Cu sites in biology are involved in a wide variety of functions including O2 binding, activation for hydroxylation and cofactor formation, the four electron reduction of O2 to H2O and the two electron reduction of N2O to N2. These often exhibit unique spectroscopic features that reflect novel geometric and electronic structures that make major contributions to function. Research involves the application of a wide variety of spectroscopic (absorption, variable-temperature variable-field magnetic circular dichroism, resonance Raman, EPR, SQUID magnetic susceptibility, X-ray absorption, etc.) and electronic structure methods (ligand field and density functional theory, etc.) to define the active sites in these proteins, related model complexes and their intermediates and determine geometric and electronic structure contributions to function.
Specific aims are:1) Definition of the reaction coordinate of oxy-tyrosinase and determination of differences in substrate interaction with the similar coupled binuclear copper sites in hemocyanin, tyrosinase, mutants of tyrosinase associated with oculocutaneous albinism, and catechol oxidase which relate to differences in function;2) Definition of the coordinatively unsaturated nature of the trinuclear Cu cluster site in the multicopper oxidases, its reaction coordinate for O2 reduction to H2O, its coupling with the Type 1 center as related to intramolecular electron transfer and its interaction with metal ion substrates relevant to iron metabolism in ceruloplasmin and its genetic disorder aceruloplasminemia, Fe uptake in yeast (Fet3p) and microbial Mn and Cu oxidation;3) Extension of Cu(II)-hydroperoxide model studies to the active sites in dopamine (3- monooxygenase and peptidylglycine a-hydroxylating monooxygenase, involved in the control of neurotransmitters and peptidic hormone production, to determine the reaction coordinate for O2 activation by a single Cu center;4) Definition of electronic structure/reactivity correlations for the m-sulfide bridged tetranuclear Cuz cluster which catalyzes the two electron reduction of the green house gas N2O;5) Determination of the nature of tyrosine residue activation by Cu(II) sites in the O2 dependent biosynthesis of the organic cofactors in amine oxidase and galactose oxidase;6) Definition of O2 intermediates in heme/Cu models of cytochrome c oxidase, the terminal enzyme in aerobic metabolism, to understand its reaction coordinate for O2 reduction relative to the multicopper oxidases and how this relates to proton pumpingfor ATP synthesis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Sechi, Salvatore
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Stanford University
Schools of Arts and Sciences
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Adam, Suzanne M; Garcia-Bosch, Isaac; Schaefer, Andrew W et al. (2017) Critical Aspects of Heme-Peroxo-Cu Complex Structure and Nature of Proton Source Dictate Metal-O(peroxo) Breakage versus Reductive O-O Cleavage Chemistry. J Am Chem Soc 139:472-481
Schaefer, Andrew W; Kieber-Emmons, Matthew T; Adam, Suzanne M et al. (2017) Phenol-Induced O-O Bond Cleavage in a Low-Spin Heme-Peroxo-Copper Complex: Implications for O2 Reduction in Heme-Copper Oxidases. J Am Chem Soc 139:7958-7973
Cowley, Ryan E; Cirera, Jordi; Qayyum, Munzarin F et al. (2016) Structure of the Reduced Copper Active Site in Preprocessed Galactose Oxidase: Ligand Tuning for One-Electron O2 Activation in Cofactor Biogenesis. J Am Chem Soc 138:13219-13229
Arcos-López, Trinidad; Qayyum, Munzarin; Rivillas-Acevedo, Lina et al. (2016) Spectroscopic and Theoretical Study of Cu(I) Binding to His111 in the Human Prion Protein Fragment 106-115. Inorg Chem 55:2909-22
Solomon, Edward I; Hadt, Ryan G; Snyder, Benjamin E R (2016) Activating Metal Sites for Biological Electron Transfer. Isr J Chem 56:649-659
Tian, Shiliang; Liu, Jing; Cowley, Ryan E et al. (2016) Reversible S-nitrosylation in an engineered azurin. Nat Chem 8:670-7
Cao, Rui; Saracini, Claudio; Ginsbach, Jake W et al. (2016) Peroxo and Superoxo Moieties Bound to Copper Ion: Electron-Transfer Equilibrium with a Small Reorganization Energy. J Am Chem Soc 138:7055-66
Garcia-Bosch, Isaac; Cowley, Ryan E; Díaz, Daniel E et al. (2016) Dioxygen Activation by a Macrocyclic Copper Complex Leads to a Cu2O2 Core with Unexpected Structure and Reactivity. Chemistry 22:5133-7
Kim, Sunghee; Lee, Jung Yoon; Cowley, Ryan E et al. (2015) A N3S(thioether)-ligated Cu(II)-superoxo with enhanced reactivity. J Am Chem Soc 137:2796-9
Garcia-Bosch, Isaac; Adam, Suzanne M; Schaefer, Andrew W et al. (2015) A ""naked"" Fe(III)-(O?²?)-Cu(II) species allows for structural and spectroscopic tuning of low-spin heme-peroxo-Cu complexes. J Am Chem Soc 137:1032-5

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