Metalloenzyme structure, function, and as targets for neurodegeneration and bacterial pathogenesis

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Heme is one of the most diverse and useful iron-containing cofactors in biology. One of the most diverse functions are in oxidative heme enzymes that are designed to store the oxidizing equivalents of H2O2 or O2 in order to carry out biologically useful oxidation reactions. These include detoxification of toxic peroxides and xenobiotics (ie drug metabolism) and the oxidation of small organic compounds in various biosynthetic pathways such as in steroid metabolism and antibiotic biosynthesis. Structural biology has played a critical role in understanding these enzymes and the Poulos lab has focused primarily, but not exclusively, on peroxidases, cytochromes P450, nitric oxide synthase (NOS), and the various auxiliary proteins required for electron transfer. Owing to the transient nature of redox partner complexes, it has been difficult to determine crystal structures which is why there are so few in the PDB. This gap in our knowledge is especially important in P450s where redox partner binding can play a critical role in controlling where the substrate is oxidized in addition to exerting an effector role critical for proton coupled electron transfer. Recent advances in the well known P450cam system has provided specific hypotheses on the structural changes induced by redox partner binding that are required for O2 activation and has resulted in a rethinking of traditional views on how P450s work. This has generated considerable discussion, some quite controversial, but also has stimulated research to test the validity of some of these new ideas. A critical question being addressed is the generality of redox partner effector control in P450 catalysis in addition to the biological basis for why such a level of control is required for some P450s but not others. NOS is a P450 and has provided deeper insights into O2 activation and substrate oxidation. NOS also has proven to be an important therapeutic target in neurodegenerative diseases and in certain pathogenic bacteria like methicillin resistant Staph aureus (MRSA). Together with the Silverman lab at Northwestern, structure-based methods are being applied to the development of highly selective NOS inhibitors. Overall, the various ongoing projects provide a synergistic mix of fundamental research in heme enzyme function with research having clearly defined biomedical relevance.