Faculty

photo by d.c. goings

Carol A. Fierke

Jerome and Isabella Karle Collegiate Professor of Chemistry
Chair, Chemistry
Professor of Biological Chemistry

Ph.D., Brandeis University
Postdoctoral Fellow, Pennsylvania State University

Research Focus: Enzyme Mechanisms and Inhibition; Protein Engineering

Phone: 734.936.2678
E-mail: fierke@umich.edu

Our goal is to understand the mechanisms used by biological catalysts, both proteins and nucleic acids, to achieve high efficiency, stringent specificity and rigorous control. We are elucidating catalytic mechanisms, essential active site features, specificity and inhibition of metalloenzymes and ribozymes, including protein farnesyltransferase, UDP-3-O-acyl-GlcNAC deacetylase, histone deacetylase, protein palmitoyltransferase and ribonuclease P. These studies should enhance the design of potent inhibitors of these enzymes useful for the treatment of cancer or bacterial infections. In particular, we are investigating the role of proteins in modulating the reactivity of bound Zn(II) or Fe(II) and developing specific inhibitors that coordinate the active site metal. We are also investigating the molecular recognition of substrates leading to the in vivo specificity of protein prenylation and acetylation using peptide and small molecule libraries. Finally, we are elucidating the role of metal ions and protein/RNA interactions as well as comparing protein and RNA-catalyzed nucleases in ribonuclease P, either the bacterial ribozyme/protein complex or the organellar protein-only enzyme using a variety of biophysical techniques, including X-crystallography and NMR and time-resolved fluorescence spectroscopy.  Additionally, we are screening for inhibitors and activators of these enzymes. These studies are increasing our understanding of the pathways and regulation of tRNA processing in bacterial and eukaryotic cells with implications for mitochondrial dysfunction diseases.

We are testing our understanding of biological catalysis by the rational design or redesign of an enzyme. To this end, we are redesigning the zinc metalloenzyme, carbonic anhydrase II, to optimize a fluorescent biosensor for measuring and imaging metal ions in complex biological mixtures. Zinc and copper ions are proposed to play important biological roles, especially in neurobiology, which can investigated using novel imaging methods.

Fierke Research Group

 

Awards

2012
Repligen Award in Chemistry of Biological Processes, Biological Chemistry Division, American Chemical Society
2011
Rackham Distinguished Graduate Mentoring Award
2009
Harold R. Johnson Diversity Service Award
2007-2008
Chair, Biological Chemistry Division, American Chemical Society
2006
Fellow of the American Association for the Advancement of Science
2005
UM Distinguished Faculty Achievement Award
2005
Sarah Power Goddard Award, Univ. Mich. Women’s Caucus
2003
Program Chair for ACS Conference, Biological Chemistry Division
2001
UM Faculty Achievement Award
1997
Chair; Enzymes, Coenzymes and Metabolic Pathways Gordon Conference
1992-1997
American Heart Association Established Investigator Award
1990-1995
David and Lucile Packard Foundation Fellowship
1989-1991
American Cancer Society Junior Faculty Research Award
1984-1987
NIH Postdoctoral Fellowship

 

Representative Publications

  1. Wang, C., Hurst, T.K., Thompson, R.B. and Fierke, C.A. (2011) Genetically encoded ratiometric biosensors to measure intracellular exchangeable zinc in Escherichia coli, J. Biomed. Optics 16, 087011.

  2. Koutmou, K.S., Day-Storms, J.J., and Fierke, C.A. (2011) The RNR motif of B, subtilis RNase P protein interacts with both PRNA and pre-tRNA to stabilize an active conformer, RNA 17, 1225-35.

  3. Cole, K. E. Gattis, S. G., Angell, H. D., Fierke, C. A., and Christianson, D. W. (2011) Structure of the Metal-Dependent Deacetylase LpxC from Yersinia enterocolitica Complexed with the Potent Inhibitor CHIR090, Biochemistry 50, 258–265.

  4. Gattis, S. G., Hernick, M. and Fierke, C. A. (2010) The active site metal ion in UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) switches between Fe(II) and Zn(II) depending on cellular conditions, J. Biol. Chem. 285, 33788-96. 

  5. Koutmou, K.S., Casiano-Negroni, A., Getz, M.M., Pazicni, S., Andrews, A.J., Penner-Hahn, J.E., Al-Hashimi, H.M. and Fierke, C.A. (2010) NMR and XAS reveal an inner-sphere metal binding site in the P4 helix of the metallo-ribozyme ribonuclease P, Proc. Natl. Acad. Sci. U.S.A. 107, 2479-84.

  6. Hougland, J. L., Hicks, K. A., Hartman, H. L., Kelly, R. A., Watt, T. J., and Fierke, C. A. (2010) Identification of novel peptide substrates for protein farnesyltransferase reveals two substrate classes with distinct sequence selectivities, J. Mol. Biol. 95, 176-90.

  7. Gantt, S.L., Joseph, C.G. and Fierke, C.A. (2010) Activation and inhibition of histone deacetylase 8 by monovalent cations, J. Biol. Chem. 285, 6036-43.

 

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