Modeling the Active Site and Reactivity of Cyt. P450 Enzymes: A New Beginning

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In this project funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Nicolai Lehnert of the Department of Chemistry at the University of Michigan will develop new classes of model systems for the active site of the Cytochrome P450 enzyme family. These enzymes play a key role in humans for the biosynthesis of steroids and the metabolism of drugs via the activation of inert C-H bonds, and are therefore of general interest for the pharmaceutical and chemical industry. The goal of this project is to build model systems that incorporate second coordination sphere effects of the protein matrix into the synthetic model systems. The new model systems will then be used to (a) explore the molecular mechanism of O2 and NO activation by Cytochrome P450s, and (b) develop Cytochrome P450 biomimics as catalysts for industrial applications, in particular for O2 reduction in fuel cells, and C-H bond activation of organic molecules. The project lies at the interface of inorganic, biological, and organic chemistry, and is therefore well suited to the education of scientists at all levels. This research group is also well-positioned to provide summer research internships for underrepresented minority high school students from the Detroit area. Due to the great potential of cytochrome P450 for practical applications, a number of model systems have previously been created to mimic the heme-thiolate active sites of cytochrome P450s. However, most of these biomimetic complexes degrade readily in the presence of O2 or NO, even in the ferric (resting) state. This unexpected lack of stability is due to a valence tautomerism, where the ferric thiolate ground state of these complexes is in equilibrium with the ferrous thiyl state at room temperature. Based on these findings, this research group plans to investigate a new series of heme-thiolate model complexes that contain (a) hydrogen-bond stabilized thiolate ligands, and (b) different types of picket fence porphyrins, where 2nd coordination sphere effects are incorporated into the distal pockets of the model systems. This new series of complexes will be used to systematically investigate the reactivity of heme-thiolate active sites with O2 and NO to obtain detailed insight into how Cytochrome P450s activate O2 and NO. These investigations will be complemented with studies under heterogeneous conditions where the complexes will be immobilized on electrode surfaces, and their ability to electrocatalytically reduce O2 (fuel cell technology) and activate C-H bonds (synthesis) will be tested.