College of Arts & Sciences

Dabney Dixon

Dabney White Dixon Professor Bioorganic Chemistry A.B. (1971):  Brown University Ph.D. (1976) :  Massachusetts Institute of Technology Postdoctoral Fellowship (1977-1978) :  University of California, San Diego Dr. Dabney White Dixon Department of Chemistry Georgia State University P.O. Box 3965 Atlanta, Georgia 30302-3965 Department Office Phone: 404-413-5500 Phone:  404-413-5508 Lab Phone:  404-413-5548 Fax:  404-413-5505 Office:  556 Natural Science Center Email:  ddixon@gsu.edu

Heme Uptake by Pathogenic Bacteria.  A number of pathogenic bacteria grow with hemin as their major or sole source of iron.

In collaboration with Dr. Caroline Genco  (Boston University) we have probed heme uptake by the outer membrane hemoglobin/heme receptor HmuR in Porphyromonas gingivalis.  Relative binding affinities of a series of porphyrins, with various central metal atoms, indicated that the active site has a histidine.  P. gingivalis has two proteases which can cleave heme-containing proteins, gingipain K (Kgp), a lysine-specific cysteine protease, and gingipain R1 (HRgpA), one of two arginine-specific cysteine proteases.  Kgp and HRgpA were demonstrated to bind various porphyrins and metalloporphyrins with affinities similar to hemin, indicating that binding of Kgp and HRgpA to these porphyrins doesnot require a metal present within the porphyrin ring.  This work continued with measurement of the heme binding.

Current work in our laboratory involves one of the ABC transporters in Streptococcus pyogenes.  This work, in collaboration with Dr. Zehava Eichenbaum (Georgia State University), focuses on the heme binding protein (HBP).  Spectroscopic characterization of the heme site and the studies of the thermodynamics of denaturation are underway.

Metalloporphyrins as Anticancer Agents.   The goal of cancer radiotherapy is to cause lethal damage to the malignant cells.  DNA is the critical target, but radiation damages all cellular components.  It would be desirable to have a sensitizing agent which targets DNA to enhance damage specifically at the DNA.  One approach is to bind specific heavy atoms to the DNA.  These can absorb the radiation and convert it to low energy electrons via a mechanism termed the Auger process.  The expectation is that the electrons released will produce substantial local damage in the DNA, which will be difficult for the cellular enzymes to repair.  Our work involves the synthesis of cationic porphyrins bearing heavy atoms.  Biological studies have been done in collaboration with Dr. Brenda Laster  (Ben Gurion University of the Negev, Israel).  Initial work involved chemical, biochemical and in vivo studies on PtTMPyP4.  Current work involves the synthesis and study of a series of indium, molybdenum, palladium, ruthenium and zirconium cationic porphyrins.

Threading Intercalators.  Intercalators are flat molecules that slide between the base pairs of duplex DNA.  Studies during the 1980s showed that intercalators bearing two side chains could form intercalative complexes with DNA in which one side chain lies in the major groove and the other side chain lies in the minor groove.  Because it was topologically necessary for the side chains to "thread" through the DNA complex to achieve this geometry, these molecules were termed "threading intercalators."  To date, we have synthesized more than 50 compounds based on the naphthalene diimide and anthraquinone ring systems.  Our kinetic studies, in collaboration with Dr. W. David Wilson (Georgia State University) show that molecules as long as 18  and with diameters as large as 8.5  can thread through duplex DNA.  Detailed studies of the association and dissociation rate constants reveal that the association rate is a function of the size of the side chain, but that the dissociation rate has little dependence on the size of the side chain.  A recent study on a series of anthraquinones established the important of the length of the chain in controlling DNA binding.  Further work in this area involves studies of the kinetics of intercalators with only one side chain, to determine if the observed size effect is unique to threading intercalators or general.  Our series of compounds, with side chains graded both in size and hydrophobicity, provides an outstanding series with which to study the details of DNA binding.

Publications 2000 - present

Weiner, S. W., Cerpovitz, P. F., Dixon, D. W., Harden, D. B., Hobbs, D. S., and Gosnell, D. L. (2000).  RasMol and Mage in the undergraduate biochemistry curriculum.  J. Chem. Educ. 77, 401-406.

Genco, C. A. and Dixon, D. W. (2001).  Emerging strategies in microbial heme capture.  Mol. Microbiol. 39, 1-11.

Olczak, T., Dixon, D. W., and Genco, C. A. (2001).  Binding specificity of the Porphyromonas gingivalis hemoglobin and heme receptor HmuR, and its cooperation with gingipain K, a putative hemophore.  J. Bacteriol. 183, 5599-5608.

Vzorov, A. N., Dixon, D. W., Trommel, J. S., Marzilli, L. G., and Compans, R. W. (2002).  Inactivation of human immunodeficiency virus type 1 by porphyrins.  Antimicrob. Agents Chemother. 46, 3917-3925.

Chen-Collins, A. R. M., Dixon, D. W., Vzorov, A. N., Marzilli, L. G., and Compans, R. W. (2003).  Prevention of poxvirus infection by tetrapyrroles.  BMC Infect. Dis. 3, 9.

Vzorov, A. N., Marzilli, L. G., Compans, R. W., and Dixon, D. W. (2003).  Prevention of HIV-1 infection by phthalocyanines.  Antiviral Res. 59, 99-109.

Dixon, D. W., Gill, A. F., and Sook, B. R. (2004).  Characterization of sulfonated phthalocyanines by mass spectrometry and capillary electrophoresis.  J. Porph. Phthalo. 8, 1300-1310.

McKnight, R. E., Zhang, J., and Dixon, D. W. (2004).  Binding of a homologous series of anthraquinones to DNA.  Bioorg. Med. Chem. Lett. 14, 401-404.

Dixon, D. W., Gill, A. F., Giribabu, L., Vzorov, A. N., Alam, A. B., and Compans, R. W. (2005).  Sulfonated naphthyl porphyrins as agents against HIV.  J. Inorg. Biochem. 99, 813-821.

Liu, X. Y., Olczak, T., Guo, H. C., Dixon, D. W., and Genco, C. A. (2006).  Identification of amino acid residues involved in heme binding and hemoprotein utilization in the Porphyromonas gingivalis heme receptor HmuR.  Infect. Immun. 74, 1222-1232.

Vzorov, A. N., Bozja, J., Dixon, D. W., Marzilli, L. G., and Compans, R. W. (2007).  Parameters of inhibition of HIV-1 infection by anionic microbicides.  Antiviral Res. 73, 60-68.

Dixon, D. W. Duplex DNA binding of nonplanar metal chelates of cationic porphyrins, in "Synthetic and Biophysical Studies of DNA Binding Compounds" Singpost, in press.