化还原调节和催化的金属蛋白机制
  • 批准号:
    10204329
  • 财政年份:
    2021
  • 资助金额:
    $ 65.29万
  • 项目类别:
Biochemical Mechanism of Mercury Methylation
汞甲基化的生化机制
  • 批准号:
    9922977
  • 财政年份:
    2018
  • 资助金额:
    $ 65.29万
  • 项目类别:
Thiol/Disulfide Redox Regulation of Heme Oxygenase-2
血红素加氧酶 2 的硫醇/二硫化物氧化还原调节
  • 批准号:
    8097426
  • 财政年份:
    2010
  • 资助金额:
    $ 65.29万
  • 项目类别:
Thiol/Disulfide Redox Regulation of Heme Oxygenase-2
血红素加氧酶 2 的硫醇/二硫化物氧化还原调节
  • 批准号:
    8501649
  • 财政年份:
    2010
  • 资助金额:
    $ 65.29万
  • 项目类别:
Thiol/Disulfide Redox Regulation of Heme Oxygenase-2
血红素加氧酶 2 的硫醇/二硫化物氧化还原调节
  • 批准号:
    7985909
  • 财政年份:
    2010
  • 资助金额:
    $ 65.29万
  • 项目类别:
Thiol/Disulfide Redox Regulation of Heme Oxygenase-2
血红素加氧酶 2 的硫醇/二硫化物氧化还原调节
  • 批准号:
    8282769
  • 财政年份:
    2010
  • 资助金额:
    $ 65.29万
  • 项目类别:
Elucidation of the Role of the Heme Regulatory Motif in Heme Oxygenase-2
阐明血红素调节基序在 Heme Oxygenase-2 中的作用
  • 批准号:
    7471874
  • 财政年份:
    2008
  • 资助金额:
    $ 65.29万
  • 项目类别:
Elucidation of the Role of the Heme Regulatory Motif in Heme Oxygenase-2
阐明血红素调节基序在 Heme Oxygenase-2 中的作用
  • 批准号:
    7583965
  • 财政年份:
    2008
  • 资助金额:
    $ 65.29万
  • 项目类别:

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