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.
