The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(I)/O2 interactions, dynamics &energetics of O2-adduct formation, as well as questions concerning structure, associated spectroscopy, O-O bond cleavage (i.e., O2-activation) and substrate oxidation chemistries. Copper-NOx interactions relate to the possible role of copper ion in nitrogen monoxide (NO) biology, then leading to oxidative and/or nitrative stress. The research divides into sub- projects, directed along various themes or chemical systems. These include: (1) dicopper chemistry studies, where recent advances have brought focus to very low coordinate Cu2 centers in particulate methane monooxygenase, of great biological and energy concerns. Attention will be paid to dicopper complexes with a single oxo ion bridge, as the possible reactive species toward methane. Also, mixed-valent bis-oxo dicopper complexes will be sought and investigations into the fundamentally important O-O cleavage process will be carried out, (2) the study of O2 and carbon monoxide (CO, as O2-surrogate) kinetics and thermodynamics of binding to tetradentate ligand CuI-chelates including with one thioether donor atom, that being biologically relevant. Previously unseen classes of copper-dioxygen complexes will also be studied employing tridentate ligand chelates. The very fast reactions involved call for application of time-resolved techniques. With new collaborators, additional state-of-the-art time-resolved methods will be applied, (3) comparative studies of copper peroxo and copper-superoxo species substrate reactivity will be carried out using ligands with synthetically placed internal substrates. In addition, we will explore the possibility that copper active-site chemistry involves methionine sulfur radical cation formation during O2-actvation and enzyme turnover, a new paradigm in the field, (4) direct in-depth reactivity studies with a series of stabilized copper-superoxo complexes. These will include oxidation of phenols, substrates with weak C-H bonds and electron-proton reduction to copper-hydroperoxo complexes. (5) advanced investigations into copper/O2/nitrogen-monoxide (nitric oxide) interactions, following a new paradigm concerning the possible role of copper ion in the biological formation of the reactive nitrogen species peroxynitrite (-OON=O). Peroxynitrite complexes with copper(II) ion will be generated and characterized in detail, and their reactions with especially phenolic or carbon dioxide substrates will be examined. Mechanistic inquiries will include their transformation to nitrite plus oxygen or to nitrate. Overall, the proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction of O2 and NOx in biology, and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.

Public Health Relevance

The proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction of O2 and NOx in biology and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028962-32
Application #
8244423
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
1981-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
32
Fiscal Year
2012
Total Cost
$351,286
Indirect Cost
$126,286
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yamada, Mihoko; Karlin, Kenneth D; Fukuzumi, Shunichi (2016) One-Step Selective Hydroxylation of Benzene to Phenol with Hydrogen Peroxide Catalysed by Copper Complexes Incorporated into Mesoporous Silica-Alumina. Chem Sci 7:2856-2863
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
Liu, Jeffrey J; Diaz, Daniel E; Quist, David A et al. (2016) Copper(I)-Dioxygen Adducts and Copper Enzyme Mechanisms. Isr J Chem 56:9-10
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
Saracini, Claudio; Ohkubo, Kei; Suenobu, Tomoyoshi et al. (2015) Laser-Induced Dynamics of Peroxodicopper(II) Complexes Vary with the Ligand Architecture. One-Photon Two-Electron O2 Ejection and Formation of Mixed-Valent Cu(I)Cu(II)-Superoxide Intermediates. J Am Chem Soc 137:15865-74
Lee, Jung Yoon; Karlin, Kenneth D (2015) Elaboration of copper-oxygen mediated C-H activation chemistry in consideration of future fuel and feedstock generation. Curr Opin Chem Biol 25:184-93
Kakuda, Saya; Rolle, Clarence J; Ohkubo, Kei et al. (2015) Lewis acid-induced change from four- to two-electron reduction of dioxygen catalyzed by copper complexes using scandium triflate. J Am Chem Soc 137:3330-7
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
Kim, Sunghee; Ginsbach, Jake W; Lee, Jung Yoon et al. (2015) Amine oxidative N-dealkylation via cupric hydroperoxide Cu-OOH homolytic cleavage followed by site-specific fenton chemistry. J Am Chem Soc 137:2867-74
Hematian, Shabnam; Garcia-Bosch, Isaac; Karlin, Kenneth D (2015) Synthetic heme/copper assemblies: toward an understanding of cytochrome c oxidase interactions with dioxygen and nitrogen oxides. Acc Chem Res 48:2462-74

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