Vivian Cody, Ph.D. 
Hauptman-Woodward Institute – Principal Scientist
Professor of Structural Biology, SUNY-Buffalo

EDUCATION
B.S., Chemistry, University of Michigan, 1965  
Ph.D., Chemistry, University of Cincinnati, 1969

Research Interests:

Structural studies of dihydrofolate reductase enzymes, drug design; DNA beta sliding clamp proteins; GTP cyclohydrolase; Hint proteins; integrins; thyroid binding proteins and deiodinase enzymes

Structure-Function Studies of Pneumocystis jirocevii Dihydrofolate reductase

Pathogens such as Pneumocystis (P), Toxoplasma gondii (Tg) and Mycobacterium avium (Ma) are major causes of opportunistic infection and mortality in immunocompromised patients, particularly those with AIDS.  Pneumocystis organisms represent a large group of species of atypical fungi with universal distribution, each with specificity for a specific mammalian host.  Pneumocystis jirovecii (pj) is the causative agent of Pneumocystis pneumonia (PcP), one of the most frequent and severe opportunistic infections in immunocompromised patients.  Current treatment for PcP combines sulfamethoxazole with trimethoprim, targeting folate biosynthesis.  Major goals of this project are to characterize pjDHFR and its variants in order to design effective inhibitors that have potential as therapeutic agents for the treatment of PcP.  Molecular modeling tools will be used for in silico screening of small molecule libraries to define novel scaffolds for synthesis and testing.  Computational methods such as 3D QSAR will be used to predict the efficacy of known antifolates for binding to pjDHFR.  These data will be used to guide synthesis of novel inhibitors.  Application of novel proteomic tools and homology modeling techniques will be used to determine residues that are critical to enzyme fold and function.  These results will help guide the design of species selective inhibitors.   

Structural Studies of Beta Sliding Clamp

The integrity of genetic information depends on the fidelity of DNA replication and on the efficiency of several DNA repair processes.  Undamaged DNA is normally replicated accurately because of the high nucleotide selectivity of replicative DNA polymerases that duplicate the information content of DNA.  The presence of lesions on DNA can severely impair its replication and result in cell damage.   We have initiated structural studies of mutant forms of the b  subunit of E. coli replicative DNA polymerase III holoenzyme that is the sliding clamp that interacts with the a polymerase subunit to maintain the high processivity of the enzyme.  The b subunit clamp slides on DNA and tethers the catalytic subunits of the polymerase to the template.  These studies will increase our knowledge of how certain cancers develop as a result of DNA replication damage.  The goal of this project is to obtain structural knowledge of E. coli b clamp-DNA polymerases in complex with small peptide inhibitors that can be potential novel antimicrobial agents.  These peptides will correspond to recognition sites from different polymerase clamp-binding domains and help to understand the role of these molecular interactions in replication among this family of polymerases.

Structural Studies of Drosophila GTP-Cyclohydrolase- a Parkinson Disease Model

Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson’s disease.  Environmental toxins such as the herbicide paraquat have been shown to reduce the number of dopaminergic neurons.  Biopterin, the regulating cofactor of tyrosine hydroxylase which catalyzes the first and rate-limiting step in dopamine biosynthesis pathway, is itself synthesized from GTP (guanosine triphosphate) by three enzymatic reactions of which GTP cyclohydrolase is the rate limiting step.  It has been shown that GTP cyclohydrolase gene mutations cause biopterin deficiency that impairs dopamine synthesis.  The Drosophilia system has been shown to be an effective model of the effects of environmental toxin-induced parkinsonism as it is a genetically tractable organism to model gene-environment interactions that could be a beneficial and useful means of identifying genetic risk factors.  By studying the differences between the structural details of drosophila GTP cyclohydrolase with that of human GTP cyclohydrolase, it is anticipated that these data will provide insight into the role of this enzyme in Parkinson’s disease.  The goal of this project is to obtain structural knowledge on a family of GTP cyclohydrolase isoenzymes from Drosophilia that when bound to herbicide or other toxins, cause the Drosophila to elicit Parkinson-like responses of distonia.  Ultimately, this information can be used to better understand the role of this enzyme in the development of Parkinson’s disease.

Selected Publications:
Dr. Cody’s publications include more than 225 papers and chapters, 310 abstracts, and two books

1. Carlson, J.C.T., Kanter, A., Thuduppathy, G.R., Cody, V., McIvor, R.S., and Wagner, C.R., Requirements for the Chemical Induction of Protein Oligomerzation, J. Amer. Chem. Soc., 125, 1501-1507 (2003).
2. Cody, V., Galitsky, N., Luft, J.R., Pangborn, W., and Gangjee, A., Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex With Human Dihdrofolate Reductase, Acta Cryst. D59, 654-661 (2003).
3. Cody, V., Luft, J.R., Pangborn, W., and Gangjee, A., Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanalino Pyridopyrimidine Antifolate Complex with Human Dihdrofolate Reductase, Acta Cryst. D59, 1603-1609 (2003).
4. Cody, V., Structure of the Thyroid Hormone and Thyroid Hormone Binding-Proteins, HOT THYROIDOLOGY, (www.hotthyroidology.com), January, No. 2, 2004.
5. Cody, V., Luft, J.R., Pangborn, W., Gangjee, A. and Queener, S.F., Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry, Acta Cryst. D60, 646-655 (2004).
6. Sikazwe, D.M.N., Li, S., Mardenborough, L., Cody, V., Roth, B.L. and Ablordeppey, S.Y., Haloperidol: Towards Further Understanding of the Structural Contributions of its Pharmacoloric Elements at D2-like Receptors, Bioorganic & Med. Chem. Let., 14, 5739-5742 (2004).
7. Cody, V., Luft, J.R., and Pangborn, W., Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH, Acta Cryst. D61, 147-155 (2005).
8. Cody, V., Chisum, K., Pope, C., and Queener, S.F., Purification and Characterization of Human-derived Pneumocystis jirovecii Dihydrofolate Reductase Expressed in Sf21 Insect Cells and in Escherichia coli, Protein Purification and Expression, 40: 417-423 (2005).
9. Davis, P.J., Davis, F.B. and Cody, V., Membrane Receptors Mediating Thyroid Hormone Action, Trends in Endocrin. Metabol., 16: 429-435 (2005).
   
10. Cody, V., Pace, J., Chisum, K., New Insights into Dihydrofolate Reductase (DHFR) Interactions: Analysis of Pneumocystis carinii and Mouse DHFR Complexes with NADPH and Two Highly Potent 5-(w-Carboxy(alkyloxy) Trimethoprim Derivatives Reveals Conformational Correlations with Activity and Novel Parallel Ring Stacking Interactions, Proteins, Structure, Function and Bioinformatics, submitted.