Mechanism of taurine: alpha-ketoglutarate dioxygenase

牛磺酸的作用机制:α-酮戊二酸双加氧酶

基本信息

  • 批准号:
    7000410
  • 负责人:
  • 金额:
    $ 25.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-01-01 至 2008-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant) The Fe(ll)-/a-ketoglutarate-dependent dioxygenases couple oxidative decarboxylation of a-ketoglutarate with hydroxylation of unactivated carbon atoms on a variety of substrates. Enzymes in this class catalyze important reactions in organisms from bacteria to humans and have essential roles in such critical processes as sensing of oxygen and response to hypoxia in mammals; synthesis of B-lactam antibiotics, collagen, and fatty acids in a range of organisms; and repair of DNA alkylation damage in bacteria and humans. In addition, dysfunction of enzymes in the class of enzymes has been associated with numerous disease states. It has been proposed that these enzymes operate by a common mechanism. Despite extensive investigation in many laboratories, there had been, until our recent work, no direct evidence for any of the several intermediate states proposed to follow after reaction of the enzyme with molecular oxygen. We have recently obtained the first direct evidence for an oxidized iron intermediate in the reaction catalyzed by one enzyme in this class, taurine/a-ketoglutarate dioxygenase (TauD), and have shown that the novel complex accumulates to levels sufficient for a thorough spectroscopic characterization. Preliminary data indicate that the intermediate has a formal Fe(IV) oxidation state and suggest two most likely structures for the complex. The main objectives of this research project are: (1) To place the novel Fe(IV) intermediate in the sequence of events leading to O2 activation, a-ketoglutarate oxidative decarboxylation, and taurine hydroxylation by a combination of rapid kinetics experiments in order to limit possible structural assignments and choose between the two most likely structures; (2) To rigorously characterize this novel reaction intermediate by a combination of spectroscopic techniques in order to elucidate its electronic and geometric structure; and (3) To use modified reactants (substrate analogues and site directed TauD variants) to accumulate and then trap and characterize intermediate states in the reaction pathway that are not accessible in the reaction with the normal components. Achievement of these goals will provide new and unprecedented insight into the molecular details of the catalytic mechanism of TauD and, more importantly, of the Fe(ll)/a-ketoglutarate-dependent dioxygenases in general.
Fe(II)-/α-酮戊二酸依赖性双加氧酶将α-酮戊二酸的氧化脱羧与多种底物上未活性碳原子的羟基化偶联。这类酶催化从细菌到人类的生物体中的重要反应,并在哺乳动物中的氧传感和对缺氧的反应等关键过程中发挥重要作用;在一系列生物体中合成β-内酰胺抗生素,胶原蛋白和脂肪酸;以及修复细菌和人类中的DNA烷基化损伤。此外,酶类中的酶功能障碍与许多疾病状态相关。已经提出这些酶通过共同的机制起作用。尽管在许多实验室进行了广泛的研究,但直到我们最近的工作,还没有直接的证据表明酶与分子氧反应后可能出现的几种中间状态。我们最近已经获得了第一个直接的证据,氧化的铁中间体的反应中催化的一类酶,牛磺酸/α-酮戊二酸双加氧酶(TauD),并已表明,新的复杂的积累水平足以进行彻底的光谱表征。初步数据表明,中间体有一个正式的Fe(IV)氧化态,并建议两个最可能的结构复杂。本研究的主要目的是:(1)通过快速动力学实验将新的Fe(IV)中间体置于导致O2活化、α-酮戊二酸氧化脱羧和牛磺酸羟基化的事件序列中,以限制可能的结构归属并在两种最可能的结构之间进行选择;(2)结合光谱技术对这一新的反应中间体进行严格表征,以阐明其电子和几何结构;(3)使用改性的反应物(底物类似物和位点定向的TauD变体)以积累然后捕获和表征反应途径中的中间状态,这些中间状态在与正常组分的反应中是不可接近的。这些目标的实现将提供对TauD的催化机制的分子细节的新的和前所未有的洞察,更重要的是,一般的Fe(II)/α-酮戊二酸依赖性双加氧酶的分子细节。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

CARSTEN KREBS其他文献

CARSTEN KREBS的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('CARSTEN KREBS', 18)}}的其他基金

Mechanisms of Mononuclear non-Heme-Iron Enzymes
单核非血红素铁酶的机制
  • 批准号:
    10394263
  • 财政年份:
    2018
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanisms of Iron-Containing Enzymes
含铁酶的机制
  • 批准号:
    10623495
  • 财政年份:
    2018
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanisms of Mononuclear non-Heme-Iron Enzymes
单核非血红素铁酶的机制
  • 批准号:
    9932533
  • 财政年份:
    2018
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanisms of Mononuclear non-Heme-Iron Enzymes
单核非血红素铁酶的机制
  • 批准号:
    9918429
  • 财政年份:
    2018
  • 资助金额:
    $ 25.87万
  • 项目类别:
Bioinorganic Workshops in 2012 and 2014 and Bioinorganic Symposium in 2014
2012年和2014年生物无机研讨会和2014年生物无机研讨会
  • 批准号:
    8257434
  • 财政年份:
    2012
  • 资助金额:
    $ 25.87万
  • 项目类别:
Bioinorganic Workshops in 2012 and 2014 and Bioinorganic Symposium in 2014
2012年和2014年生物无机研讨会和2014年生物无机研讨会
  • 批准号:
    8635375
  • 财政年份:
    2012
  • 资助金额:
    $ 25.87万
  • 项目类别:
Bioinorganic Workshops in 2012 and 2014 and Bioinorganic Symposium in 2014
2012年和2014年生物无机研讨会和2014年生物无机研讨会
  • 批准号:
    8448218
  • 财政年份:
    2012
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanism of taurine: alpha-ketoglutarate dioxygenase
牛磺酸的作用机制:α-酮戊二酸双加氧酶
  • 批准号:
    7162139
  • 财政年份:
    2004
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanism of taurine: alpha-ketoglutarate dioxygenase
牛磺酸的作用机制:α-酮戊二酸双加氧酶
  • 批准号:
    7334215
  • 财政年份:
    2004
  • 资助金额:
    $ 25.87万
  • 项目类别:
Mechanism of taurine: alpha-ketoglutarate dioxygenase
牛磺酸的作用机制:α-酮戊二酸双加氧酶
  • 批准号:
    6837204
  • 财政年份:
    2004
  • 资助金额:
    $ 25.87万
  • 项目类别:

相似海外基金

New directions for x-ray spectrometry from portable to synchrotron science
X 射线光谱测定从便携式到同步加速器科学的新方向
  • 批准号:
    RGPIN-2018-03902
  • 财政年份:
    2022
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
New directions for x-ray spectrometry from portable to synchrotron science
X 射线光谱测定从便携式到同步加速器科学的新方向
  • 批准号:
    RGPIN-2018-03902
  • 财政年份:
    2021
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
New directions for x-ray spectrometry from portable to synchrotron science
X 射线光谱测定从便携式到同步加速器科学的新方向
  • 批准号:
    RGPIN-2018-03902
  • 财政年份:
    2020
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
New directions for x-ray spectrometry from portable to synchrotron science
X 射线光谱测定从便携式到同步加速器科学的新方向
  • 批准号:
    RGPIN-2018-03902
  • 财政年份:
    2019
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
New directions for x-ray spectrometry from portable to synchrotron science
X 射线光谱测定从便携式到同步加速器科学的新方向
  • 批准号:
    RGPIN-2018-03902
  • 财政年份:
    2018
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
Advances in x-ray spectrometry: new science through new sources
X 射线光谱测定的进展:新来源的新科学
  • 批准号:
    261523-2013
  • 财政年份:
    2017
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
Advances in x-ray spectrometry: new science through new sources
X 射线光谱测定的进展:新来源的新科学
  • 批准号:
    261523-2013
  • 财政年份:
    2016
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
Advances in x-ray spectrometry: new science through new sources
X 射线光谱测定的进展:新来源的新科学
  • 批准号:
    261523-2013
  • 财政年份:
    2015
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
Application of energy dispersive X-ray spectrometry (EDX) in forensic practice
能量色散 X 射线光谱 (EDX) 在法医学实践中的应用
  • 批准号:
    15K19273
  • 财政年份:
    2015
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Advances in x-ray spectrometry: new science through new sources
X 射线光谱测定的进展:新来源的新科学
  • 批准号:
    261523-2013
  • 财政年份:
    2014
  • 资助金额:
    $ 25.87万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了