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

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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.