Mary Kay Pflum Title Associate Professor Division Organic (Biological Chemistry) Education B.A. Carleton College, 1992 Ph.D. Yale University, 1999 NIH Postdoctoral Fellow, Harvard University, 1999-2001 Office Chem 323 Phone (313)577-1515 E-Mail Group http://chem.wayne.edu/pflumgroup

Research in the Pflum group integrates organic chemistry with biology to examine pertinent biological and medicinal issues. We are particularly interested in understanding how the expression of the estimated 30,000 genes in our chromosomes is regulated. The transcription and translation of these genes into their encoded protein is a controlled interplay of macromolecular interactions, including protein-protein and protein-DNA complexes. Alteration of only one of these interactions could lead to the unregulated production of proteins that cause illness or death. Our goal is to characterize and ultimately manipulate the proteins and protein modifications governing normal cellular function and disease development using tools from synthetic organic chemistry, biochemistry, and cell biology.

Our group focuses on three main projects:

I. Histone Deacetylase Proteins
Histone Deacetylase (HDAC) proteins are transcription factors that influence cell proliferation, differentiation, and cancer formation. In fact, several small molecule inhibitors of HDAC proteins are in clinical trials to treat cancer (Figure 1). Unfortunately, the known drugs typically interact with eleven human HDAC proteins nonspecifically. To overcome the limitation of available drugs, we are developing a strategy where proteins engineered to bind small molecules with altered affinity are used to dissect the functions of individual family members. Our goal is to expand the utility of small molecule-based HDAC characterization in cancer research by combining synthetic organic chemistry and cell biology.

II. bZIP Proteins
Basic region-leucine zipper (bZIP) proteins are a family of transcriptional activator proteins that employ a dimer of a-helices to bind the major groove of DNA. Our lab is interested in characterizing the DNA binding and dimerization preferences of bZIP proteins to better understand their role in fundamental events as diverse as circadian rhythms and hepatitis B viral infection. This work ultimately will be extended to rationally design disrupters or stabilizers of protein-protein interactions using techniques from biochemistry and cell biology.

III. Post-translational Modifications
Protein phosphorylation is a ubiquitous post-translational modification that can profoundly influence protein function. However, identifying the position of phosphorylated amino acids and the physiological significance of phosphorylation has been challenging due to the paucity of available tools. We are interested in developing facile chemical methods to characterize post-translational modifications of proteins, including HDAC and bZIP proteins. One of our projects explores methods to modify and enrich phosphorylated proteins from protein or peptide mixtures. These studies will pioneer advances in phosphoproteomics research by coupling synthetic organic methods with biochemistry.

Fig. 1. Structures of select HDAC inhibitors, A) trichostatin (TSA), B) suberoylanilide hydroxamic acid (SAHA).



REPRESENTATIVE PUBLICATIONS

Cyclic AMP Response Element-Binding Protein (CREB) and CAAT/Enhancer-Binding Protein beta (C/EBPbeta) Bind Chimeric DNA Sites with High Affinity, J. Flammer, K. Popova, and M. K. H. Pflum Biochemistry, 2006, 45, 9615-23.

H-NS gives invading DNA the silent treatment M. K. H. Pflum, Nature Chem. Biol., 2006, 2, 400-401.

Miniature DNA Binding Proteins. M. K. H. Pflum, Chemistry and Biology, 2004, 11, 3-4

Histone Deacetylase 1 Phosphorylation Promotes Enzymatic Activity and Complex Formation. M. K. H. Pflum, J. K. Tong, W. S. Lane, S. L. Schreiber, Journal of Biological Chemistry, 2001, 50, 47733-47741.