Synthetic Modeling of Copper Protein Active Sites

Summary

Principal Investigator: William B Tolman
Abstract: 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.
Funding Period: 1992-08-01 - 2018-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Models for dioxygen activation by the CuB site of dopamine beta-monooxygenase and peptidylglycine alpha-hydroxylating monooxygenase
    Benjamin F Gherman
    Department of Chemistry and Supercomputer Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA
    J Biol Inorg Chem 11:197-205. 2006
  2. pmc Generating Cu(II)-oxyl/Cu(III)-oxo species from Cu(I)-alpha-ketocarboxylate complexes and O2: in silico studies on ligand effects and C-H-activation reactivity
    Stefan M Huber
    Department of Chemistry, Center for Metals in Biocatalysis and Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis MN 55455, USA
    Chemistry 15:4886-95. 2009
  3. pmc Intermediates in reactions of copper(I) complexes with N-oxides: from the formation of stable adducts to oxo transfer
    Sungjun Hong
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 48:6323-5. 2009
  4. pmc Effects of electron-deficient beta-diketiminate and formazan supporting ligands on copper(I)-mediated dioxygen activation
    Sungjun Hong
    Department of Chemistry, Center for Metals in Biocatalysis, and Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 48:4514-23. 2009
  5. pmc Binding and activation of N2O at transition-metal centers: recent mechanistic insights
    William B Tolman
    Department of Chemistry, Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55410, USA
    Angew Chem Int Ed Engl 49:1018-24. 2010
  6. pmc Copper/alpha-ketocarboxylate chemistry with supporting peralkylated diamines: reactivity of copper(I) complexes and dicopper-oxygen intermediates
    Aalo K Gupta
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 49:3531-9. 2010
  7. pmc An anionic, tetragonal copper(II) superoxide complex
    Patrick J Donoghue
    Department of Chemistry, Supercomputing Institute, and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    J Am Chem Soc 132:15869-71. 2010
  8. pmc Reactions of Ph3Sb═S with copper(I) complexes supported by N-donor ligands: formation of stable adducts and S-transfer reactivity
    Lei Yang
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    Inorg Chem 50:2606-12. 2011
  9. pmc X-ray absorption spectroscopic and computational investigation of a possible S···S interaction in the [Cu3S2]3+ core
    Ritimukta Sarangi
    Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA
    J Am Chem Soc 133:17180-91. 2011
  10. ncbi Type 1 copper site synthetic model complexes with increased redox potentials
    Lei Yang
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN 55455, USA
    J Biol Inorg Chem 17:285-91. 2012

Detail Information

Publications32

  1. ncbi Models for dioxygen activation by the CuB site of dopamine beta-monooxygenase and peptidylglycine alpha-hydroxylating monooxygenase
    Benjamin F Gherman
    Department of Chemistry and Supercomputer Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA
    J Biol Inorg Chem 11:197-205. 2006
    ..Another implication is that a neutral ligand set will be critical in biomimetic models in order to stabilize eta (1) dioxygen coordination...
  2. pmc Generating Cu(II)-oxyl/Cu(III)-oxo species from Cu(I)-alpha-ketocarboxylate complexes and O2: in silico studies on ligand effects and C-H-activation reactivity
    Stefan M Huber
    Department of Chemistry, Center for Metals in Biocatalysis and Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis MN 55455, USA
    Chemistry 15:4886-95. 2009
    ....
  3. pmc Intermediates in reactions of copper(I) complexes with N-oxides: from the formation of stable adducts to oxo transfer
    Sungjun Hong
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 48:6323-5. 2009
    ..Key results include the identification of novel copper(I) N-oxide adducts, aryl substituent hydroxylation, and bis(mu-oxo)dicopper complex formation via a route involving oxo transfer...
  4. pmc Effects of electron-deficient beta-diketiminate and formazan supporting ligands on copper(I)-mediated dioxygen activation
    Sungjun Hong
    Department of Chemistry, Center for Metals in Biocatalysis, and Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 48:4514-23. 2009
    ....
  5. pmc Binding and activation of N2O at transition-metal centers: recent mechanistic insights
    William B Tolman
    Department of Chemistry, Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55410, USA
    Angew Chem Int Ed Engl 49:1018-24. 2010
    ..These ideas are likely to inform efforts to design more effective catalysts for N(2)O remediation...
  6. pmc Copper/alpha-ketocarboxylate chemistry with supporting peralkylated diamines: reactivity of copper(I) complexes and dicopper-oxygen intermediates
    Aalo K Gupta
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 49:3531-9. 2010
    ....
  7. pmc An anionic, tetragonal copper(II) superoxide complex
    Patrick J Donoghue
    Department of Chemistry, Supercomputing Institute, and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    J Am Chem Soc 132:15869-71. 2010
    ....
  8. pmc Reactions of Ph3Sb═S with copper(I) complexes supported by N-donor ligands: formation of stable adducts and S-transfer reactivity
    Lei Yang
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    Inorg Chem 50:2606-12. 2011
    ..C.; York, J. T.; Antholine, W. E.; Ruiz, E.; Alvarez, S.; Tolman, W. B. J. Am. Chem. Soc. 2005, 127, 13752-13753)...
  9. pmc X-ray absorption spectroscopic and computational investigation of a possible S···S interaction in the [Cu3S2]3+ core
    Ritimukta Sarangi
    Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA
    J Am Chem Soc 133:17180-91. 2011
    ..These features result in donation of electron density from the S-S σ* to the Cu and result in some bonding interaction between the two S atoms at ~2.69 Å in [Cu(3)S(2)](3+), stabilizing a delocalized S = 1 ground state...
  10. ncbi Type 1 copper site synthetic model complexes with increased redox potentials
    Lei Yang
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN 55455, USA
    J Biol Inorg Chem 17:285-91. 2012
    ..g., azurin, stellacyanin) and approximately 0.5 V higher than those of previously reported model compounds. Thus, the new complexes mimic key aspects of both the structure and the function of type 1 copper sites...
  11. pmc Rapid C-H bond activation by a monocopper(III)-hydroxide complex
    Patrick J Donoghue
    Department of Chemistry, Center for Metals in Biocatalysis, and Supercomputing Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    J Am Chem Soc 133:17602-5. 2011
    ..4(2) kcal mol(-1), ΔS(‡) = -30(2) eu) and with very large kinetic isotope effects (cf. k(H)/k(D) = 44 at -70 °C). The findings suggest that a Cu(III)-OH moiety is a viable reactant in oxidation catalysis...
  12. pmc Copper-, palladium-, and platinum-containing complexes of an asymmetric dinucleating ligand
    Mohammad Reza Halvagar
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    Inorg Chem 52:793-9. 2013
    ..The heterodinuclear complexes were also prepared by addition of CuCl(2) to [(LH(2))MCl]Cl...
  13. pmc Isolation of a 2-hydroxytetrahydrofuran complex from copper-promoted hydroxylation of THF
    Mohammad Reza Halvagar
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    Inorg Chem 52:8306-8. 2013
    ..18)O-labeling studies support incorporation of the O atom from μ-OH into the coordinated THF-2-ol ligand. ..
  14. pmc Linkage isomerism in transition-metal complexes of mixed (arylcarboxamido)(arylimino)pyridine ligands
    David W Boyce
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    Inorg Chem 53:5788-96. 2014
    ..Base-induced linkage isomerization from O,N,N'-carboxamide to N,N',N″-carboxamido coordination is also confirmed by multiple forms of spectroscopy. ..
  15. pmc Reduction of nitrous oxide to dinitrogen by a mixed valent tricopper-disulfido cluster
    Itsik Bar-Nahum
    Department of Chemistry, Center for Metals in Biocatalysis, and Supercomputing Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    J Am Chem Soc 131:2812-4. 2009
    ..Computations implicate a transition state structure that features mu-1,1-bridging of N(2)O via its O-atom to a [L(2)Cu(2)(mu-S(2))](+) fragment and provide chemical precedence for an alternative pathway for N(2)O reduction by N(2)OR...
  16. ncbi Using synthetic chemistry to understand copper protein active sites: a personal perspective
    William B Tolman
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA
    J Biol Inorg Chem 11:261-71. 2006
    ....
  17. pmc Heterobimetallic activation of dioxygen: characterization and reactivity of novel Cu(I)-Ge(II) complexes
    John T York
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota, USA
    Inorg Chem 45:4191-8. 2006
    ..The isolation of the latter species by direct oxygenation of a Cu(I)-Ge(II) precursor represents a new route to heterobimetallic oxidants comprising copper...
  18. pmc X-ray absorption edge spectroscopy and computational studies on LCuO2 species: Superoxide-Cu(II) versus peroxide-Cu(III) bonding
    Ritimukta Sarangi
    Department of Chemistry, Stanford University, Stanford, California 94305, USA
    J Am Chem Soc 128:8286-96. 2006
    ..The charge on the Cu in the Cu(III) complex is found to be similar to that in Cu(II) complexes, which indicates a much stronger interaction with the ligand, leading to extensive charge transfer...
  19. ncbi Characterization of the structure and reactivity of monocopper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands
    Benjamin F Gherman
    Department of Chemistry and Supercomputer Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA
    J Comput Chem 27:1950-61. 2006
    ....
  20. pmc Ligand structural effects on Cu2S2 bonding and reactivity in side-on disulfido-bridged dicopper complexes
    Eric C Brown
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street Southeast, Minneapolis, Minnesota 55455, USA
    Inorg Chem 46:486-96. 2007
    ....
  21. pmc Mononuclear Cu-O2 complexes: geometries, spectroscopic properties, electronic structures, and reactivity
    Christopher J Cramer
    Department of Chemistry, Supercomputer Institute, and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street Southeast, Minneapolis, Minnesota 55410, USA
    Acc Chem Res 40:601-8. 2007
    ..In particular, these studies have shed new light on the factors that influence the mode of O 2 coordination (end-on vs side-on) and the electronic structure, which can vary between Cu(II)-superoxo and Cu(III)-peroxo extremes...
  22. pmc Heterobimetallic dioxygen activation: synthesis and reactivity of mixed Cu-Pd and Cu-Pt bis(mu-oxo) complexes
    John T York
    Department of Chemistry, Center for Metals in Biocatalysis, and Supercomputer Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    J Am Chem Soc 129:7990-9. 2007
    ..Theoretical evaluation of the electron affinities, basicities, and H-atom transfer kinetics and thermodynamics of the Cu2 and CuM (M=Pd, Pt) cores showed that the latter are more basic and form stronger O-H bonds...
  23. ncbi Structural diversity in copper-sulfur chemistry: synthesis of novel Cu/S clusters through metathesis reactions
    John T York
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    Inorg Chem 46:8105-7. 2007
    ..Copper(II) and/or Copper(III) and variable sulfur oxidation levels, including S(2-), S(2)(2-), and S(2)(-*), were identified by X-ray crystallography and spectroscopy...
  24. pmc Copper(I)-alpha-ketocarboxylate complexes: characterization and O2 reactions that yield copper-oxygen intermediates capable of hydroxylating arenes
    Sungjun Hong
    Department of Chemistry Supercomputer Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA
    J Am Chem Soc 129:14190-2. 2007
  25. ncbi Novel reactivity of side-on (disulfido)dicopper complexes supported by bi- and tridentate nitrogen donors: impact of axial coordination
    Itsik Bar-Nahum
    Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN 55455, USA
    Angew Chem Int Ed Engl 47:533-6. 2008
  26. pmc X-ray absorption spectroscopic and theoretical studies on (L)2[Cu2(S2)n]2+ complexes: disulfide versus disulfide(*1-) bonding
    Ritimukta Sarangi
    Department of Chemistry, Stanford University, Stanford, California 94305, USA
    J Am Chem Soc 130:676-86. 2008
    ..This leads to an inverted bonding scheme in 3 with dominantly ligand-based holes in its ground state, consistent with its description as a dicopper(II)-bis-disulfide(*1-) complex...
  27. pmc Hydroxo-bridged dicopper(II,III) and -(III,III) complexes: models for putative intermediates in oxidation catalysis
    Mohammad Reza Halvagar
    Department of Chemistry, Center for Metals in Biocatalysis, Chemical Theory Center, and Minnesota Supercomputing Institute, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
    J Am Chem Soc 136:7269-72. 2014
    ....