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Biochemistry Department - Primary Faculty

Michael E. Harris, Ph.D.

Associate Professor of Biochemistry, Case Western Reserve University
Director, Cell and Molecular Biology Training Program

Education

  • Ph.D.: University of Alabama at Birmingham, Birmingham, AL
  • Postdoc: Indiana University, Bloomington, IN

Research Interests

The overall goal of our laboratory is to understand the fundamental chemical and physical properties of RNA and proteins, and how these properties determine their roles in Biology, in particular their ability to function as catalysts. Although there have been explosive advances in understanding the structures and biological roles of RNA and protein enzymes, understanding the mechanisms by which they function at a chemical level has progressed less rapidly. This is due in part to the complexity of the problem, but also to the lack of experimental tools to reveal chemical detail. Knowledge of the chemical and physical basis of enzyme catalysis is fundamental to the design of non-biological catalysts with unique properties and the design of inhibitors as therapeutics.

The primary focus of our enzyme studies is on phosphoryl transfer, perhaps the most important enzyme catalyzed reaction in biology given its central roles in energy metabolism, storage and transfer of information contained in nucleic acids, and signal transduction. To better understand the kinds of chemical interactions that provide transition state stabilization we are analyzing the mechanisms of non-enzymatic catalyst in solution to isolate and characterize individual catalytic modes. In parallel, we are engaged in similarly detailed studies of RNA and protein enzyme mechanism to dissect the roles of individual active site residues in transition state stabilization and specificity. We are particularly interested is the role of divalent metal ions in catalysis as these are common cofactors in the active sites of both RNA and protein enzymes.

In describing RNA catalysts we are also interested in understanding the roles of metal ions play in folding the RNA polymer into its native, catalytically active structure. A key feature of our approach is the application of new biophysical and spectroscopic methods to quantify the association of metal ions with RNA and to characterize the kinds of chemical interactions that metal ions make with RNA functional groups. In doing so we are defining the chemical and biophysical linkages between RNA structure and function. Together with our enzyme studies we hope the new information we gain will provide insight into the capabilities and limitations of RNA catalysts, and help resolve the properties or macromolecules that are fundamental to biological catalysts.

Selected References

  • Dissanayake T., Swails J. M., Harris M. E., Roitberg A. E., and York D. M.
    “Interpretation of pH-activity profiles for acid-base catalysis from molecular simulations”
    Biochemistry 54 (6): 1307-13 (2015). Read article in PubMedCentral
  • Harris M. E., Piccirilli J. A., and York D. M.
    “Integration of kinetic isotope effect analyses to elucidate ribonuclease mechanism”
    Biochim Biophys Acta : (2015).
  • Kellerman D. L., Simmons K. S., Pedraza M., Piccirilli J. A., York D. M., and Harris M. E.
    “Determination of hepatitis delta virus ribozyme N(-1) nucleobase and functional group specificity using internal competition kinetics”
    Anal Biochem 483: 12-20 (2015). Read article in PubMedCentral
  • Mojica M. F., Mahler S. G., Bethel C. R., Taracila M. A., Kosmopoulou M., Papp-Wallace K. M., Llarrull L. I., Wilson B. M., Marshall S. H., Wallace C. J., Villegas M. V., Harris M. E., Vila A. J., Spencer J., and Bonomo R. A.
    “Exploring the Role of Residue 228 in Substrate and Inhibitor Recognition by VIM Metallo-beta-lactamases”
    Biochemistry 54 (20): 3183-96 (2015).
  • Chen H., Giese T. J., Huang M., Wong K. Y., Harris M. E., and York D. M.
    “Mechanistic insights into RNA transphosphorylation from kinetic isotope effects and linear free energy relationships of model reactions”
    Chemistry 20 (44): 14336-43 (2014). Read article in PubMedCentral
  • Kellerman D. L., York D. M., Piccirilli J. A., and Harris M. E.
    “Altered (transition) states: mechanisms of solution and enzyme catalyzed RNA 2'-O-transphosphorylation”
    Curr Opin Chem Biol 21: 96-102 (2014). Read article in PubMedCentral
  • Lin H. C., Yandek L. E., Gjermeni I., and Harris M. E.
    “Determination of relative rate constants for in vitro RNA processing reactions by internal competition”
    Anal Biochem 467: 54-61 (2014). Read article in PubMedCentral
  • Corriveau M., Mullins M. R., Baus D., Harris M. E., and Taylor D. J.
    “Coordinated interactions of multiple POT1-TPP1 proteins with telomere DNA”
    J Biol Chem 288 (23): 16361-70 (2013). Read article in PubMedCentral
  • Gu H., Zhang S., Wong K. Y., Radak B. K., Dissanayake T., Kellerman D. L., Dai Q., Miyagi M., Anderson V. E., York D. M., Piccirilli J. A., and Harris M. E.
    “Experimental and computational analysis of the transition state for ribonuclease A-catalyzed RNA 2'-O-transphosphorylation”
    Proc Natl Acad Sci U S A 110 (32): 13002-7 (2013). Read article in PubMedCentral
  • Guenther U. P., Yandek L. E., Niland C. N., Campbell F. E., Anderson D., Anderson V. E., Harris M. E., and Jankowsky E.
    “Hidden specificity in an apparently nonspecific RNA-binding protein”
    Nature 502 (7471): 385-8 (2013). Read article in PubMedCentral
  • Radak B. K., Harris M. E., and York D. M.
    “Molecular simulations of RNA 2'-O-transesterification reaction models in solution”
    J Phys Chem B 117 (1): 94-103 (2013). Read article in PubMedCentral
  • Radak B. K., Harris M. E., and York D. M.
    “Molecular simulations of RNA 2'-O-transesterification reaction models in solution”
    J Phys Chem B 117 (1): 94-103 (2013). Read article in PubMedCentral
  • Yandek L. E., Lin H. C., and Harris M. E.
    “Alternative substrate kinetics of Escherichia coli ribonuclease P: determination of relative rate constants by internal competition”
    J Biol Chem 288 (12): 8342-54 (2013). Read article in PubMedCentral
  • Levitt P. S., Papp-Wallace K. M., Taracila M. A., Hujer A. M., Winkler M. L., Smith K. M., Xu Y., Harris M. E., and Bonomo R. A.
    “Exploring the role of a conserved class A residue in the Omega-Loop of KPC-2 beta-lactamase: a mechanism for ceftazidime hydrolysis”
    J Biol Chem 287 (38): 31783-93 (2012). Read article in PubMedCentral

 

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