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Biomimetic Studies of NO-binding Respiratory Chain Hemes

NO 结合呼吸链血红素的仿生研究

基本信息

批准号：
7388223
负责人：
JAMES P COLLMAN
金额：
$ 29.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2009-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388223
关键词：
Active Sites Alzheimer&apos s Disease Amines Amyotrophic Lateral Sclerosis Behavior Binding Biochemical Biochemistry Biological Biomimetics Catabolism Cell Respiration Characteristics Chemicals Chemistry Complex Condition Consumption Copper Dioxygen Distal Electrochemistry Electron Transport Electronics Electrons Elements Environment Enzymes Extravasation Family Free Radicals Goals Heme Heme Iron Huntington Disease Imidazole Investigation Ions Kinetics Knowledge Laboratories Ligands Link Mediating Mediator of activation protein Metabolism Metalloporphyrins Metals Modeling Nature Nitrates Nitric Oxide Nitrites Nitrogen Nitrous Oxide Numbers Oxidases Oxidation-Reduction Oxides Oxygen Parkinson Disease Pathology Pathway interactions Peroxonitrite Pliability Porphyrins Production Property Proteins Reaction Regulation Reporting Research Respiration Respiratory Chain Role Site Solutions Structure Structure-Activity Relationship System Tail Techniques Variant Water Work X ray diffraction analysis X-Ray Diffraction analog catalyst copper cytochrome c cytochrome c oxidase denitrification heme a in vivo inhibitor/antagonist metal complex mutant nitrate nitric oxide reductase progenitor research study small molecule solid state

项目摘要

DESCRIPTION (provided by applicant): Respiration, the consumption of dioxygen at the cellular level to provide energy for metabolic processes, is mediated by terminal oxidases such as cytochrome c oxidase (CcO). Recent experimental work has revealed more complexity in the regulation of energy production by CcO than hitherto appreciated. One specific factor has been the realization that nitric oxide (NO), a gaseous free radical, has an important role in vivo as a competitive inhibitor of dioxygen binding to CcO. Aside from the normal, although poorly understood, regulatory role of NO in vivo this important discovery opened the prospect that a considerable number of pathological conditions arise from abnormal levels of NO and its subsequent reactions with proteins such as those of the electron transport chain (of which CcO is terminal element). Parkinson's, Alzheimer's, Huntington's disease and ALS have been linked to the NO/CcO couple. While there are a plethora of phenomenological experiments demonstrating the connection between energy regulation and NO levels, the mechanism of reaction of NO and the physicochemical characteristics of intermediates at the heme/copper active site of CcO as they relate to regulation and pathology remain controversial. Significantly, an ancestral progenitor of CcO, Nitric Oxide Reductase (NOR), is not inhibited by NO, but reduces it to N20 with release of energy, a reaction analogous to the reduction of O2 to H2O by CcO. The mechanism by which NOR reduces NO and the relationship of its structure to this activity is little known. Continuing a long-term goal of understanding biomimetic reactions of small molecules at the active sites of terminal oxidases, this project aims to characterize the reaction of NO with heme/copper (CcO) and heme/iron (NOR) biomimetic complexes. Through spectroscopic and electrochemical investigation of previously-developed ligand systems, using numerous bimetallic complexes with metal ion combinations not possible to obtain biologically, but essential for isolating the factors that are contributing to the enzymatic characteristics in vivo, we aim to answer many questions concerning the differences in NO reaction with CcO and NOR. The identification of reaction intermediates, their reactivity, leakage and possible biological consequences will be a focus for study. An emphasis will be placed on kinetic and mechanistic studies to elucidate the putitive reaction pathways of CcO and NOR.

描述（由申请人提供）：呼吸，即在细胞水平消耗分子氧以为代谢过程提供能量，由末端氧化酶如细胞色素c氧化酶（CcO）介导。最近的实验工作揭示了更多的复杂性，在能源生产的监管CCO比迄今为止赞赏。一个特定的因素是认识到一氧化氮（NO），一种气态自由基，在体内作为分子氧结合CcO的竞争性抑制剂具有重要作用。除了正常的，虽然知之甚少，NO在体内的调节作用，这一重要发现打开了前景，即相当数量的病理条件产生于异常水平的NO和其随后的反应与蛋白质，如那些电子传递链（其中CcO是终端元件）。帕金森氏症、阿尔茨海默氏症、亨廷顿氏病和肌萎缩侧索硬化症都与NO/CcO这对基因有关。虽然有大量的现象学实验证明能量调节和NO水平之间的联系，NO的反应机制和在血红素/铜活性位点的CcO的中间体的物理化学特性，因为它们涉及到调节和病理仍然存在争议。值得注意的是，CcO的祖先，一氧化氮还原酶（NOR），不受NO的抑制，而是通过释放能量将其还原为N2 O，这是一种类似于CcO将O2还原为H2O的反应。NOR还原NO的机制及其结构与这种活性的关系鲜为人知。继续理解末端氧化酶活性位点的小分子仿生反应的长期目标，该项目旨在表征NO与血红素/铜（CcO）和血红素/铁（NOR）仿生复合物的反应。通过光谱和电化学研究以前开发的配体系统，使用许多金属离子组合的配合物不可能获得生物学，但重要的是隔离的因素，有助于在体内的酶的特性，我们的目标是回答许多问题的差异NO反应与CCO和NOR。反应中间体的鉴定、反应性、泄漏和可能的生物学后果将是研究的重点。重点将放在动力学和机理研究，以阐明CcO和NOR的假定反应途径。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selective anodic desorption for assembly of different thiol monolayers on the individual electrodes of an array.

DOI：
10.1021/la8043363
发表时间：
2009-06-02
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
0
作者：
Collman JP;Hosseini A;Eberspacher TA;Chidsey CE
通讯作者：
Chidsey CE

Three toxic gases meet in the mitochondria.

DOI：
10.3389/fphys.2015.00210
发表时间：
2015
期刊：
Frontiers in physiology
影响因子：
4
作者：
Decréau RA;Collman JP
通讯作者：
Collman JP

Ferrocene embedded in an electrode-supported hybrid lipid bilayer membrane: a model system for electrocatalysis in a biomimetic environment.

DOI：
10.1021/la1029118
发表时间：
2010-10
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
0
作者：
A. Hosseini;J. Collman;Anando Devadoss;Genevieve Y. Williams;Christopher J. Barile;T. Eberspacher
通讯作者：
A. Hosseini;J. Collman;Anando Devadoss;Genevieve Y. Williams;Christopher J. Barile;T. Eberspacher

Intermediates involved in the two electron reduction of NO to N2O by a functional synthetic model of heme containing bacterial NO reductase.