Professor Carol Ann Fierke is an authority on enzyme structure-mechanism relationships, tRNA processing, and on the mechanisms of metal homeostasis in cells. She applies basic principles of enzyme action to a wide range of problems with both medical and industrial applications. Professor Fierke came to the U of M in 1999 as a Professor of Chemistry, a Professor of Biological Chemistry at the Medical School, and as an Associate Faculty member in the Biophysics Research Division. In 2003 she was named the Jerome and Isabella Karle Collegiate Professor of Chemistry and she became the Chair of the Chemistry Department in 2005. She has been active in the NSF-funded ADVANCE project, including serving as a member of the STRIDE committee since 2002. She has received recognition for her research (i.e. Repligen Award and AAAS Fellow), her mentorship (i.e. Rackham Distinguished Graduate Mentoring Award, Harold R. Johnson Diversity Award, Sarah Power Goddard Award) and her leadership (i.e. chair of the Biological Chemistry Division of the ACS and chair of the Chemistry Department). From 1987 to 1999 she taught and conducted research at the Duke University Medical School in North Carolina. Carol earned her B.A. at Minnesota’s Carleton College in 1978 and her doctorate in biochemistry from Brandeis University in Massachusetts in 1984.
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. An understanding of these principles is essential for: understanding biological catalysis in vivo, designing novel inhibitors for therapeutic use, and developing novel catalysts for a variety of tasks, including organic synthesis and quantitative analysis of complex mixtures. We are elucidating catalytic mechanisms and essential active site features of metalloenzymes and ribozymes, including protein farnesyltransferase, UDP-3-O-acyl-GlcNAC deacetylase, histone deacetylase and ribonuclease P. These studies should enhance our ability to design 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) and developing methods for identifying novel metal sites in proteins. We are also investigating the biological importance of protein prenylation and acetylation. Finally, we are elucidating the role of metal ions and protein/RNA interactions in ribonuclease P, a ribozyme/protein complex. These studies are increasing our understanding of the catalytic modes used by ribozymes in comparison to protein catalysts.
Wang, D., Hosteen, O. and Fierke, C. A. (2012) ZntR-mediated transcription of zntA responds to nanomolar intracellular free zinc, J. Inorg. Biochem. 11, 173-81. PMCID: PMC3408962
Wang, Y., Liu, X., Schneider, B., Zverina, E. A., Russ, K., Wijeyesakere, S. J., Fierke, C. A., Richardson, R. J. and Philbert, M. A. (2012) Mixed Inhibition of Adenosine Deaminase Activity by 1,3-Dinitrobenzene: A Model for Understanding Cell-Selective Neurotoxicity in Chemically Induced Energy Deprivation Syndromes in Brain, Toxicol Sci.125, 509-21. PMCID: PMC3262860
McCranor, B. J., Bozym, R.A., Vitolo, M.I., Fierke, C.A., Bambrick, L., Polster, B. M., Fiskum, G. and Thompson, R.B. (2012) Quantitative imaging of mitochondrial and cytosolic free zinc levels in an in vitro model of ischemia/reperfusion, J Bioenerg Biomembr. 44 253 - 263. PMID 22430627
Cheriyan, M., Toone E. J. and Fierke, C. A. (2012) Improving upon Nature: Active Site Remodeling Produces Highly Efficient Aldolase Activity toward Hydrophobic Electrophilic Substrates. Biochemistry 51, 1658-68. PMCID: PMC3315183
Yang, Y., Wang, B., Ucisik, M. N., Cui, G., Fierke, C. A. and Merz, K. M. Jr. (2012) Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS. J. Am. Chem. Soc. 134, 820-3. PMCID: PMC3277741
Howard, M.J., Lim, W.H, Fierke, C.A. and Koutmos, M. (2012) Mitochondrial Ribonuclease P Structure Provides Insight into the Evolution of Catalytic Strategies for Precursor-tRNA Processing, Proc. Natl. Acad. Sci. U.S.A. 109, 16149-54.
Subramanian, T., Pais, J.E., Liu, S., Troutman, J., Suzuki, Y., Subramanian, K., Fierke, C.A., Andres, D., Spielmann, H. P. (2012) Farnesyl Diphosphate Analogues with Aryl Moieties are Efficient Alternate Substrates for Protein Farnesyltransferase, Biochemistry, in press.
Hougland, J.L, Gangopadhyay, S. A. and Fierke, C. A. (2012) Expansion of Protein Farnesyltransferase Specificity Using “Tunable” Active Site Interactions: Development of Bioengineered Prenylation Pathways, J. Biol. Chem. 287, 38090-100.
Wolfson, N.A., Pitcairn, C.A. and Fierke, C. A. (2012) HDAC8 Substrates: Histones and Beyond, Biopolymers, in press.
Zverina, E.A., Lamphear, C.L., Wright, E.N. and Fierke, C. A. (2012) Recent Advances in Protein Prenyltransferases: Substrate Identification, Regulation, and Disease Interventions, Curr. Op. Chem. Biol., in press.