Enzyme Mechanisms and Rational Drug Design

Ph.D., 1986, University of Birmingham, England
SERC-NATO Postdoctoral Research Fellowship
National Research Council Canada, 1986-1988
Alfred P. Sloan Research Fellowship, 2001

Our laboratory utilizes a variety of spectroscopic techniques, principally vibrational spectroscopy and NMR spectroscopy, to develop precise structure-reactivity correlation's for enzyme-catalyzed reactions. Detailed information is obtained concerning the geometry of the bound substrate, the energy of specific enzyme-substrate contacts and the changes that occur in the electronic structure of the substrate on binding. This approach provides fundamental insight into the mechanism of enzyme catalysis and facilitates the rational design of enzyme inhibitors for use as novel therapeutics. Electrostatic forces and 'electric fields' play a major role in enzyme-catalyzed reactions. Vibrational spectroscopy enables us to analyze and quantitate alterations in electron density in substrates on binding to enzymes and to quantitate the electric field responsible for the perturbation in electronic structure. Research projects comprise both biological and chemical components, involving techniques such as cloning and overexpression of target enzymes, site directed mutagenesis, enzyme kinetics, substrate synthesis, NMR, Raman and FTIR spectroscopies.

For more information see Peter Tonge's Chemistry Homepage.

Selected Publications

• He, X., Bell, A.F. and Tonge, P.J. (2002) Organic Letters, ASAP. Synthesis and Spectroscopic Studies of Model Red Fluorescent Protein Chromophores.
  
  
• He, X., Bell, A.F. and Tonge, P.J. (2002) J. Phys. Chem., accepted. Isotopic Labeling and Normal Mode Analysis of a Model Green Fluorescent Protein Chromophore.
  
  
• Bell, A.F., Wu, J., Feng, Y. and Tonge, P.J. (2001) Biochemistry, 40, 1725-1733. Involvement of G141 in substrate activation by enoyl-CoA hydratase.
  
  
• Dai, M., Feng, Y. and Tonge, P.J. (2001) J. Am. Chem. Soc., 123, 506-507. Synthesis of crotonyl-oxyCoA: A mechanistic probe of the reaction catalyzed by enoyl-CoA hydratase.
  
  
• Bell, A.F., He, X., Ridge, J.P., Hanson, G.R., McEwan, A.G. and Tonge, P.J. (2001) Biochemistry, 40, 440-448. Active site heterogeneity in DMSO Reductase from Rhodobacter capsulatus revealed by Raman spectroscopy.
  
  
• Pellett, J.D., Sabaj, K.M., Stephens, A.W., Bell, A.F., Wu, J., Tonge, P.J. and Stankovich, M.T. (2000) Biochemistry, 39, 13982-13992. Medium-Chain Acyl-Coenzyme A Dehydrogenase Bound to a Product Analogue, Hexadienoyl-Coenzyme A: Effects on Reduction Potential, pKa, and Polarization.
  
  
• Gawlita, E., Lantz, M., Paneth, P., Bell, A.F., Tonge, P.J. and Anderson, V.E. (2000) J. Am. Chem. Soc., 122, 11660-11669. H-Bonding in Alcohols Is Reflected in the C-H Bond Strength: Variation of C-D Vibrational Frequency and Fractionation Factor.