Managing Ionic Iron: Molecular Architecture and Mechanism of Cell Iron Metabolism

管理离子铁:细胞铁代谢的分子结构和机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): The solution and redox properties of iron that make it the metal prosthetic group of choice for the activation of otherwise kinetically inert substrates, including dioxygen, also make ionic Fe cytotoxic to aerobic organisms. Eukaryotes from yeast to humans have to manage ferrous iron's inherent reactivity with dioxygen and ferric iron's instability in water; the oft-cited role of iron in human pathology from post-ischemic tissue damage to neurodegenerative disease is testament to the importance of managing ionic iron. We propose that the Fe-traffieking pathway that succeeds in suppressing Fe's abiologic side-reactions has two essential and inter-related features: sequential Fe-trafficking components are spatially contiguous and thereby are architecturally organized to support the channeling of ionic Fe species along the Fe-metabolic pathway. This model will be tested at three steps in the ionic Fe pathway in Saccaromyces cerevisiae, the most tractable eukaryotic cell for a systematic test of this Fe-metabolic model. These three steps are: at the plasma membrane where ferrireduction is coupled to iron permeation; in the cytoplasm where Fe is trafficked from the PM to protein acceptor sites; and in the vacuole where Fe-redox cycling is coupled to Fe-storage in reactions that precisely mirror those that occur in ferritin. A primary strategy to ascertain conformational contiguity of Fe-handling proteins will be fluorescence resonance energy transfer; we propose to use FRET to examine the spatial relationships between reductase and permease partners in the plasma and vacuolar membranes. A primary strategy in quantifying the relative partitioning of newly-arrived Fe will be the use of cells engineered to turn on or turn off production of these putative Fe-handling proteins. A new role in Fe- handling is proposed for the yeast HSP90 proteins, Hsp82 and Hsc82; in addition, we suggest that nitric oxide and glutathione combine in a dinitrosyldithiolato-Fe complex that plays a significant role in cytoplasmic Fe-handling. Outstanding progress has been made on the metabolism of Fe-prosthetic groups like heme and Fe/S clusters; ionic Fe is the precursor to these "caged" Fe-species and is responsible for the "corrosive chemistry" that characterizes the relationship between Fe and dioxygen. An understanding of how cells suppress this chemistry would make a significant contribution to our eventual elucidation of the molecular basis for the multitude of human pathologies often attributed in part to mismanaged ionic iron.
描述(由申请人提供):铁的溶液和氧化还原特性使其成为激活其他惰性底物(包括双氧)的金属假体基的选择,也使离子铁对需氧生物具有细胞毒性。从酵母菌到人类的真核生物必须处理亚铁与二氧的固有反应性和铁在水中的不稳定性;从缺血后组织损伤到神经退行性疾病,铁在人类病理中经常被引用的作用证明了管理离子铁的重要性。我们提出,成功抑制铁的非生物副反应的铁运输途径具有两个基本和相互关联的特征:顺序的铁运输组分在空间上是连续的,因此在结构上有组织,以支持离子铁沿着铁代谢途径的通道。该模型将在酿酒酵母(sacaryces cerevisiae)中进行离子铁途径的三步测试,酿酒酵母是最容易进行铁代谢模型系统测试的真核细胞。这三个步骤是:在质膜上,铁还原与铁渗透耦合;在细胞质中,铁从PM转运到蛋白质受体位点;在液泡中,铁的氧化还原循环与铁的储存相结合,其反应恰好反映了铁蛋白中发生的反应。确定铁处理蛋白构象连续性的主要策略是荧光共振能量转移;我们建议使用FRET来检查血浆和液泡膜中还原酶和渗透酶伙伴之间的空间关系。量化新到达的铁的相对分裂的一个主要策略将是使用经过工程改造的细胞来打开或关闭这些假定的铁处理蛋白质的生产。提出了酵母HSP90、Hsp82和Hsc82蛋白在铁处理中的新作用;此外,我们认为一氧化氮和谷胱甘肽结合成二硝基二硫代酸铁复合物,在细胞质铁处理中起重要作用。血红素和铁/S簇等铁辅助基团的代谢研究取得了显著进展;离子铁是这些“笼状”铁的前体,也是铁和二氧之间的“腐蚀性化学”的主要原因。了解细胞如何抑制这种化学反应将对我们最终阐明多种人类病理的分子基础做出重大贡献,这些病理通常部分归因于离子铁管理不当。

项目成果

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DANIEL J. KOSMAN其他文献

DANIEL J. KOSMAN的其他文献

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{{ truncateString('DANIEL J. KOSMAN', 18)}}的其他基金

Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier
铁转运蛋白和 APP:血脑屏障铁运输的调节
  • 批准号:
    9367484
  • 财政年份:
    2017
  • 资助金额:
    $ 27.99万
  • 项目类别:
Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier
铁转运蛋白和 APP:血脑屏障铁运输的调节
  • 批准号:
    10183344
  • 财政年份:
    2017
  • 资助金额:
    $ 27.99万
  • 项目类别:
Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier
铁转运蛋白和 APP:血脑屏障铁运输的调节
  • 批准号:
    9540089
  • 财政年份:
    2017
  • 资助金额:
    $ 27.99万
  • 项目类别:
FASEB SRC on Trace Elements in Biology and Medicine
FASEB SRC 关于生物学和医学中的微量元素
  • 批准号:
    9121906
  • 财政年份:
    2016
  • 资助金额:
    $ 27.99万
  • 项目类别:
Managing Ionic Iron: Molecular Architecture and Mechanism of Cell Iron Metabolism
管理离子铁:细胞铁代谢的分子结构和机制
  • 批准号:
    7891090
  • 财政年份:
    2009
  • 资助金额:
    $ 27.99万
  • 项目类别:
Managing Ionic Iron: Molecular Architecture and Mechanism of Cell Iron Metabolism
管理离子铁:细胞铁代谢的分子结构和机制
  • 批准号:
    7243948
  • 财政年份:
    2007
  • 资助金额:
    $ 27.99万
  • 项目类别:
Production of Recombinant Eukaryotic Ferroxidases as Protein Therapeutics
作为蛋白质治疗剂的重组真核铁氧化酶的生产
  • 批准号:
    7455765
  • 财政年份:
    2007
  • 资助金额:
    $ 27.99万
  • 项目类别:
Production of Recombinant Eukaryotic Ferroxidases as Protein Therapeutics
作为蛋白质治疗剂的重组真核铁氧化酶的生产
  • 批准号:
    7291433
  • 财政年份:
    2007
  • 资助金额:
    $ 27.99万
  • 项目类别:
Iron Trafficking to Ribonucleotide Reductases
铁转运至核糖核苷酸还原酶
  • 批准号:
    6868889
  • 财政年份:
    2003
  • 资助金额:
    $ 27.99万
  • 项目类别:
Iron Trafficking to Ribonucleotide Reductases
铁转运至核糖核苷酸还原酶
  • 批准号:
    6618783
  • 财政年份:
    2003
  • 资助金额:
    $ 27.99万
  • 项目类别:

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临床记录中缩写词的实时消歧
  • 批准号:
    8077875
  • 财政年份:
    2010
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  • 批准号:
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