Mechanistic and Structural Studies of Novel Heme-Containing Enzymes

新型含血红素酶的机理和结构研究

基本信息

  • 批准号:
    0820456
  • 负责人:
  • 金额:
    $ 59.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-01 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

Intellectual Merit. Heme-iron containing peroxidases are enzymes that catalyze organic substrate oxidation while reducing hydrogen peroxide to water. Two novel heme peroxidases isolated from marine sea worms, one able to incorporate halide ions such as chloride and bromide into aromatic molecules and the other able to remove them, will be studied. The haloperoxidase, Notomastus lobatus chloroperoxidase (NCPO), halogenates phenols and is unusual in requiring an organic flavin component. Amphitrite ornata dehaloperoxidase (DHP) dehalogenates halophenols. Surprisingly, the structure of DHP is that of a globin - the same protein fold found in hemo- and myoglobin (Mb). It is the first known enzymatic globin. The unique structural properties of these two peroxidases bring into question whether they utilize a new peroxidase mechanism. A four-prong hypothesis-driven experimental plan will be followed. First, rapid kinetics experiments will probe the mechanism of DHP and NCPO catalysis and directly determine whether the traditional or an alternative mechanism is employed. Second, the ability of DHP and NCPO to carry out standard peroxidase reactions will be extensively tested in order to advance our understanding of DHP and NCPO function. Third, designed DHP and Mb mutants will be prepared to probe the mechanistic role of specific amino acids near the DHP heme and explore factors in the heme/globin environment that enhance DHP function relative to Mb. Fourth, NCPO will be cloned, expressed and structurally characterized. Small NCPO crystals have been obtained. NCPO is a complex multi-subunit hemoflavoenzyme; the roles of its subunits are unknown. Such enzymes with peroxidase activity have not yet been reported. Studies of its structure and mechanism will provide new information about halogenation in higher organisms. Investigations of complex multi-subunit-containing systems, such as those proposed herein, are at the cutting edge of mechanistic enzymology. Overall, the two novel peroxidases challenge the current view of how peroxidases function. The research will probe how nature has redesigned small globin-fold proteins into peroxidases and thereby will extend the boundaries of our understanding of structure/function relations in such enzymes. Broader Impacts. The research combines the diverse disciplines of chemistry, molecular genetics and evolution, structural biology, and spectroscopy, and promotes interaction among chemistry and biology faculty and students via regular meetings of the three research groups. Students, from high school to post-graduate, will be trained. Undergraduates will continue to make significant research contributions. The three PIs have strong records training underrepresented minorities recently including two African-American students. One of the PIs directs SCienceLab, an outreach program for middle/high school science teachers and students. A specific 'Enzyme-Catalyzed Toxic Cleanup' SCiLab designed around biological dehaloperoxidases will provide a daylong hands-on, inquiry-based lab experience and convey the excitement of interfacing biological, chemical and environmental research. The goal is to show students how biological catalysts might be used in bioremediation technology. Moreover, the research results will continue to be used teaching graduate enzymology, crystallography and metallobiochemistry courses. The fundamental chemical/biochemical progress achieved may lead to the development of applications in the broader areas of biotechnology and bioremediation and will impact related ecological and environmental research.
知识价值。含血红素铁过氧化物酶是催化有机底物氧化,同时将过氧化氢还原为水的酶。将研究从海洋蠕虫中分离出的两种新型血红素过氧化物酶,一种能够将氯离子和溴离子等卤化物离子结合到芳香分子中,另一种能够去除它们。卤素过氧化物酶,无叶草氯过氧化物酶(NCPO),卤化酚,是不寻常的,需要有机黄素成分。双栖藻脱卤过氧化物酶(DHP)能脱卤酚。令人惊讶的是,DHP的结构与血红蛋白和肌红蛋白(Mb)的结构相同。它是第一个已知的酶促珠蛋白。这两种过氧化物酶的独特结构性质使人们怀疑它们是否利用了一种新的过氧化物酶机制。将遵循四方面假设驱动的实验计划。首先,快速动力学实验将探索DHP和NCPO催化的机理,并直接确定是采用传统机制还是替代机制。其次,将广泛测试DHP和NCPO进行标准过氧化物酶反应的能力,以促进我们对DHP和NCPO功能的了解。第三,制备设计的DHP和Mb突变体,探索DHP血红素附近特定氨基酸的机制作用,探索血红素/珠蛋白环境中相对于Mb增强DHP功能的因素。第四,克隆、表达NCPO并进行结构表征。得到了小的NCPO晶体。NCPO是一种复杂的多亚基血黄酶;其亚基的作用尚不清楚。这种具有过氧化物酶活性的酶尚未被报道。对其结构和机理的研究将为高等生物的卤化提供新的信息。复杂的多亚基含系统的研究,如在这里提出的,是在机械酶学的前沿。总的来说,这两种新的过氧化物酶挑战了目前关于过氧化物酶如何起作用的观点。该研究将探索大自然如何将小珠蛋白折叠蛋白重新设计成过氧化物酶,从而扩展我们对此类酶的结构/功能关系的理解。更广泛的影响。该研究结合了化学、分子遗传学和进化、结构生物学和光谱学等不同学科,并通过三个研究小组的定期会议促进化学和生物教师和学生之间的互动。从高中到研究生的学生都将接受培训。本科生将继续做出重要的研究贡献。这三所私立学院最近在培训未被充分代表的少数族裔方面有着良好的记录,其中包括两名非裔美国学生。其中一位pi负责SCienceLab,这是一个面向初高中科学教师和学生的拓展项目。一个特定的“酶催化毒性清理”SCiLab围绕生物脱氢过氧化物酶设计,将提供为期一天的动手,探究式的实验室体验,并传达连接生物,化学和环境研究的兴奋。目的是向学生展示如何将生物催化剂应用于生物修复技术。研究成果将继续用于酶学、晶体学、金属生物化学等研究生课程的教学。取得的基本化学/生物化学进展可能导致在更广泛的生物技术和生物修复领域的应用发展,并将影响相关的生态和环境研究。

项目成果

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John Dawson其他文献

ヨーロッパ家電小売業の競争構造-ユーロニクス、ディクソンズ、メディア=ザトゥーンの国際化戦略
欧洲消费电子零售业竞争格局——Euronics、Dixons、Media-Zathun的国际化战略
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    薄井和夫;John Dawson
  • 通讯作者:
    John Dawson
Standardized protocol for hip fracture care leads to similar short-term outcomes despite socioeconomic differences in patient populations: a retrospective cohort study
尽管患者群体存在社会经济差异,但髋部骨折护理的标准化方案会导致相似的短期结果:一项回顾性队列研究
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0.3
  • 作者:
    Corey Bindner;Christopher J Wester;Ramesh B. Ghanta;Austin E. Wininger;Aalok P. Patel;Omar H. Atassi;Christopher H. Perkins;John Dawson
  • 通讯作者:
    John Dawson
Some Topics about Preservation and Utilization of Modern Architecture in japan
日本近代建筑保护与利用的若干问题
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chieko Minami;John Dawson;林倬史;Nishizawa Yasuhiko
  • 通讯作者:
    Nishizawa Yasuhiko
Book Review : Decolonizing International Health : India and Southeast Asia, 1930-65
书评:国际卫生非殖民化:印度和东南亚,1930-65
アメリカ労使関係における「ジョブ・コントロール・ユニオニズム」
美国劳资关系中的“工作控制工会主义”
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chieko Minami;John Dawson;佐藤 健司;柳澤悠;Noboru Matsushima(eds.);西村 優子;Kohei Wakimura;Chieko Minami;高橋勅徳;佐藤 健司;高橋 邦丸;上野直樹(第一著者);Kohei Wakimura;関口 定一
  • 通讯作者:
    関口 定一

John Dawson的其他文献

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{{ truncateString('John Dawson', 18)}}的其他基金

PARASOL - European Doctoral Network for Safe and Sustainable by Design Electromagnetic Shielding Material
PARASOL - 欧洲安全和可持续设计电磁屏蔽材料博士网络
  • 批准号:
    EP/X033481/1
  • 财政年份:
    2022
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Research Grant
Acquisition of a computer cluster for wide range chemical applications and education
购买计算机集群用于广泛的化学应用和教育
  • 批准号:
    1048629
  • 财政年份:
    2011
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Standard Grant
Mechanistic and Structural Studies of Novel Heme-Containing Peroxidases
新型含血红素过氧化物酶的机理和结构研究
  • 批准号:
    9604004
  • 财政年份:
    1997
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant
Collective Absorption Processes of Neutrinos in Supernovae
超新星中中微子的集体吸收过程
  • 批准号:
    9713234
  • 财政年份:
    1997
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant
Symposium on Metal Ions in Biology and Medicine: Natural and Synthetic Approaches to be held in Honolulu, Hawaii 17-22 December 1995.
生物和医学金属离子研讨会:天然和合成方法将于 1995 年 12 月 17 日至 22 日在夏威夷檀香山举行。
  • 批准号:
    9511927
  • 财政年份:
    1995
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Standard Grant
Computer Simulation of Plasmas at UCLA
加州大学洛杉矶分校的等离子体计算机模拟
  • 批准号:
    9319198
  • 财政年份:
    1994
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant
Establishment of a Fermentation Facility
建立发酵设施
  • 批准号:
    9118102
  • 财政年份:
    1992
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Standard Grant
Numerical Studies of Magnetospheric Dynamics and Related Space Plasma Processes
磁层动力学及相关空间等离子体过程的数值研究
  • 批准号:
    9201662
  • 财政年份:
    1992
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant
Computer Simulation of Plasmas at UCLA
加州大学洛杉矶分校的等离子体计算机模拟
  • 批准号:
    9121052
  • 财政年份:
    1992
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant
Computer Simulation of Plasmas at UCLA (Physics)
加州大学洛杉矶分校的等离子体计算机模拟(物理学)
  • 批准号:
    8922487
  • 财政年份:
    1990
  • 资助金额:
    $ 59.77万
  • 项目类别:
    Continuing Grant

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Understanding structural evolution of galaxies with machine learning
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Iron-sulfur cluster-containing sensor regulators: mechanistic and structural studies of DNA-binding
含铁硫簇的传感器调节器:DNA 结合的机制和结构研究
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    BB/V001892/1
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