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

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与血红素-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、光谱学和反应性的基本方面。这些进化上相关的酶在需氧和厌氧生物的生物能量学中起着关键作用，并且共同具有血红素/M（M =铜或非血红素铁）活性位点，其分别还原性地裂解分子氧（O2）或一氧化氮（NO，一氧化氮）。该研究有助于更好地理解酶的结构和机制，并为氧气和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与氮氧化物相关的问题提供基本见解。具体目标包括（1）血红素-过氧-Cu络合物、新的质子化和新的低自旋衍生物的表征，以及它们的过氧连接性和电子结构的阐明，（2）通过已经充分表征的血红素-过氧-Cu络合物体系促进的还原O-O裂解的研究，以及对该过程的关键因素的阐明，包括化学或生物化学体系中“氧活化”的关键方面，（3）设计具有连接的苯酚-咪唑部分的铜的新配体，以阐明这样的基团如何参与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在自然界中酶His-Tyr交联可能如何形成，（4）血红素/NO/O2配位化学的研究-包括二亚硝酰基血红素复合物的表观可逆形成和模拟血红素蛋白作用，例如在酶NO-双加氧酶中发生的血红素蛋白作用，（5）研究血红素/非血红素二铁和血红素/铜配合物NO还原酶活性的新方法。包括设计一些双金属化学系统，用于系统地询问它们还原偶联两个NO分子的能力，产生一氧化二氮（N2 O），以及（6）血红素、血红素/铜和血红素/非血红素二铁络合物中一氧化氮的金属结合动力学的详细研究-这样的光引发反应可以提供对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/迁移的详细理解，如与HCO和NOR生物化学相关的。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。这些生物学上重要的气体小分子与这种金属依赖性酶的相互作用对正常功能和健康至关重要。这一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的治疗策略。

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.