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，在细胞水平上消耗二氧化物以提供代谢过程的能量，是由末端氧化酶（例如细胞色素c氧化酶（CCO））介导的。最近的实验工作表明，CCO对能源生产的调节比迄今为止所欣赏的更为复杂。一个具体因素是认识到，一氧化氮（NO）是气态自由基，在体内具有重要作用，作为与CCO的二氧化物结合的竞争抑制剂。除了正常的（尽管知之甚少）外，NO在体内的调节作用这一重要发现开辟了前景，即NO的异常水平及其随后与蛋白质（例如CCO是最终元素）的蛋白质的异常反应引起的。帕金森氏症，阿尔茨海默氏症，亨廷顿氏病和ALS与No/CCO夫妇有关。尽管有很多现象学实验证明了能量调节与NO水平之间的联系，但NO反应的机理与CCO的血红素/铜活性位点的中间体的物理化学特征与调节和病理学相关，这仍然是有争议的。值得注意的是，NO不会抑制CCO，一氧化氮还原酶（NOR）的祖先祖细胞，而是通过释放能量抑制N20，这是类似于CCO将O2还原为H2O的反应。鲜为人知的机制或减少否和其结构与该活动的关系的机制鲜为人知。该项目旨在继续理解小分子在末端氧化酶的活性位点的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。通过对先前开发的配体系统的光谱和电化学研究，使用了许多具有金属离子组合的双金属复合物，无法获得生物学上获得，但对于隔离体内酶促特征的因素至关重要，我们旨在回答与CCO和NOR反应的许多问题。反应中间体的鉴定，其反应性，泄漏和可能的生物学后果将成为研究的重点。将重点放在动力学和机械研究上，以阐明CCO和NOR的推动反应途径。

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.