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.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM047365-23
Application #
8702189
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Halvagar, Mohammad Reza; Solntsev, Pavlo V; Lim, Hyeongtaek et al. (2014) Hydroxo-bridged dicopper(II,III) and -(III,III) complexes: models for putative intermediates in oxidation catalysis. J Am Chem Soc 136:7269-72
Boyce, David W; Salmon, Debra J; Tolman, William B (2014) Linkage isomerism in transition-metal complexes of mixed (arylcarboxamido)(arylimino)pyridine ligands. Inorg Chem 53:5788-96
Halvagar, Mohammad Reza; Tolman, William B (2013) Isolation of a 2-hydroxytetrahydrofuran complex from copper-promoted hydroxylation of THF. Inorg Chem 52:8306-8
Halvagar, Mohammad Reza; Neisen, Benjamin; Tolman, William B (2013) Copper-, palladium-, and platinum-containing complexes of an asymmetric dinucleating ligand. Inorg Chem 52:793-9
Taguchi, Taketo; Gupta, Rupal; Lassalle-Kaiser, Benedikt et al. (2012) Preparation and properties of a monomeric high-spin Mn(V)-oxo complex. J Am Chem Soc 134:1996-9
Yang, Lei; Tolman, William B (2012) Type 1 copper site synthetic model complexes with increased redox potentials. J Biol Inorg Chem 17:285-91
Yang, Lei; Tehranchi, Jacqui; Tolman, William B (2011) Reactions of Ph3Sb?S with copper(I) complexes supported by N-donor ligands: formation of stable adducts and S-transfer reactivity. Inorg Chem 50:2606-12
Donoghue, Patrick J; Tehranchi, Jacqui; Cramer, Christopher J et al. (2011) Rapid C-H bond activation by a monocopper(III)-hydroxide complex. J Am Chem Soc 133:17602-5
Sarangi, Ritimukta; Yang, Lei; Winikoff, Stuart G et al. (2011) X-ray absorption spectroscopic and computational investigation of a possible S···S interaction in the [Cu3S2]3+ core. J Am Chem Soc 133:17180-91
Gupta, Aalo K; Tolman, William B (2010) Copper/alpha-ketocarboxylate chemistry with supporting peralkylated diamines: reactivity of copper(I) complexes and dicopper-oxygen intermediates. Inorg Chem 49:3531-9

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