Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions
定义基于辅因子的酶促氧化还原反应中催化偏差的机械决定因素
基本信息
- 批准号:10034848
- 负责人:
- 金额:$ 36.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationActive SitesAdoptedAmino Acid SubstitutionAutomobile DrivingBiochemicalBiochemical ProcessBiochemical ReactionBiological AssayBiological ModelsBiophysicsCatalysisCell physiologyCellsCharacteristicsElectronsElectrostaticsEnergy MetabolismEnvironmentEnzymesExhibitsFoundationsGene FusionGoalsHealthHumanHydrogenHydrogenaseLeadLifeMetabolic ControlMetabolismMetalsMissionModelingModificationMolecularMolecular ConformationMovementOutcomeOxidation-ReductionPropertyProteinsProtonsReactionResearchResourcesRoentgen RaysRoleSiteSite-Directed MutagenesisSpectroscopy, Fourier Transform InfraredSpectrum AnalysisStructureSystemTestingThermodynamicsUnited States National Institutes of HealthWorkbasecatalystchemical reactioncofactordrug developmentexperimental studyimprovedinnovationoxidationphysical propertytargeted treatment
项目摘要
PROJECT SUMMARY
Enzymatic reactions comprise the basic building blocks essential to the biochemical processes of cellular
metabolism. While most enzymatic reactions are reversible, certain enzymes accelerate a reaction in one
direction significantly differently than the reverse direction. The mechanistic determinants of this phenomenon –
often referred to as “catalytic bias” – are generally unknown. Our long-term goal of this project is to identify the
fundamental principles adopted by redox enzymes (enzymes involved in oxidation-reduction reactions) that
provide molecular level control of the catalytic bias. In doing so, we will provide a greater fundamental
understanding of the factors that control metabolic processes in all life. Specifically, the objective of this proposal
is to delineate determinants that influence the directional reactivity of model Fe containing hydrogenases that
are structurally related but exhibit large differences in catalytic bias for the specific reversible hydrogen (H2)
oxidation reaction from electron and protons. The central hypothesis is that catalytic bias commonly in redox
enzymes results from the relative differential stabilization and destabilization of oxidation states of the respective
redox cofactors critical to determining the rate limiting step of the catalytic cycle. The rationale underlying the
proposal is that the implementation will result in defining mechanistic determinants of the proposed model
system. The proposed work will culminate in elucidating universal, mechanistic factors of catalytic bias that
govern a large number of, if not all, redox enzymes. The central hypothesis will be tested by pursuing three
specific aims that examine how 1) the reduction potential of the active site proximal accessory redox clusters; 2)
the characteristics of the active site cluster protein environment; and 3) the secondary coordination sphere
structural dynamics can control reactivity and catalytic bias in cofactor-based oxidation reduction catalysis. To
pursue these aims, we will employ an innovative strategy integrating biochemical, structural, spectroscopic, and
computational approaches on a unique, one-of-a-kind model hydrogenase platform. The proposed research is
significant, because it will delineate molecular determinants that influence the fine-tuning of redox cofactors
through the relative stabilization or destabilization of oxidation states to afford certain reactivity fundamental to
directing energy and matter in cells. The work will provide additional foundational resources in the form of a
blueprint for integrating multiple biophysical and computational approaches.
项目摘要
酶促反应包括细胞生物化学过程所必需的基本构件,
新陈代谢.虽然大多数酶促反应是可逆的,但某些酶在一种酶促反应中加速反应。
方向明显不同于反向。这种现象的机械决定因素-
通常被称为“催化偏差”-通常是未知的。我们这个项目的长期目标是确定
氧化还原酶(参与氧化还原反应的酶)采用的基本原理,
提供催化偏置的分子水平控制。在这样做的时候,我们将提供一个更大的基础,
了解所有生命中控制代谢过程的因素。具体而言,本提案的目标
描述影响含铁氢化酶模型定向反应性的决定因素,
结构上相关,但对特定可逆氢(H2)的催化偏置表现出很大差异
电子和质子的氧化反应。中心假设是,在氧化还原反应中,
酶的结果从各自的氧化态的相对差异稳定和不稳定
氧化还原辅因子对决定催化循环的限速步骤至关重要。的基本原理,
建议是,实施将导致定义拟议模型的机械决定因素
系统拟议的工作将最终阐明普遍的,机械因素的催化偏见,
控制大量的氧化还原酶,如果不是全部的话。中心假设将通过追求三个测试
具体的目的是研究1)活性位点的还原电位如何接近辅助氧化还原簇; 2)
活性位点簇蛋白环境的特征; 3)次级配位球
结构动力学可以控制基于辅因子的氧化还原催化中的反应性和催化偏差。到
为了实现这些目标,我们将采用一种创新的战略,将生物化学、结构、光谱和
在一个独特的,独一无二的模型氢化酶平台上的计算方法。拟议的研究是
意义重大,因为它将描绘影响氧化还原辅因子微调的分子决定因素
通过氧化态的相对稳定化或不稳定化来提供一定的反应性,
引导细胞中的能量和物质。这项工作将提供额外的基础资源,
整合多种生物物理和计算方法的蓝图。
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 }}
JOHN W PETERS其他文献
JOHN W PETERS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('JOHN W PETERS', 18)}}的其他基金
Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions
定义基于辅因子的酶促氧化还原反应中催化偏差的机械决定因素
- 批准号:
10874184 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions
定义基于辅因子的酶促氧化还原反应中催化偏差的机械决定因素
- 批准号:
10437871 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions
定义基于辅因子的酶促氧化还原反应中催化偏差的机械决定因素
- 批准号:
10259728 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions
定义基于辅因子的酶促氧化还原反应中催化偏差的机械决定因素
- 批准号:
10645050 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
STUDIES ON ENZYMES INVOLVED IN THE GLOBAL CYCLING OF HYDROGEN, NITROGEN AND CARB
参与氢、氮和碳水化合物全球循环的酶的研究
- 批准号:
8362120 - 财政年份:2011
- 资助金额:
$ 36.72万 - 项目类别:
STUDIES ON ENZYMES INVOLVED IN THE GLOBAL CYCLING OF HYDROGEN, NITROGEN AND CARB
参与氢、氮和碳水化合物全球循环的酶的研究
- 批准号:
8170030 - 财政年份:2010
- 资助金额:
$ 36.72万 - 项目类别:
PROBING NITROGENASE FE PROTEIN NUCLEOTIDE DEPENDENT CONFORMATIONAL CHANGES USING
使用 探测固氮酶 FE 蛋白质核苷酸依赖的构象变化
- 批准号:
8170039 - 财政年份:2010
- 资助金额:
$ 36.72万 - 项目类别:
STUDIES ON ENZYMES INVOLVED IN THE GLOBAL CYCLING OF HYDROGEN, NITROGEN AND CARB
参与氢、氮和碳水化合物全球循环的酶的研究
- 批准号:
7954345 - 财政年份:2009
- 资助金额:
$ 36.72万 - 项目类别:
PROBING NITROGENASE FE PROTEIN NUCLEOTIDE DEPENDENT CONFORMATIONAL CHANGES USING
使用 探测固氮酶 FE 蛋白质核苷酸依赖的构象变化
- 批准号:
7954363 - 财政年份:2009
- 资助金额:
$ 36.72万 - 项目类别:
STUDIES ON ENZYMES INVOLVED IN THE GLOBAL CYCLING OF HYDROGEN, NITROGEN AND CARB
参与氢、氮和碳水化合物全球循环的酶的研究
- 批准号:
7721997 - 财政年份:2008
- 资助金额:
$ 36.72万 - 项目类别:
相似海外基金
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334970 - 财政年份:2024
- 资助金额:
$ 36.72万 - 项目类别:
Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
- 批准号:
2400195 - 财政年份:2024
- 资助金额:
$ 36.72万 - 项目类别:
Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334969 - 财政年份:2024
- 资助金额:
$ 36.72万 - 项目类别:
Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
- 批准号:
23K04919 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
- 批准号:
22KJ2957 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
- 批准号:
23K04494 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
- 批准号:
23K13831 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
- 批准号:
2238379 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
- 批准号:
2154399 - 财政年份:2022
- 资助金额:
$ 36.72万 - 项目类别:
Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
- 批准号:
RGPIN-2019-06633 - 财政年份:2022
- 资助金额:
$ 36.72万 - 项目类别:
Discovery Grants Program - Individual