Copper plays a key role in numerous environmentally and biologically important processes, particularly when encapsulated within enzymes that are widely distributed in Nature. The copper ions in the active sites of enzymes perform a variety of significant functions, including the binding and activation of dioxygen (O2) for effecting metabolically significant chemical reactions and the reduction of oxidized nitrogen-containing compounds like nitrite and nitrous oxide (N2O) during microbial respiratory processes important within the global nitrogen cycle. Despite extensive research, many questions remain unanswered concerning the detailed molecular level pathways of these processes. The research described herein addresses some of these questions through the synthetic modeling approach. In this approach, low molecular weight complexes designed to replicate aspects of copper enzyme active site structure and function are characterized and their reactivity studied. The goals are to develop detailed understanding of geometries, electronic structures, bonding, and reaction mechanisms relevant to the biological systems. Ultimately, the studies of synthetic compounds show what is possible for copper protein active sites in terms of structures, bonding, reactivity, and reaction pathways, thus providing a fundamental basis for understanding copper protein structure/function relationships. In particular, the research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved In the binding and activation of O2 and N2O. Progress since the original grant proposal (July 2007) Is documented in 21 publications that have appeared or have been submitted for publication, as well as 3 Ph.D. theses and an Inorganic Chemistry """"""""Forum"""""""" co-edited under the rubric of the current grant. Future research will address: (1) Copper-Sulfur Chemistry for Modeling the Cuz Site of Nitrous Oxide Reductase, (2) Dioxygen Activation at Monocopper Sites, and (3) Dioxygen Activation at Multicopper Sites.
In aim (1), new multicopper(l)-sulfide models of the unusual tetracopper-sulflde cluster (Cuz) found in an environmentally Important enzyme, nitrous oxide reductase, will be synthesized and their reactivity with N2O will be studied.
In aims (2) and (3), synthetic analogs of highly reactive mono- and multicopper oxidizing species will be prepared in order to evaluate their possible role In enzymes that bind and activate O2. In addition to aspiring to a deep understanding of copper enzyme structure/function relationships, the proposed work is aimed at developing novel copper chemistry of fundamental significance.

Public Health Relevance

The research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved in the binding and activation of O2 and N2O. The dioxygen-activating enzymes are involved in a plethora of important biological processes central to life, including respiration, metal ion homeostasis (the disruption of which causes disease), and the production of important organic metabolites, hormones, and neurotransmitters essential to human health. The reduction of N2O by the microbial enzyme nitrous oxide reductase converts this greenhouse gas to inert N2 in a process recognized to be a critical component of the global nitrogen cycle and thus directly relevant to public health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Anderson, Vernon
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University of Minnesota Twin Cities
Schools of Arts and Sciences
United States
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Dhar, Debanjan; Yee, Gereon M; Markle, Todd F et al. (2017) Reactivity of the copper(iii)-hydroxide unit with phenols. Chem Sci 8:1075-1085
Spaeth, Andrew D; Gagnon, Nicole L; Dhar, Debanjan et al. (2017) Determination of the Cu(III)-OH Bond Distance by Resonance Raman Spectroscopy Using a Normalized Version of Badger's Rule. J Am Chem Soc 139:4477-4485
Neisen, Benjamin D; Gagnon, Nicole L; Dhar, Debanjan et al. (2017) Formally Copper(III)-Alkylperoxo Complexes as Models of Possible Intermediates in Monooxygenase Enzymes. J Am Chem Soc 139:10220-10223
Elwell, Courtney E; Gagnon, Nicole L; Neisen, Benjamin D et al. (2017) Copper-Oxygen Complexes Revisited: Structures, Spectroscopy, and Reactivity. Chem Rev 117:2059-2107
Dhar, Debanjan; Yee, Gereon M; Spaeth, Andrew D et al. (2016) Perturbing the Copper(III)-Hydroxide Unit through Ligand Structural Variation. J Am Chem Soc 138:356-68
Eisenhart, Reed J; Rudd, P Alex; Planas, Nora et al. (2015) Pushing the Limits of Delta Bonding in Metal-Chromium Complexes with Redox Changes and Metal Swapping. Inorg Chem 54:7579-92
Gagnon, Nicole; Tolman, William B (2015) [CuO](+) and [CuOH](2+) complexes: intermediates in oxidation catalysis? Acc Chem Res 48:2126-31
Neisen, Benjamin D; Solntsev, Pavlo; Halvagar, Mohammad R et al. (2015) Secondary Sphere Hydrogen Bonding in Monocopper Complexes of Potentially Dinucleating Bis(carboxamide) Ligands. Eur J Inorg Chem 2015:5856-5863
Dhar, Debanjan; Tolman, William B (2015) Hydrogen atom abstraction from hydrocarbons by a copper(III)-hydroxide complex. J Am Chem Soc 137:1322-9
Yee, Gereon M; Tolman, William B (2015) Transition metal complexes and the activation of dioxygen. Met Ions Life Sci 15:131-204

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