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

通过这一奖项，化学系的生命过程化学项目资助密歇根大学的Nicolai Lehnert博士研究细菌如何分解一氧化氮分子。一氧化氮(NO)在人体生理中是一种简单但非常重要的分子，因为它参与了血压的控制，并作为关键的免疫防御剂。然而，一些细菌通过使用某些酶来破坏这种分子，从而进化出对这种分子的防御。该项目正在努力了解这些酶能够分解NO的基本机制。对这些细菌酶催化的化学物质的基本了解有助于找到治疗耐药细菌感染的新方法。此外，该项目还对研究生和本科生进行化学合成、分析表征技术、高级光谱方法以及如何处理和解决科学问题方面的培训。这些都是学生在进入就业市场时的宝贵技能。最后，与底特律卡斯技术高中的接触被纳入到该项目中，允许未被充分代表的少数族裔高中生暑期在Lehnert实验室工作并获得研究经验。这项研究的目的是使用黄素二铁一氧化氮还原酶(FNORs)活性中心的模型络合物来描绘非血红素二铁中心如何完成NO还原的潜在化学途径。在以前的工作中，Lehnert小组准备了第一个功能模型复合体，这构成了当前机制研究的基础。通过光谱和动力学研究，再加上DFT计算，研究人员确定了该络合物催化NOR反应的分子机制。通过制备合适的该物种的衍生物，他们定义了一般情况下非血红素双铁活性中心有效还原NO和产生N2O的几何和电子要求，并进一步探索了不同的机理可能性。这些研究最终确定了FNORs中NO还原的化学可行途径，并提供了这一反应的重要中间体的指纹。该研究小组对这一模型体系进行了详细的反应性研究，以更好地了解非血红素(高自旋)铁(II)-氮氧基配合物如何参与NOR催化，并潜在地参与HNO的生物合成。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicolai Lehnert from the University of Michigan to study how the molecule nitric oxide is broken down by bacteria. Nitric oxide (NO) is a simple but very important molecule in human physiology as it is involved in the control of blood pressure and serves as a key immune defense agent. However, some bacteria have evolved defenses against this molecule by using certain enzymes which destroy it. This project is working toward understanding the fundamental mechanism by which these enzymes are able to break down NO. The fundamental understanding of the chemistry that these bacterial enzymes catalyze is contributing to the effort to find new cures against drug resistant bacterial infections. In addition, this project is training graduate and undergraduate students in chemical synthesis, analytical characterization techniques, advanced spectroscopic methods, and how to approach and solve scientific problem). These are all valuable skills for students when they enter the job market. Finally, outreach with Cass Technical High School in Detroit is integrated in to this project by allowing underrepresented minority high school students to work in the Lehnert laboratory over the summer and obtain research experience. This research project is aimed at using model complexes for the active site of flavodiiron nitric oxide reductases (FNORs) to map out potential chemical pathways of how NO reduction can be accomplished by non-heme diiron sites. In previous work, the Lehnert group prepared the first functional model complex, which forms the basis for the current mechanistic studies. Using spectroscopic and kinetic studies, coupled to DFT calculations, the researchers determine the molecular mechanism by which this complex catalyzes the NOR reaction. By preparing suitable derivatives of this species, they define the geometric and electronic requirements for efficient NO reduction and N2O generation by non-heme diiron active sites in general, and further explore different mechanistic possibilities. These studies ultimately identify chemically feasible pathways for NO reduction in FNORs and provide fingerprints of important intermediates of this reaction. The research group performs detailed reactivity studies on this model system in order to gain a better understanding of how non-heme (high-spin) iron(II)-nitroxyl complexes could be involved in NOR catalysis and, potentially, HNO biosynthesis.