Why does Nature use modular enzyme architectures for biological catalysis?

为什么 Nature 使用模块化酶结构进行生物催化?

基本信息

  • 批准号:
    BB/N013972/1
  • 负责人:
  • 金额:
    $ 52.16万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2017
  • 资助国家:
    英国
  • 起止时间:
    2017 至 无数据
  • 项目状态:
    已结题

项目摘要

Redox proteins, including metalloproteins, form a large portion of the protein kingdom. Metalloproteins themselves form ~ 30% of a genome. These contain metal ions either as a single atom or as part of a cluster and play a variety of life sustaining roles in the microbial, plant and animal kingdoms. Many enzymes exploit the oxidation states of metals to perform redox cycling. Fundamental biological processes in which metalloproteins participate include electron storage and transfer, dioxygen binding, storage and activation, and substrate transport, and catalysis. In many metalloenzymes such as cytochrome c oxidase (essential for mammalian life through respiratory requirements), nitrogenases and nitrite reductases (essential in view of their central position in the nitrogen cycle), hydrogenases (producers of molecular hydrogen - a candidate for a future alternative energy source), catalysis involves the controlled delivery of electrons and protons to the active site where substrate is utilised. Nitrite reductases are central to the denitrification process, an important branch of microbial bioenergetics and crucial to terrestrial and oceanic nitrogen cycling, since it makes an increasing contribution to global warming by release of N2O, an ozone-depleting and greenhouse gas some 300-fold more potent than CO2. The current proposal builds on close collaboration between the applicants where they collectively have made major contributions in the field of denitrification and have provided significant advances in our understanding of complex processes that are involved in biological mechanisms of metalloenzymes. Our combined approaches puts us in a very strong position to undertake an integrated structural-mechanistic programme that is aimed at addressing the question of whether Nature exploits tethered domains to enhance catalysis compared to transient protein complexes in biological reactions in globally important biological systems. We focus on Cu-containing nitrite reductases (CuNiRs) - exploiting their natural encounter (freely diffusing) and tethered complexes - to learn Nature's design rules for construction of optimally configured and integrated redox devices. We will elucidate design principles that define catalytic efficiencies and enable coupling of long-range electron movements to active site redox chemistry. This requires understanding of how coordinated protein movements impact on (i) mechanisms of long-range electron transfers, (ii) localised chemical change (bond formation / breakage) and (iii) how these can change the rate-limiting step in catalysis by driving the formation of different oxidation states of the active site. General design principles will emerge that will guide predictive engineering of biological redox devices for synthetic biology.New methods and approaches developed in this programme (e.g. (i) combined stopped-flow and FRET-based approach enabling the reporting on redox chemistry via a 'molecular beacon' approach and (ii) development of laboratory-based size-exclusion chromatography-small angle X-ray scattering with dynamic light scattering (SEC-SAXS-DLS) for studying protein complexes) will have broad relevance to our capabilities for studying protein complexes. These new capabilities and the scientific outcome will have significant impact on structural-mechanistic biology and keep the UK at the forefront of global effort in this important field.
氧化还原蛋白,包括金属蛋白,形成蛋白质王国的很大一部分。金属蛋白本身占基因组的30%。它们含有金属离子作为单个原子或作为簇的一部分,并在微生物,植物和动物王国中发挥各种生命维持作用。许多酶利用金属的氧化态来进行氧化还原循环。金属蛋白参与的基本生物学过程包括电子储存和转移、分子氧结合、储存和活化、底物转运和催化。在许多金属酶中,如细胞色素c氧化酶(通过呼吸需求对哺乳动物生命至关重要)、固氮酶和亚硝酸盐还原酶(鉴于其在氮循环中的中心位置而至关重要)、氢化酶(分子氢的生产者-未来替代能源的候选者),催化涉及电子和质子到利用底物的活性位点的受控递送。亚硝酸盐还原酶是反硝化过程的核心,反硝化过程是微生物生物能量学的一个重要分支,对陆地和海洋氮循环至关重要,因为它通过释放N2 O对全球变暖的贡献越来越大,N2 O是一种臭氧消耗和温室气体,比CO2强300倍。本提案建立在申请人之间的密切合作基础上,他们共同在反硝化领域做出了重大贡献,并为我们理解金属酶生物机制中涉及的复杂过程提供了重大进展。我们的综合方法使我们处于一个非常有利的地位,进行一个综合的结构-机制方案,旨在解决这样一个问题,即与全球重要生物系统中的生物反应中的瞬时蛋白质复合物相比,大自然是否利用拴系结构域来增强催化作用。我们专注于含铜的亚硝酸盐还原酶(CuNiRs)-利用它们的自然相遇(自由扩散)和拴系复合物-学习大自然的设计规则,用于构建最佳配置和集成的氧化还原器件。我们将阐明设计原则,定义催化效率,使耦合的远程电子运动的活性部位氧化还原化学。这需要了解协调的蛋白质运动如何影响(i)远程电子转移机制,(ii)局部化学变化(键形成/断裂)以及(iii)这些如何通过驱动活性位点的不同氧化态的形成来改变催化中的限速步骤。将出现一般的设计原则,将指导合成生物学的生物氧化还原装置的预测工程。(例如(i)结合停流和FRET方法,通过“分子信标”方法报告氧化还原化学,以及(ii)开发基于实验室的分子排阻色谱-小角X射线散射和动态光散射(SEC-SAXS-DLS)研究蛋白质复合物)将有广泛的相关性,我们的能力,研究蛋白质复合物。这些新的能力和科学成果将对结构机械生物学产生重大影响,并使英国在这一重要领域处于全球努力的前沿。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An unprecedented dioxygen species revealed by serial femtosecond rotation crystallography in copper nitrite reductase.
  • DOI:
    10.1107/s2052252517016128
  • 发表时间:
    2018-01-01
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Halsted TP;Yamashita K;Hirata K;Ago H;Ueno G;Tosha T;Eady RR;Antonyuk SV;Yamamoto M;Hasnain SS
  • 通讯作者:
    Hasnain SS
Identification of a tyrosine switch in copper-haem nitrite reductases.
  • DOI:
    10.1107/s2052252518008242
  • 发表时间:
    2018-07-01
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Dong J;Sasaki D;Eady RR;Antonyuk SV;Hasnain SS
  • 通讯作者:
    Hasnain SS
Characterization of the quinol-dependent nitric oxide reductase from the pathogen Neisseria meningitidis, an electrogenic enzyme.
  • DOI:
    10.1038/s41598-018-21804-0
  • 发表时间:
    2018-02-26
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Gonska N;Young D;Yuki R;Okamoto T;Hisano T;Antonyuk S;Hasnain SS;Muramoto K;Shiro Y;Tosha T;Ädelroth P
  • 通讯作者:
    Ädelroth P
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Samar Hasnain其他文献

Samar Hasnain的其他文献

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{{ truncateString('Samar Hasnain', 18)}}的其他基金

Towards a paradigm shift in understanding of membrane-bound Nitric Oxide reductase and its complexes with the electron donor and NO-producing enzyme
膜结合一氧化氮还原酶及其与电子供体和 NO 产生酶复合物的理解的范式转变
  • 批准号:
    BB/X015491/1
  • 财政年份:
    2023
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Japan Partnering : Damage free structures of enzymes of denitrification pathway and their complexes using SF-ROX and SFX at SACLA XFEL
日本合作:在 SACLA XFEL 使用 SF-ROX 和 SFX 反硝化途径酶及其复合物的无损伤结构
  • 批准号:
    BB/S020055/1
  • 财政年份:
    2019
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Transient and Stable Macromolecular Complexes Formed by Denitrifying Enzymes
反硝化酶形成的瞬时和稳定的大分子复合物
  • 批准号:
    BB/L006960/1
  • 财政年份:
    2014
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Provision of the MAD/XAFS facility for the UK structural biology community
为英国结构生物学界提供 MAD/XAFS 设施
  • 批准号:
    BB/E001971/2
  • 财政年份:
    2009
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Elucidating mechanisms of proton coupled and conformationally coupled electron transfer in redox enzymes catalysis
阐明氧化还原酶催化中质子耦合和构象耦合电子转移的机制
  • 批准号:
    BB/G005869/1
  • 财政年份:
    2009
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Towards a complete structure-function description of the denitrification pathway
实现反硝化途径的完整结构功能描述
  • 批准号:
    BB/D016290/2
  • 财政年份:
    2008
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Towards a complete structure-function description of the denitrification pathway
实现反硝化途径的完整结构功能描述
  • 批准号:
    BB/D016290/1
  • 财政年份:
    2006
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant
Provision of the MAD/XAFS facility for the UK structural biology community
为英国结构生物学界提供 MAD/XAFS 设施
  • 批准号:
    BB/E001971/1
  • 财政年份:
    2006
  • 资助金额:
    $ 52.16万
  • 项目类别:
    Research Grant

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衍射光学三维信息加密与隐藏的研究
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