Non-Heme Iron-Nitroxyl Complexes: Key Intermediates for Nitrogen-Nitrogen (N-N) Bond Forming Reactions in Nature

有了这个奖项，化学部的生命过程化学计划正在资助密歇根大学的Nicolai Lehnert博士。一氧化氮（NO）是人体生理中非常重要的分子。例如，它是一种关键的免疫防御剂，由免疫系统的细胞释放，以应对引起疾病的细菌。然而，致病菌已经进化出了对NO的防御。这些细菌使用称为黄二铁NO还原酶（FNORs）的酶，通过将其转化为毒性较小的分子N2 O来有效地去除NO。因此，有害细菌可以在人体内繁殖，并可能导致难以治愈的感染。Lehnert博士实验室的研究有助于阐明FNORs通过使用模拟FNORs活性位点的分子来分解NO的催化反应机制。了解FNORs的化学性质可以加速发现新的治疗细菌感染的方法，特别是那些由耐药菌株引起的细菌感染。研究生和本科生谁做的研究获得的知识和技能，先进的化学合成，分析和先进的光谱方法，并成为精通如何接近和解决科学问题。这些技能有助于学生在就业市场上成功竞争。最后，与底特律卡斯技术高中的外联活动也被纳入了这个项目。在这里，代表性不足的少数民族高中学生参加真实的研究在Lehnert实验室在整个夏天。这个研究项目的目的是使用模型复合物，以获得洞察的活性部位的flavodiiron一氧化氮还原酶（FNORs）。 重点是阐明影响NO还原为N2 O的催化作用的酶的二铁活性位点的结构和电子性质。在以前的工作中，Lehnert博士已经合成了模型复合物，代表了FNORs如何结合和激活NO的所有三种机制可能性。开发下一代模型系统来研究氧化还原电位和这些酶的二铁核心的第二配位球如何影响酶的反应性，并确定NO结合和激活的机制。根据DFT计算，FNORs中N-N键形成的关键中间体是次硝酸盐，但到目前为止，研究人员还无法捕获这些（或任何）反应中间体。在这里，模型复合物被用来调查次硝酸盐与非血红素铁中心的配位化学，并建立次硝酸盐的结合模式和铁络合物介导N2 O生成的能力之间的关系。最后，以前的工作表明，非血红素铁网站可以形成三种不同的氧化态，Fe II/III/IV-NO（-）的NO复合物。相应的FeIV-NO（-）物种最近被用作含有N-亚硝基的天然产物的生物合成途径中的中间体。Lehnert博士使用该物种唯一已知的模型复合物来研究FeIV-NO β型中间体在N-N键形成反应中的生物相关反应性。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估而被认为值得支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicolai Lehnert from the University of Michigan. Nitric oxide (NO) is a very important molecule in human physiology. It is, for example, a key immune defense agent released by cells from the immune system in response to encounters with bacteria that cause diseases. However, pathogenic bacteria have evolved defenses against NO. These bacteria use enzymes called flavodiiron NO reductases (FNORs) to efficiently remove NO by transforming it into the less toxic molecule N2O. As a result, harmful bacteria can proliferate in the human body and can cause hard to cure infections. The research in Dr. Lehnert’s laboratory contributes to the elucidation of the mechanism of catalytic reactions by which FNORs break down NO by using molecules that mimic the active site of FNORs. Understanding the chemistry of FNORs can accelerate finding new cures against bacterial infections, in particular those caused by drug-resistant strains. The graduate and undergraduate students who do the research acquire knowledge and skills in advanced chemical synthesis, analytical and advanced spectroscopic methods, and become versed in how to approach and solve scientific problems. These skills help the students to successfully compete in the job market. Finally, outreach with Cass Technical High School in Detroit is integrated in this project. Here, underrepresented minority high school students participate in real research in the Lehnert laboratory over the summer.This research project is aimed at using model complexes to gain insight in the active site of flavodiiron nitric oxide reductases (FNORs). The focus is on the elucidation of the structural and electronic properties of the diiron active sites of the enzymes that influence the catalysis of the NO reduction to N2O. In previous work, Dr. Lehnert has synthesized model complexes that represent all three mechanistic possibilities of how FNORs could bind and activate NO. Next generation model systems are developed to investigate how the redox potential and the second coordination sphere of the diiron core of these enzymes affects the reactivity of the enzyme, and to determine the mechanism by which NO is bound and activated. According to DFT calculations, the key intermediate following N-N bond formation in FNORs is hyponitrite, but so far, researchers have not been able to trap these (or any) intermediates of the reaction. Here, model complexes are used to investigate the coordination chemistry of hyponitrite with non-heme iron centers and to establish relationships between the hyponitrite binding mode and the ability of the iron complexes to mediate N2O generation. Finally, previous work has shown that non-heme iron sites can form NO complexes in three different oxidation states, FeII/III/IV-NO(-). The corresponding FeIV-NO(-) species have recently been invoked as intermediates in biosynthetic pathways for natural products that contain the N-nitroso group. Dr. Lehnert uses the only known model complex for this species to investigate the biologically-relevant reactivity of FeIV-NO type intermediates in N-N bond forming reactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.