Heme/Copper and Heme/Nonheme Iron O(2) and NO Reactivity

血红素/铜和血红素/非血红素铁 O(2) 和 NO 反应性

基本信息

批准号：
7730922
负责人：
KENNETH D. KARLIN
金额：
$ 29.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7730922
关键词：
Active Sites Address Aerobic Anions Basic Science Binding Biochemical Biochemistry Bioenergetics Biological Process Biomimetics Carbon Monoxide Chemicals Chemistry Classification Cleaved cell Complex Copper Development Dioxygen Dioxygenases Disease Electrons Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Equilibrium Generations Health Heme Heme Iron Hemeproteins Imidazole Investigation Iron Kinetics Ligands Ligation Link Metals Methods Modeling Molecular Monitor Nature Nitrates Nitric Oxide Nitrogen Oxides Nitrous Oxide Organism Oxidases Oxygen Peroxonitrite Pharmaceutical Preparations Phenols Play Process Protons Raman Spectrum Analysis Reaction Research Role Side Site Spectroscopy, Fourier Transform Infrared Spectrum Analysis Structure Study models Superoxides System Tail Techniques Testing Therapeutic Thermodynamics absorption adduct base chelation cofactor cold temperature copper oxidase crosslink cryogenics design electronic structure enzyme structure heme a insight irradiation meetings migration nitric oxide reductase novel strategies photolysis preference public health relevance research study response small molecule

项目摘要

DESCRIPTION (provided by applicant): The long-term research objective is to design, synthesize and investigate model compound systems which can help elucidate fundamental aspects of structure, metal ligation, spectroscopy and reactivity relevant to the chemistry utilized by heme-copper oxidases (HCOs) and nitric oxide reductases (NORs). These evolutionarily related enzymes play critical roles in the bioenergetics of aerobic and anaerobic organisms, and have in common a heme/M (M = copper or non-heme iron) active site which reductively cleaves dioxygen (O2) or nitric oxide (NO, nitrogen monoxide), respectively. The research proposed can contribute to a better understanding of enzyme structure and mechanism and provide fundamental insights into the biological processing of dioxygen and NO, the chemistry and biochemistry of nitrogen oxides, as well as address issues related to nitrogen oxides in the environment. Specific aims include (1) the characterization of heme-peroxo-Cu complexes, new protonated and new low-spin derivatives and elucidation of their peroxo- connectivity and electronic structures, (2) the study of reductive O-O cleavage promoted by already well characterized heme-peroxo-Cu complex systems, and elucidation of the factors crucial for this process, comprising a critical aspect of 'oxygen activation' in chemical or biochemical systems, (3) the design of new ligands for copper which possess a linked phenol-imidazole moiety, to elucidate how such a group may take part in O-O cleavage chemistry, i.e., HCO function. Other new binucleating ligands for heme/Cu will be designed to test how in nature the enzyme His-Tyr crosslink might form, (4) investigation of heme/NO/O2 coordination chemistry - including the apparent reversible formation of a dinitrosyl heme complex and modeling heme protein actions such as occur in enzyme NO-dioxygenases, (5) new approaches to the study of NO reductase activity of heme/non-heme diiron and heme/Cu complexes, including design of a number of dimetal chemical systems for the systematic interrogation of their ability to reductively couple two NO molecules to produce nitrous oxide (N2O), and (6) detailed investigations of the metal-binding dynamics of nitrogen monoxide in heme, heme/copper and heme/non-heme diiron complexes - such photoinitiated reactions can provide a detailed understanding of the kinetics, thermodynamics, and metal preference/migration of these small molecules in interactions with heme/non-heme metal sites, as is relevant to HCO and NOR biological chemistry. PUBLIC HEALTH RELEVANCE: The proposed research will contribute to a deeper understanding of the connection between heme, non- heme iron and copper biochemistries, and their utilization of molecular oxygen and nitrogen monoxide. The interactions of these biologically important small gaseous molecules with such metal dependent enzymes are critical in normal functioning and health. Potential long-term applications of this basic research include development of enzyme inhibitors as drugs and relevant disease therapeutic strategies.

描述（由申请人提供）：长期研究目标是设计，合成和研究模型复合系统，这些系统可以帮助阐明与血红素 - 碳酸氧化酶（HCOS）使用的化学相关的结构，金属连接，光谱和反应性的基本方面，并有助于阐明结构的基本方面，并有助于阐明结构，金属连接，光谱和反应性。这些与进化相关的酶在有氧和厌氧生物的生物能学中起关键作用，并具有共同的血红素/M（M = M =铜或非血红素铁）活性位点，可在分别还原二氧化二氧化碳（O2）或硝酸氧化物（NO，NININITROGEN NITOREGEN）。提出的研究可以有助于更好地理解酶的结构和机制，并为二氧化物的生物加工和NO（NO，NO，氮氧化物的化学和生物化学）提供基本见解，并解决与环境中氮氧化物有关的问题。具体目的包括（1）血红素 - 过氧-CU复合物的表征，新的质子和新的低旋转衍生物以及其过氧连通性和电子结构的阐明，（2）研究的还原性O-O裂解的研究是由已经表现出良好表征的血红素 - 孔子-CU复合体系的质疑构成的构成的构成构成的构成的构成，并列出了该因素的构成，并阐明了构成“构成”的构成。或生化系统，（3）具有连接的苯酚 - 咪唑部分的铜的新配体设计，以阐明该组如何参与O-O裂解化学，即HCO功能。 Other new binucleating ligands for heme/Cu will be designed to test how in nature the enzyme His-Tyr crosslink might form, (4) investigation of heme/NO/O2 coordination chemistry - including the apparent reversible formation of a dinitrosyl heme complex and modeling heme protein actions such as occur in enzyme NO-dioxygenases, (5) new approaches to the study of NO reductase activity of heme/non-heme diiron and heme/Cu complexes, including design of a number of dimetal chemical systems for the systematic interrogation of their ability to reductively couple two NO molecules to produce nitrous oxide (N2O), and (6) detailed investigations of the metal-binding dynamics of nitrogen monoxide in heme, heme/copper and heme/non-heme diiron complexes - such photoinitiated reactions可以详细了解这些小分子在与血红素/非血红素金属位点相互作用中的动力学，热力学和金属偏好/迁移，与HCO和非生物学相关。公共卫生相关性：拟议的研究将有助于更深入地了解血红素，非血红素铁和铜生物化学之间的联系，以及它们对分子氧和一氧化氮的利用。这些在生物学上重要的小气体分子与这种依赖性酶的相互作用在正常功能和健康中至关重要。这项基础研究的潜在长期应用包括开发酶抑制剂作为药物和相关疾病治疗策略。