faculty

Chair and Professor of Chemistry
Jerome and Isabella Karle Collegiate Professor of Chemistry
Ph. D., Brandeis University

Biological Catalysis; Molecular Recognition, Enzyme Engineering

Phone: (734) 936-2678
E-mail: fierke@umich.edu

Research Group

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.

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 ions are proposed to play important signaling roles in vivo, especially in neurobiology, which can investigated using novel imaging methods. Additionally, we are using "directed evolution" approaches to prepare and identify aldolase variants with novel substrate specificities. These aldolase variants will be used to improve the utility of these enzymes as biocatalysts for organic synthetic reactions. Characterization of the structure and function of these novel proteins will provide insights into catalysis, molecular recognition and molecular evolution.

AWARDS

• Chair, Biological Chemistry Division, American Chemical Society
• 2005 Distinguished Faculty Achievement Award
• 2005 Power Award
• 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

REPRESENTATIVE PUBLICATIONS

1. Frederickson, C. J., Giblin, L. J., Krezel, A., McAdoo, D. J., Mueller, R. A., Zeng, Y., Balaji, R. V., Masalha, R., Thompson, R. B., Fierke, C. A., Sarvey, J. M, de Valdenebro, M., Prough, D. S., Zornow, M. H., (2006) Concentrations of Extracellular Free Zinc  (pZn) in the Central Nervous System of Man, Rat and Rabbit During Anesthesia, Ischemia and Reperfusion, Exp. Neurol., in press.
2. Xiao, S., Hsieh, J., Nugent, R. L., Coughlin, D. J., Fierke, C. A. and Engelke, D. R. (2006) Functional characterization of the conserved amino acids in Pop1p, the largest common protein subunit of yeast RNases P and MRP, RNA, in press.
3. Gantt, S. L., Gattis, S. G. and Fierke, C. A. (2006) Catalytic Activity and Inhibition of Human Histone Deacetylase 8 Is Dependent on the Identity of the Active Site Metal Ion, Biochemistry, in press.
4. Bozym, R. A., Thompson, R. B., Stoddard, A. K. and Fierke, C. A. (2006) Measuring picomolar intracellular exchangeable zinc in PC-12 cells using a ratiometric fluorescence biosensor, ACS Chemical Biology1, 103-111.
5. Fullerton, S. W. B., Griffiths, J. S., Merkel, A. B., Cheriyan, M., Wymer, N. J., Hutchins, M. J., Fierke, C. A., Toone, E. J. and Naismaith, J. H. (2006) Mechanism of the Class I KDPG aldolases, Bioorg. Med. Chem. Lett.14, 3002-3010.
6. Sumner, J. P., Westerberg, N. M., Stoddard, A. K., Hurst, T. K., Cramer, M., Thompson, R. B., Fierke, C. A. and Kopelman, R. (2006) DsRed as a Highly Sensitive, Selective and Reversible Fluorescence-Based Bioensor for Both Cu+ and Cu2+ Ions, Biosens. Bioelect. 15, 1302-1208.