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John T. Groves

Research Focus

Groves

The major thrust of our research program is at the interface of organic, inorganic, and biological chemistry. Many biochemical transformations as well as important synthetic and industrial processes are catalyzed by metals. Current effort focus on the design of new, biomimetic catalysts and the molecular mechanisms of these processes, the design and assembly of large scale membrane-protein-small molecule constructs, studies of host-pathogen interactions related to iron acquisition by small molecule siderophores and molecular probes of the role of peroxynitrite in biological systems.

  • The heme prosthetic group is found in a variety of enzymes involved in oxygen metabolism. The cytochromes P450 of lung, liver and epithelial tissue are known to play a central role in carcinogen activation, drug and xenobiotic detoxification, steroid and prostaglandin metabolism, and, most recently, the production of the intracellular signal molecule NO. The goals of this program have been to elucidate the organic and inorganic chemistry of these processes. Our two-pronged approach has been (i) to employ substrates for cytochrome P450 designed to reveal the nature of unseen intermediates in the reaction mechanism and (ii) to develop model systems as chemical paradigms for these processes. One specific application of the work is the design of selective inhibitors which could have pharmacological uses.
  • The characterization of synthetic oxo-metalloporphyrin complexes as models of the cytochrome P450 active site has begun to provide a rational basis for the development of new catalysts and selective molecular detectors. Thus, relatively small changes in the size and shape of a metalloporphyrin catalyst may cause large changes in the relative reactivity of various substrates. The same criteria have allowed the development of chiral porphyrins capable of catalytic asymmetric epoxidation and hydroxylation. In the most favorable case found to date, the epoxidation of styrene was found to occur with a 95% enantiomeric excess. In a recently-initiated project, we are employing arrays of metalloporphyrin catalysts to reliably and efficiently produce the anticipated human metabolites of drug molecules
  • We have discovered that ruthenium porphyrin complexes are competent catalysts for the aerobic oxidation of simple organic compounds at ambient temperature and pressure. Very high catalytic efficiencies and turnover rates have been achieved with this system. We are investigating the mechanism of this remarkably mild process for which there is considerable commercial interest. Another recent outgrowth of these studies has been the recognition that trans-dioxomanganese(V) complexes [O=MnV=O] are stable and isolable. Yet upon protonation these catalysts re able to insert oxygen into unreactive C-H bonds at stupendous rates.
  • Our interest in oxidizing enzymes has led us to develop techniques for characterizing and using the oxygenase enzymes found within whole cells. This approach has enabled us to look directly at thte mechanism of action of alkane hydroxylases in new and uncharacterized organisms.
  • In another outgrowth of the water-soluble metalloporphyrins project, we have shown that the peroxynitrite ion, which can be formed in vivo from the facile reaction of superoxide with NO, has the unique ability to cross phospholipid membranes and diffuse freely from compartment to compartment within a cell. Damage done to proteins, such as protein tyrosine nitration, by peroxynitrite may form part of molecular bases of the immune response and cytochrome c-mediated apoptosis. These pathways may also explain such conditions as diabetes and ischemia-reperfusion injury.
  • Knowledge of the chemical mechanisms of cell damage due to oxidative processes could lead to effective pharmacological treatments. Our water-soluble metalloporphyrins, such as FP15, a PEGylated iron porphyrin, has shown profound biological activities in animals by capturing peroxynitrite within cells and preventing the tissue damage caused by this powerful oxidant.
  • We have an active interest in elucidating the molecular mechanisms and pathways by which pathogenic organisms sequester the iron they need from the host organism. Our primary pathway is the biosynthesis of small molecule 'siderophores'. A very interesting class of iron-binding siderophores has amphiphilic properties, having a polar head group containing the iron binding site and one or two hydrophobic side chains reminiscent of a phospholipid. The first of these to be discovered were the exochelins and mycobactins of Mycobacter tuberculosis, rhizobactin 1021 from a terrestrial, nitrogen-fixing symbiont and acinetoferrin from the pathogens Acinetobacter haemoliticus and Acinetobacter baumanii. The amphiphilic marinobactins and acquachelins have been discovered more recently in marine bacteria, indicating that such structures are widely distributed in nature. Current interest in the iron-uptake strategies of pathogenic organisms stems from their increasing antibiotic resistance and the rising numbers of difficult-to-treat infections in humans. Our interest in iron and membrane dynamics has led us to investigate how the amphiphilic nature of these compounds may be advantageous to these organisms. The effort has involved chemical synthesis of siderophores and their analogs and the characterization of the behavior of these molecules in phospholipids membranes and whole cells.

Honors

  • Ira Remsen Award, American Chemical Society, 2010
  • Hans Fischer Award in Porphyrin Chemistry, 2010
  • Fellow of the Royal Society of Chemistry, 2009-
  • Frontiers in Biological Chemistry Award, Max Planck Institute, 2009
  • Grand Prix, Maison de la Chimie (Paris) Laureate, 2008
  • National Science Foundation Extension Award for Special Creativity, 2008-2010
  • National Institute of General Medical Sciences, NIH, MERIT Award, 2007-
  • Distinguished Visiting Professor University of Hong Kong, 2003
  • Alfred Bader Award in Bioorganic and Bioinorganic Chemistry, American Chemical Society, 1996
  • Fellow, Japan Society for the Promotion of Science, 1997 and 1987
  • Fellow, American Academy of Arts and Sciences, 1993-
  • Morris S. Kharasch Visiting Professor, University of Chicago, 1993
  • Hugh Stott Taylor Chair in Chemistry, Princeton University, 1991-
  • A. C. Cope Scholar Award, American Chemical Society, 1991
  • National Science Foundation Extension Award for Special Creativity, 1990-1992
  • Fellow, American Association for the Advancement of Science
  • Phi Lambda Upsilon Award for Teaching and Leadership

Selected Recent Publications

  • N. Basak Surmeli and John T. Groves, Peroxynitrite Mediates Active Site Tyrosine Nitration in Manganese Superoxide Dismutase. Evidence of a Role for the Carbonate Radical Anion, J. Am. Chem. Soc., 2010, 132, 17174-17185.
     
  • Thomas P. Umile and John T. Groves, Catalytic Generation of Chlorine Dioxide from Chlorite Using a Water-soluble Manganese Porphyrin, Angew. Chem. 2011, 123, 721–724.
     
  • Ning Jin, Dorothee E. Lahaye, and John T. Groves, A “Push Pull” Mechanism for Heterolytic O-O Bond Cleavage in Hydroperoxo Manganese Porphyrins, Inorg. Chem. 2010, 24, 11516-11524.
     
  • Harriet L. R. Cooper and John T. Groves, Molecular Probes of the Mechanism of Cytochrome P450. Oxygen Traps a Substrate Radical Intermediate. Arch. Biochem. Biophys. 2011, 507, 111–118.
     
  • Seth R. Bell and John T. Groves, A Highly Reactive P450 Model Compound I, J. Am. Chem. Soc., 2009, 131, 9640-9641.
     
  • Jia Su and John T. Groves, Direct Detection of the Oxygen Rebound Intermediates, Ferryl Mb and NO2, in the Reaction of metMyoglobin with Peroxynitrite J. Am. Chem. Soc ., 2009 , 131 , ASAP.
     
  • Rachel N. Austin*, Kate Luddy, Karla Erickson, Marilla Pender-Cudlip, Erin Bertrand, Dayi Deng, Ryan S. Buzdygon, Jan B. van Beilen, John T. Groves*, Cage Escape Competes with Geminate Recombination during Alkane Hydroxylation by the Diiron Oxygenase AlkB, Angew. Chem. 2008, 47, 5232-5234. DOI: 10.1002/anie.200801184
     
  • Elena A. Rozhkova-Novosad, Jong-Chan Chae, Gerben J. Zylstra, Erin M. Bertrand, Marselle Alexander-Ozinskas, Rachel N. Austin, and John T. Groves, Functional profiling of bacterial alkane hydroxylases with the diagnostic substrate norcarane, Chemistry and Biology, 2007, 14, 165–172.
     
  • Tamás Radovits, Leila Seres, Domokos Gerö, Irina Berger, John T. Groves, Csaba Szabó and Gábor Szabó, The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction, Mechanisms of Ageing and Development, 2007, 128 (2): 173-181, doi:10.1016/j.mad.2006.09.005 .
     
  • Sarmistha Chakrabarty, Rachel N. Austin, Dayi Deng, John T. Groves and John D. Lipscomb,, Radical Intermediates in Monooxygenase Reactions of Rieske Dioxygenases, J. Am. Chem. Soc., 2007, 129(12); 3514-3515.    DOI: 10.1021/ja068188v.
     
  • Gurusamy Balakrishnan, Ying Hu, Oyeyemi F. Oyerinde, Jia Su, John T. Groves, Thomas G. Spiro, A Conformational Switch to β-sheet Structure in Cytochrome c Leads to Heme Exposure; Implications for Cardiolipin Peroxidation and Apoptosis, J. Am. Chem. Soc., 2007, 129 (3): 504-505, DOI:10.1021/ja0678727.
     
  • Ankona Datta, Suzanne M. Quintavalla and John T. Groves, Kinetic selectivity in the N-alkylation of 2-pyridyl porphyrins: a facile approach to the aabb -scaffold, J. Org. Chem. 2007, 72(5); 1818-1821.    DOI: 10.1021/jo062017r .
     
  • Dorothee Lahaye and   John T. Groves, Modeling the Haloperoxidases.   Reversible Oxygen Atom Transfer between Bromide Ion and an Oxo-Mn(V) Porphyrin, J. Inorg. Biochem. 2007, 101, 1786–1797, doi.org/10.1016/j.jinorgbio.2007.07.017.
     
  • Ning Jin, Mohammed Ibrahim, Thomas G. Spiro and John T. Groves, trans-Dioxo Manganese(V) Porphyrins, J. Am. Chem. Soc., 2007, 129, 12416-12417.
     
  • Viktor R.Drel, Pal Pacher, Igor Vareniuk, Ivan A. Pavlov, Olga Ilnytska, Valeriy V. Lyzogubov, Seth R. Bell, John T. Groves, and Irina G. Obrosova,  Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes, International Journal of Molecular Medicine , 2007, 20, 783-792.
     
  • Mrinalini Puranik, Dorothee Lahaye, Shinichi Taoka, Steen Brondsted Nielsena,   John T. Groves, Ruma Banerjee and Thomas G. Spiro, “Dynamics of Carbon Monoxide Binding to Cyctathionine b -Synthase”,   J. Biol. Chem., 2006, 281 (19): 13433-13438.
     
  • Rachel N. Austin, Dayi Deng, Yongying Jiang, Kate Luddy, Jan B. van Beilen, Paul R. Ortiz de Montellano, John T. Groves, The Diagnostic Substrate Bicyclohexane Reveals a Radical Mechanism for Bacterial Cytochrome P450 in Whole Cells, Angew. Chem. 2006, 45(48), 8192-8194, DOI : 10.1002/anie.200603282.
     
  • Minkui Luo, Hening Lin, Michael A. Fischbach, David R. Liu, Christopher T. Walsh, John T. Groves, Enzymatic Tailoring of Enterobactin Alters Membrane Partitioning and Iron Acquisition , ACS Chemical Biology 2006, 1(1); 29-32,   DOI: 10.1021/cb0500034.
     
  • John T. Groves, High-Valent Iron in Chemical and Biological Oxidations, J. Inorg. Biochem. 2006 , 100, 434-447, doi:10.1016/j.jinorgbio.2006.01.012 .
     
  • Chuanqing Wang, Kirill V. Shalyaev, Marcella Bonchio, Tommaso Carofiglio, and John T. Groves*, Fast Catalytic Hydroxylation of Hydrocarbons with Ruthenium Porphyrins, Inorg. Chem., 2006, 45(12), 4769-4782.   DOI: 10.1021/ic0520566 .
     
  • Filippo De Angelis, Ning Jin,   Roberto Car,   John T. Groves,   Electronic Structure and Reactivity of Isomeric Oxo-Mn(V) Porphyrins: Effects of Spin-State Crossing and pKa Modulation, Inorg. Chem., 2006, 45 (10); 4268-4276.   DOI: 10.1021/ic060306s.
     
  • Minkui Luo, Evgeny A. Fadeev and John T. Groves. “ Membrane Dynamics of the Amiphiphilic Siderophore, Acinetoferrin ”,   J. Am. Chem. Soc., 2005, 127, 1726-1736.
     
  • Minkui Luo, Evgeny A. Fadeev and John T. Groves, “Mycobactin-mediated iron acquisition within macrophages”, Nature Chem. Biol. 2005, 1, 149-153.
     
  • Melanie S. Sanford and John T. Groves, “ Anti-Markovnikov Hydrofunctionalization of Olefins Mediated by Rhodium Porphyrins,” Angew. Chemie 2004, 116, 598-600.

  • John T. Groves, "Models and Mechanisms of Cytochrome P-450 Action" Ch. 1 in Cytochrome P450: Structure, Mechanism, and Biochemistry , 3e, edited by Paul R. Ortiz de Montellano, Kluwer Academic / Plenum Publishers, New York, 2004. Pp1-44.
     
  • Evgeny A. Fadeev, Minkui Luo and John T. Groves. “Synthesis, Structure and Molecular Dynamics of Iron and Gallium Complexes of Schizokinen and the Amphiphilic Siderophore Acinetoferrin”,   J. Am. Chem. Soc., 2004, 126 (38); 12065-12075.
     
  • Mrinalini Puranik, S. B. Nielsen, H. Youn, A. N. Hvitved, James L. Bourassa JL, Martin A. Case, C. Tengroth, G. Balakrishnan, M. V. Thorsteinsson , John T. Groves, George L. McLendon, G. P. Roberts, J. S. Olson, Thomas G. Spiro, “Dynamics of carbon monoxide binding to CooA”, J. Biol. Chem. 2004, 279, 21096-21108.
     
  • Luke A. Moe, Zhengbo Hu, Dayi Deng, Rachel N. Austin, John T. Groves, and Brian G. Fox, “Remarkable Aliphatic Hydroxylation by the Diiron Enzyme Toluene 4-Monooxygenase in Reactions with Radical/Cation Diagnostic Probes Norcarane, 1,1-Dimethylcyclopropane, and 1,1-Diethylcyclopropane”, Biochemistry, 2004, 43, 15688-15701.

John T. Groves

Groves Lab Webpage
jtgroves@princeton.edu
Frick Laboratory, 232
Phone: 609-258-3593

Faculty Assistant:
Denise D'Auria
denised@princeton.edu
Frick Laboratory, 228
Phone: 609-258-5202