Studies ongoing in the laboratory are focused on the characterization of proteins with potential therapeutic value in the treatment of the trypanosome and malarial parasites. These parasites cause major pathology throughout the third world and current drug therapy is limited. In the trypanosome parasite our studies focus on polyamine and glutathione biosynthetic enzymes, including characterization of ornithine decarboxylase and S-adenosylmethionine decarboxylase, two enzymes that are essential for polyamine biosynthesis, and g-glutamylcysteine synthetase, which catalyzes the first committed step in glutathione biosynthesis. In the malarial parasite we are studying dihydroorotate dehydrogenase, a key enzyme in the de novo pyrimidine biosynthetic pathway. Although these enzymes are essential to all organisms, differences between the host and parasite metabolism can be exploited to design selectively toxic inhibitors. Our goals are to elucidate the mechanism of catalysis, the basis for substrate and cofactor specificity, and the energetic basis for subunit-subunit interactions for each enzyme. Site-directed mutagenesis, steady-state and presteady-state kinetic analysis and X-ray crystallography are key tools for these analyses. In addition regulation of these enzyme pathways is being studied in the trypanosome parasite utilizing tools such as RNAi and gene over-expression. Projects to exploit these targets for the development of new chemotherapy are also underway.
RESEARCH INTERESTS
Regulation and function of polyamine biosynthesis in African trypanosomes
Pyrimidine biosynthesis as a drug target in malarial parasites
Drug design in protozoan parasites
RECENT PUBLICATIONS
Xiao, Y., McCloskey, D.E. and Phillips, M.A., "Ornithine decarboxylase and spermidine synthase RNAi-mediated gene silencing in Trypanosoma brucei provides insight into the regulation of polyamine biosynthesis" Eukaryotic Cell, 8(5):747-55, 2009
Rodgers, M., Albanesi, J.P. and Phillips, M.A., "Phosphatidylinositol 4-kinase type III beta is required for cytokinesis and golgi formation in Trypanosoma brucei" Eukaryotic Cell, 6:1108-1118, 2007
Deng X, Gujjar R, El Mazouni F, Kaminsky W, Malmquist NA, Goldsmith EJ, Rathod PK, Phillips MA, "Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds." J Biol Chem, in press 2009
Lee, J., Sperandio, V., Frantz, D.E., Longgood, J., Camilli, A., Phillips, M.A. and Michael, A.J., "An alternative polyamine biosynthetic pathway is prevalent in bacteria and essential for biofilm formation in Vibrio cholerae" J. Biol. Chem., 284:9899-907, 2009
Gujjar, R., Marwaha, A., El Mazouni, F., White, J., White, K.L., Creason, S., Shackleford, D.M., Baldwin, J., Charman, W.N., Buckner, F.S., Charman, S., Rathod, P.K. and Phillips, M.A., "Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with anti-malarial activity in mice." J. Med. Chem, 52:1864-72, 2009
SIGNIFICANT PUBLICATIONS
Willert, E.K. and Phillips, M.A., "Regulated expression of an essential allosteric activator of polyamine biosynthesis in African trypanosomes" PLoS pathogens, 4 (10):e1000183, October 2008
Willert, E.K. and Phillips, M.A., "Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog" Proc. Natl. Acad. Sci. USA, 104:8275-8280, 2007
Phillips, M.A., Gujjar, R., Malmquist, N.A., White, J., El Mazouni, F., Baldwin, J. and Rathod, P.K., "Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite" J. Med. Chem., 51:3649-3653, 2008
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