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

描述(申请人提供)：长期的研究目标是设计、合成和研究模型化合物系统，该系统可以帮助阐明结构、金属连接、光谱和与血红素-铜氧化物酶(HCOs)和一氧化氮还原酶(NORs)所利用的化学有关的基本方面。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关键作用，并具有共同的血红素/M(M=铜或非血红素铁)活性部位，分别还原分解氧气(O2)或一氧化氮(NO)。建议的研究有助于更好地理解酶的结构和机理，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与环境中氮氧化物有关的问题提供基本的见解。具体目标包括(1)表征血红素-过氧铜络合物、新的质子化和新的低自旋衍生物及其过氧连接性和电子结构；(2)研究已被表征良好的血红素-过氧铜络合物体系促进的还原O-O裂解，并阐明这一过程的关键因素，包括在化学或生化体系中‘氧活化’的关键方面；(3)设计具有连接的苯酚-咪唑基团的铜的新配体，以阐明这种基团如何参与O-O裂解化学，即HCO功能。其他用于血红素/铜的新的双核配体将被设计来测试酶His-Tyr交联物在自然界中可能如何形成，(4)对血红素/NO/O2配位化学的研究-包括明显可逆地形成二亚硝基血红素复合体和模拟血红素蛋白质的作用，例如发生在酶的非双加氧酶中，(5)研究血红素/非血红素二铁和血红素/铜络合物的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将两个NO分子还原耦合以产生N2O的能力，以及(6)详细研究一氧化氮在血红素、血红素/铜和血红素/非血红素二铁络合物中的金属结合动力学-这种光引发的反应可以详细地了解这些小分子与血红素/非血红素金属中心相互作用的动力学、热力学和金属的选择性/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、非血红素铁和铜生物化学之间的联系，以及它们对分子氧和氮氧化物的利用。这些具有重要生物意义的气体小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的疾病治疗策略。

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.