Non-Heme Iron(II)-Nitrosyl and -Nitroxyl Complexes: Key Intermediates in Nitric Oxide Reductases

获得这一奖项的是密歇根大学生命过程化学计划资助的Nicolai Lehnert博士，他为细菌一氧化氮还原酶(NORs)活性部位的单核和双核非血红素铁中心制备模型络合物，并研究相应的亚硝酰基(NO)和氮氧基(NO-/HNO)络合物在这些酶的机制中所起的作用。将采用先进的动力学和光谱方法，包括共振拉曼光谱和磁圆二色谱。NORs在反硝化细菌和病原菌中都有发现，被认为在它们感染哺乳动物宿主的能力中发挥了作用，因为NORs使这些细菌对NO产生抵抗力，而NO是哺乳动物的主要免疫防御剂。此外，非血红素铁酶可能通过形成Fe(II)-NO/HNO中间体参与生物体系中氮氧基的产生和传感，但这些物种的性质尚不清楚。莱纳特博士和他的团队将着手确定这些物种的几何和电子结构，并研究它们在生物上的相关反应。在哺乳动物中，一氧化氮(NO)是作为信号分子和免疫防御剂(由巨噬细胞)合成的，以抵御入侵的病原体。然而，某些细菌已经进化出一种名为一氧化氮还原酶(NORs)的酶，它通过还原成无毒的一氧化二氮(N2O)和水来有效地解毒NO。因此，NORs被认为会促进人体感染，导致慢性病。尽管NORs在细菌发病中具有重要作用，但这些酶还原NO的基本机制尚不清楚。拟议的研究试图阐明这些酶的机制。这一追求将使研究生和本科生获得高级合成和光谱方法以及计算化学方面的专门培训。提出的计划包括一项外展计划，将传统上在STEM学科中代表性较低的群体的高中生介绍给基础科学方面的实践研究。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicolai Lehnert from the University of Michigan to prepare model complexes for the mono- and dinuclear non-heme iron centers in the active sites of bacterial nitric oxide reductases (NORs), and to investigate the mechanistic role that corresponding nitrosyl (NO) and nitroxyl (NO-/HNO) complexes play in the mechanisms of these enzymes. Advanced kinetic and spectroscopic methods, including resonance Raman and magnetic circular dichroism, are to be employed. NORs are found in both denitrifying and pathogenic bacteria, and are thought to play a role in their ability to infect mammalian hosts, as NORs equip these bacteria with resistance to NO, which is a primary immune defense agent in mammals. In addition, non-heme iron enzymes may be involved in the generation and sensing of nitroxyl in biological systems via formation of Fe(II)-NO/HNO intermediates, but the properties of these species are not well understood. Dr. Lehnert and his team will set out to determine the geometric and electronic structures of these species and investigate their biologically relevant reactivity.Nitric oxide (NO) is biosynthesized in mammals as a signaling molecule, and as an immune defense agent (by macrophages) to fight off invading pathogens. However, certain bacteria have evolved enzymes called nitric oxide reductases (NORs), which efficiently detoxify NO by reduction to non toxic nitrous oxide (N2O) and water. Hence, NORs are thought to promote infection of the human body, leading to chronic diseases. Despite this importance of NORs for bacterial pathogenesis, the fundamental mechanism of NO reduction by these enzymes is not well understood. The proposed studies seek to elucidate the mechanisms of these enzymes. This pursuit will allow graduate students and undergraduates to acquire specialized training in advanced synthetic and spectroscopic methods and computational chemistry. Plans are put forward to include an outreach program to introduce high school students from groups traditionally underrepresented in the STEM disciplines to hands-on research in the fundamental sciences.