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: 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
• 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

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，该系统可以帮助阐明与血红素铜氧化酶（HCO）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）和一氧化氮还原酶（NOR）。这些与进化相关的酶在需氧和厌氧生物体的生物能学中发挥着关键作用，并且共同具有血红素/M（M = 铜或非血红素铁）活性位点，可还原裂解双氧 (O2) 或一氧化氮（NO、氮）一氧化碳）分别。所提出的研究有助于更好地理解酶的结构和机制，并为分子氧和一氧化氮的生物加工、氮氧化物的化学和生物化学提供基础见解，并解决与环境中氮氧化物相关的问题。具体目标包括 (1) 血红素-过氧-Cu 复合物、新型质子化和新型低自旋衍生物的表征，并阐明其过氧连接性和电子结构，(2) 研究已充分表征的血红素促进的还原性 O-O 裂解-过氧化铜复杂系统，并阐明该过程的关键因素，包括化学或生化系统中“氧活化”的关键方面，（3）新的设计具有连接的苯酚-咪唑部分的铜配体，以阐明这样的基团如何参与 O-O 裂解化学，即 HCO 功能。其他新的血红素/铜双核配体将被设计来测试酶 His-Tyr 交联在本质上如何形成，(4) 血红素/NO/O2 配位化学的研究 - 包括二亚硝基血红素复合物的明显可逆形成和建模血红素蛋白的作用，例如 NO-双加氧酶中发生的作用，(5) 研究血红素/非血红素二铁和血红素/铜复合物的 NO 还原酶活性的新方法，包括设计一些二金属化学系统的系统性询问其还原偶联两个 NO 分子产生一氧化二氮 (N2O) 的能力，以及 (6) 血红素、血红素/铜和一氧化氮中一氧化氮的金属结合动力学的详细研究血红素/非血红素二铁络合物 - 这种光引发反应可以提供对这些小分子与相互作用的动力学、热力学和金属偏好/迁移的详细了解血红素/非血红素金属位点，与 HCO 和 NOR 生物化学相关。公共健康相关性：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。这些生物学上重要的小气体分子与金属依赖性酶的相互作用对于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药物和相关疾病治疗策略。