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
Yokoyama, Atsutoshi; Han, Jung Eun; Karlin, Kenneth D et al. (2014) An isoelectronic NO dioxygenase reaction using a nonheme iron(III)-peroxo complex and nitrosonium ion. Chem Commun (Camb) 50:1742-4
Kieber-Emmons, Matthew T; Ginsbach, Jake W; Wick, Patrick K et al. (2014) Observation of a Cu(II)(2) (?-1,2-peroxo)/Cu(III)(2) (?-oxo)(2) equilibrium and its implications for copper-dioxygen reactivity. Angew Chem Int Ed Engl 53:4935-9
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Park, Ga Young; Lee, Jung Yoon; Himes, Richard A et al. (2014) Copper-peptide complex structure and reactivity when found in conserved His-X(aa)-His sequences. J Am Chem Soc 136:12532-5
Lee, Jung Yoon; Peterson, Ryan L; Ohkubo, Kei et al. (2014) Mechanistic insights into the oxidation of substituted phenols via hydrogen atom abstraction by a cupric-superoxo complex. J Am Chem Soc 136:9925-37
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Kim, Sunghee; Siegler, Maxime A; Karlin, Kenneth D (2014) Peroxynitrite chemistry derived from nitric oxide reaction with a Cu(II)-OOH species and a copper mediated NO reductive coupling reaction. Chem Commun (Camb) 50:2844-6
Das, Dipanwita; Lee, Yong-Min; Ohkubo, Kei et al. (2013) Temperature-independent catalytic two-electron reduction of dioxygen by ferrocenes with a copper(II) tris[2-(2-pyridyl)ethyl]amine catalyst in the presence of perchloric acid. J Am Chem Soc 135:2825-34
Qayyum, Munzarin F; Sarangi, Ritimukta; Fujisawa, Kiyoshi et al. (2013) L-edge X-ray absorption spectroscopy and DFT calculations on Cu2O2 species: direct electrophilic aromatic attack by side-on peroxo bridged dicopper(II) complexes. J Am Chem Soc 135:17417-31
Peterson, Ryan L; Ginsbach, Jake W; Cowley, Ryan E et al. (2013) Stepwise protonation and electron-transfer reduction of a primary copper-dioxygen adduct. J Am Chem Soc 135:16454-67

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