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

• 批准号: 7934676
• 负责人: KENNETH D. KARLIN
• 金额: $ 31.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/7934676
• 关键词: Active Sites; Address; Aerobic; Anions; Basic Science; Binding; Biochemical; Biochemistry; Bioenergetics; Biological Process; Biomimetics; Carbon Monoxide; Chemicals; Chemistry; 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

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、合成和研究模型化合物系统，这些系统可以帮助阐明血红素-铜氧化酶（HCOs）和一氧化氮还原酶（NORs）所利用的化学相关的结构、金属连接、光谱和反应性的基本方面。这些进化相关的酶在好氧和厌氧生物的生物能量学中起着至关重要的作用，并且具有共同的血红素/M （M =铜或非血红素铁）活性位点，分别还原裂解二氧（O2）或一氧化氮（NO，一氧化氮）。本研究将有助于更好地了解酶的结构和机制，为研究双氧和NO的生物处理、氮氧化物的化学和生物化学以及解决环境中氮氧化物的相关问题提供基础见解。具体目标包括：(1)血红素-过氧铜配合物的表征，新的质子化和新的低自旋衍生物，并阐明它们的过氧连接和电子结构；(2)研究已经被很好地表征的血红素-过氧铜配合物系统促进的还原性O-O裂解，并阐明这一过程的关键因素，包括化学或生化系统中“氧活化”的关键方面。(3)设计新的铜配体，其具有连接的酚-咪唑基团，以阐明该基团如何参与O-O裂解化学，即HCO功能。血红素/Cu的其他新的双核配体将被设计用于测试His-Tyr交联酶在自然界中的形成方式，(4)研究血红素/NO/O2配位化学-包括二硝基血红素复合物的明显可逆形成和模拟血红素蛋白的作用，如NO-双加氧酶，(5)研究血红素/非血红素双铁和血红素/Cu复合物的NO还原酶活性的新方法。包括设计了一些双金属化学系统，系统地研究了它们还原两个NO分子产生氧化亚氮（N2O）的能力，以及(6)对血红素、血红素/铜和血红素/非血红素双铁络合物中一氧化氮的金属结合动力学的详细研究——这些光引发反应可以提供对动力学、热力学、以及这些小分子在与血红素/非血红素金属位点相互作用时的金属偏好/迁移，这与HCO和NOR生物化学有关。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、非血红素铁和铜之间的生物化学联系，以及它们对分子氧和一氧化氮的利用。这些具有重要生物学意义的小气体分子与这些依赖金属的酶的相互作用对正常功能和健康至关重要。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。