Department of Chemistry
A headshot

Carol Fierke
Provost & Executive VP
Professor

Other Affiliations
  • Biochemistry
Contact
Department of Chemistry
Texas A&M University
College Station, TX 77843-3255

P: 979-845-4016
cafierke@tamu.edu
Web Sites Areas & Divisions

Current Activities

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. We are particularly focussed on the mechanism of medically important metalloenzymes. We are investigating the catalytic mechanism and specificity of protein farnesyltransferase and protein geranylgeranyltransferase I. These enzymes catalyze the addition of a prenyl group onto a C-terminal cysteine on a variety of substrates involved in signal transduction. Compounds that inhibit FTase are being investigated as possible antitumor agents. A second enzyme, UDP-3-O-acyl-GlcNAC deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the pathway to form Lipid A, a crucial component of the outer membrane of gram negative bacteria. Inhibitors of this enzyme have antibacterial activity. To further the development of novel inhibitors we are elucidating detailed structure-function relationships in the active site of these proteins using mutagenesis, kinetic analysis, X-ray crystallography, and spectroscopic studies. Additionally, we have begun mechanistic studies of two related enzymes, histone deacetylase and protein palmitoyltransferase. For all of the metalloenzymes, a key question is the identify of the in vivo metal ion and whether metal switching is an important regulatory mechanism. Finally, we are developing methods for high-throughput screens of protein-bound transition metal ions for use in assaying all of the proteins in the yeast proteome to identify the yeast "metallome".

We also investigating the catalytic modes of ribozymes compared to proteins by determining the structure and mechanism of ribonuclease P (RNase P), a ribonucleoprotein complex that catalyzes the cleavage of tRNA precursors. We have demonstrated that the protein component enhances the catalytic efficiency by interacting with both P RNA and pre-tRNA. In the future, we will elucidate the structure of the holoenzyme using fluorescence resonance energy transfer, crystallography and spectroscopy. Finally, we will investigate the mechanism of yeast RNase P (in collaboration with Dr. D. Engelke) which contains one RNA and multiple protein subunits and purify, clone and characterize the RNase P from mammalian mitochondria which is proposed to be a protein catalyst.

Zinc, iron and copper ions are proposed to play important biological roles, especially in neurobiology, as well as playing important roles in the development of a number of diseases, including diabetes. Furthermore, a number of metals, such as lead and cadmium, are toxic. We are investigating the mechanisms of metal homeostasis and metal toxicity using a combination of biochemistry, genetics and imaging. To this end, we are redesigning the zinc metalloenzyme, carbonic anhydrase II, to optimize a fluorescent biosensor for measuring and imaging "readily exchangeable" metal ions in complex biological mixtures, such as cells, plasma and sea water and are developing similar sensors to measure cellular iron concentrations. Additionally, we are using X-ray fluorescence microprobe imaging to image total metal ions in wild-type and mutant yeast cells. These imaging methods are being used to understand basic mechanisms of metal homeostasis. Finally, we are examining the metal content and the mechanisms of metal insertion into proteins in vivo using biochemistry and analysis of libraries of deletion mutants. These studies should lead to a better understanding of the functions and regulation of biological transition metals.

Educational Background

B. A. – Chemistry, 1978, Carleton College

Ph. D. – Biochemistry, 1984, Brandeis University

Postdocoral – 1984-1987, Pennsylvania State University

Awards & Recognition

  • 1992-1997 Am. Heart Assoc. Established Investigator Award
  • 2001 Faculty Recognition Award
  • 2003 Jerome and Isabella Karle Collegiate Prof. of Chemistry
  • 2005 Sarah Power Goddard Award
  • 2005 Distinguished Faculty Achievement Award
  • 2007 AAAS Fellow
  • 2012 Repligen Award

Selected Publications

  • Liu X, Chen Y, Fierke CA. "Inner-Sphere Coordination of Divalent Metal Ion with Nucleobase in Catalytic RNA. J Am Chem Soc., 2017, 139 (48), 17457-17463.
  • Castañeda CA, Wolfson NA, Leng KR, Kuo YM, Andrews AJ, Fierke CA. HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides." J Biol Chem., 2017, 292 (52), 21568-21577.
  • Lopez JE, Haynes SE, Majmudar JD, Martin BR, Fierke CA. "HDAC8 Substrates Identified by Genetically Encoded Active Site Photocrosslinking." J Am Chem Soc., 2017, 139 (45), 16222-16227.
  • Niu S, Kim BC, Fierke CA, Ruotolo BT. "Ion Mobility-Mass Spectrometry Reveals Evidence of Specific Complex Formation between Human Histone Deacetylase 8 and Poly-r(C)-binding Protein 1." Int J Mass Spectrom., 2017, 420, 9-15.
  • Castañeda CA, Lopez JE, Joseph CG, Scholle MD, Mrksich M, Fierke CA. "Active Site Metal Identity Alters Histone Deacetylase 8 Substrate Selectivity: A Potential Novel Regulatory Mechanism." Biochemistry, 2017, 56 (42), 5663-5670.