Carol Fierke

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Office Location(s): 4525 Chemistry
Phone: 734.936.2678
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  • About

    Our overall research goal is to understand the mechanisms used by biological catalysts, both proteins and nucleic acids, to achieve high efficiency and stringent specificity. To this end, we probe structure-function relationships in enzymes using a combination of molecular biology techniques, thermodynamic and kinetic methods, and spectroscopic methods.

    We are currently elucidating catalytic mechanisms and essential active site features of several medically important metalloenzymes, including protein farnesyltransferase, UDP-3-O-acyl-GlcNAC deacetylase and histone deacetylase. Inhibitors of these enzymes may be useful for the treatment of cancer and bacterial infections. To understand the role of proteins in modulating the reactivity of bound zinc, we are elucidating detailed structure-function relationships using mutagenesis, kinetic analysis, X-ray crystallography, and NMR spectroscopy. In conjunction with spectral and structural studies, these experiments should enhance our understanding of catalytic zinc sites and our ability to design potent inhibitors for these enzymes. Additionally, we are investigating the biological importance of these posttranslational modifications (prenylation and acetylation). Finally, we are developing methods to identify novel metal sites in proteins to elucidate the yeast “metallome”.

    Our understanding of biological catalysis can be tested by the rational design or redesign of an enzyme. To this end, we are redesigning the affinity and specificity of the metal binding site in human carbonic anhydrase II. These enzyme variants are useful for optimizing a CAII-based fluorescent biosensor to measure and image metal ions in complex mixtures, including plasma, seawater and cells. We are using these imaging techniques to probe zinc homeostasis and zinc signaling in vivo in yeast and E. coli. Additionally, we are using "directed evolution" approaches to obtain altered enzyme function. Currently we use in vitro evolution methods to prepare and identify aldolase variants with novel substrate specificities. Characterization of the structure and function of these novel proteins will provide insights into catalysis, molecular recognition and molecular evolution.

    We also investigate the structure, mechanism and substrate specificity of ribonuclease P (RNase P), a ribonucleoprotein complex that catalyzes the cleavage of tRNA precursors, an essential step in tRNA maturation. We are currently elucidating the structure of the RNase P holoenzyme using crosslinking, site-specific cleavage, crystallography, fluorescence resonance energy transfer and NMR spectroscopy. Furthermore, we are probing the catalytic mechanism of hydrolysis, including the role of magnesium ions, using structure-function relationships and isotope effects. These studies are increasing our understanding of the catalytic modes used by ribozymes in comparison to protein catalysts.

    • Chair-elect, 2005-2006, Biological Chemistry Division, American Chemical Society
    • Program Chair, 2003, ACS Meeting, Biological Chemistry Division
    • Chair; Enzymes, Coenzymes and Metabolic Pathways Gordon Conference Editorial Board, RNA
    • American Heart Association Established Investigator Award
    • David and Lucile Packard Foundation Fellowship
    • American Cancer Society Junior Faculty Research Award
    • National Institutes of Health Postdoctoral Fellow
    • UM Distinguished Faculty Achievement Award - 2005
    • Sarah Power Goddard Award, Univ. Mich. Women’s Caucus - 2005

  • Education
    • Ph.D., Brandeis University
  • Research Areas of Interest
    • Biological Catalysis
    • Molecular Recognition, Directed Evolution
  • Selected Publications:
  • Articles