CAREER: The Interaction of Nitric Oxide with Cytochrome P450

无机，生物无机和有机化学计划以及分子和细胞生物学计划的职业奖支持密歇根大学教授Nicolai Lehnert的工作，以探索一氧化氮（NO）与细胞色素P450的相互作用。该项目的目标是获得基本的洞察光谱的氧化还原转换的NO，可以催化细胞色素P450。调查利用酶细胞色素P450cam和合成模型复合物。磁性圆二色谱和共振拉曼光谱用于建立在不同的模型复合物和P450 cam野生型和突变体的硫醇配体的相对供体强度。亚铁和铁血红素亚硝基的制备和它们的光谱性质，电子结构和反应性的硫醇供体强度的函数进行了研究。然后研究这些亚硝酰基络合物的生物学相关反应，特别是包括由P450nor介导的NO还原为N2O（NO解毒）和亚铁血红素亚硝酰基与O2和超氧化物的反应（亚硝化应激）。目前正在编制一门关于金属在生命中的作用的新的本科课程，以吸引人数不足的少数民族学生学习基础科学。该课程侧重于基本生物和化学过程之间的关系，以及对健康，环境和替代能源等社会的高电流影响问题。在这些领域的实践研究经验的后续计划是为这些学生设计的。一氧化氮在生物系统中是一把双刃剑：它对许多信号和调节过程至关重要，但浓度过高也会对生物体构成致命威胁。阐明细胞色素P450与NO之间的基本反应对于生物化学家确定P450如何参与NO信号传导、转化和解毒的生物网络至关重要。特别是，预计研究中确定的NO和细胞色素P450之间的反应可能与人体生理学相关。

This CAREER award in the Inorganic, Bioinorganic and Organometallic Chemistry program and the Molecular and Cellular Biology program supports work by Professor Nicolai Lehnert at the University of Michigan to probe the interaction of nitric oxide (NO) with cytochrome P450. The goal of this project is to obtain fundamental insight into the spectrum of redox transformations of NO that can be catalyzed by cytochrome P450s. The investigations utilize both the enzyme cytochrome P450cam and synthetic model complexes. Magnetic circular dichroism and resonance Raman spectroscopy are used to establish the relative donor strengths of the thiolate ligands in different model complexes and P450cam wild type and mutants. Ferrous and ferric heme nitrosyls are prepared and their spectroscopic properties, electronic structures, and reactivities are studied as a function of the thiolate donor strength. Biologically relevant reactions of these nitrosyl complexes are then investigated, including in particular the reduction of NO to N2O as mediated by P450nor (NO detoxification) and the reaction of ferrous heme nitrosyls with O2 and superoxide (nitrosative stress). A new undergraduate course on the role of metals in life is being developed to attract underrepresented minority students to the basic sciences. The class focuses on the relation between fundamental biological and chemical processes and questions of high current impact in society like health, the environment and alternative energy sources. Follow-up programs for hands-on research experiences in these areas are designed for these students. Nitric oxide is a double-edged sword in biological systems: it is of central importance for many signaling and regulating processes, but at too high concentrations it also constitutes a deadly threat to the organism. The clarification of the fundamental reactions between cytochrome P450s and NO is of key importance for biological chemists to determine how P450s could participate in the biological network of NO signaling, transformation and detoxification. In particular, it is expected that the reactions between NO and cytochrome P450s identified in the research could potentially be relevant to human physiology.