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

非血红素铁-硝酰基复合物：自然界中氮-氮 (N-N) 键形成反应的关键中间体

• 批准号: 2002885
• 负责人: Nicolai Lehnert
• 金额: $ 52.4万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2002885&HistoricalAwards=false
• 关键词: Non; Heme; Iron; Nitroxyl; Complexes

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.

通过这个奖项，化学部的生命过程化学项目为密歇根大学的Nicolai Lehnert博士提供了资金。一氧化氮(NO)是人体生理中一种非常重要的分子。例如，它是一种关键的免疫防御剂，由免疫系统的细胞在遇到导致疾病的细菌时释放出来。然而，病原菌已经进化出对NO的防御。这些细菌使用名为黄二铁NO还原酶(FNORs)的酶，通过将NO转化为毒性较低的分子N2O来有效地去除NO。因此，有害细菌可能会在人体内繁殖，并可能导致难以治愈的感染。Lehnert博士实验室的这项研究有助于阐明FNORs通过使用模拟FNORs活性部位的分子来分解NO的催化反应机理。了解FNORs的化学成分可以加速找到治疗细菌感染的新方法，特别是那些由耐药菌株引起的感染。从事研究的研究生和本科生获得高级化学合成、分析和高级光谱方法方面的知识和技能，并精通如何处理和解决科学问题。这些技能帮助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联系也纳入了这个项目。在这里，未被充分代表的少数族裔高中生参加了莱纳特实验室整个夏天的真实研究。这项研究项目的目的是使用模型复合体来深入了解黄二铁一氧化氮还原酶(FNORs)的活性部位。重点阐述了影响NO还原为N2O催化作用的酶的二铁活性中心的结构和电子性质。在之前的工作中，Lehnert博士已经合成了代表FNORs如何结合和激活NO的所有三种机制可能性的模型络合物。下一代模型系统被开发来研究这些酶的氧化还原电位和双铁核心的第二配位球如何影响酶的反应活性，并确定NO被结合和激活的机制。根据DFT计算，FNORs中N-N键形成后的关键中间体是次硝酸盐，但到目前为止，研究人员还没有能够捕获这些(或任何)反应中间体。在这里，我们使用模型络合物来研究次亚硝酸盐与非血红素铁中心的配位化学，并建立次亚硝酸盐结合模式与铁络合物调节N2O生成的能力之间的关系。最后，以前的工作表明，非血红素铁中心可以在三种不同的氧化态FeII/III/IV-NO(-)中形成NO络合物。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。莱纳特博士使用该物种唯一已知的模型复合体来研究FeIV-NO类型中间体在N-N键形成反应中的生物相关反应性。这一奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Exploring second coordination sphere effects in flavodiiron nitric oxide reductase model complexes

• DOI: 10.1039/d3dt02828c
• 发表时间: 2023-10-31
• 期刊: DALTON TRANSACTIONS
• 影响因子: 4
• 作者: Bracken，Abigail J.;Dong，Hai T.;Lehnert，Nicolai
• 通讯作者: Lehnert，Nicolai

Exploring the Limits of Dative Boratrane Bonding: Iron as a Strong Lewis Base in Low-Valent Non-Heme Iron-Nitrosyl Complexes.

• DOI: 10.1021/acs.inorgchem.0c01686
• 发表时间: 2020-10-19
• 期刊: Inorganic chemistry
• 影响因子: 4.6
• 作者: Dong HT;Chalkley MJ;Oyala PH;Zhao J;Alp EE;Hu MY;Peters JC;Lehnert N
• 通讯作者: Lehnert N

Bacterial nitric oxide reductase (NorBC) models employing click chemistry

• DOI: 10.1016/j.jinorgbio.2023.112280
• 发表时间: 2023-06-21
• 期刊: JOURNAL OF INORGANIC BIOCHEMISTRY
• 影响因子: 3.9
• 作者: Harland，Jill B.;Samanta，Subhra;Lehnert，Nicolai
• 通讯作者: Lehnert，Nicolai