Toxoplasmosis leads to loss of life and suffering. Better understanding of key metabolic pathways in Toxoplasma gondii, that are not present in humans, provides a basis for development of improved antimicrobial agents. Thus, characterization of the synthesis of chorismate from erythrose 4 phosphate and phosphoenol pyruvate (i.e., the shikimate pathway) and the production of additional aromatic compounds from chorismate in T. gondii have potential importance and practical value. Goals of our project are to further characterize the T. gondii shikimate pathway, determine whether it serves as the basis for production of other aromatic compounds besides folate, its regulation, and to study its stage-associated expression, regulation and subcellular localization. We will further characterize T. gondii chorismate synthase, the seventh enzyme in the shikimate pathway, and deoxy 2-arabino heptulosonic acid 7-phosphate synthase, the first enzyme in the pathway, and their stage associated regulation. Whether the general control activator (GCN 4) and an upstream activator TGACTC have a role in regulation of these enzymes and flux through the pathway will be determined. The phenotype of chorismate synthase knockout parasites and whether novel inhibitors of the shikimate pathway and its branches inhibit T gondii also will be studied. These studies are significant because they will provide fundamental insights into the stage-associated metabolism of T. gondii, its gene regulation, organelle targeting and better characterization of possible novel antimicrobial agent targets in the shikimate pathway and its branches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043228-08
Application #
6882689
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Coyne, Philip Edward
Project Start
1997-09-30
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2008-03-31
Support Year
8
Fiscal Year
2005
Total Cost
$440,385
Indirect Cost
Name
University of Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Hutson, Samuel L; Mui, Ernest; Kinsley, Karen et al. (2010) T. gondii RP promoters & knockdown reveal molecular pathways associated with proliferation and cell-cycle arrest. PLoS One 5:e14057
Mui, Ernest J; Schiehser, Guy A; Milhous, Wilbur K et al. (2008) Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. PLoS Negl Trop Dis 2:e190
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Muench, Stephen P; Prigge, Sean T; Zhu, Liqun et al. (2006) Expression, purification and preliminary crystallographic analysis of the Toxoplasma gondii enoyl reductase. Acta Crystallogr Sect F Struct Biol Cryst Commun 62:604-6
Richards, Thomas A; Dacks, Joel B; Campbell, Samantha A et al. (2006) Evolutionary origins of the eukaryotic shikimate pathway: gene fusions, horizontal gene transfer, and endosymbiotic replacements. Eukaryot Cell 5:1517-31
Henriquez, Fiona L; Richards, Thomas A; Roberts, Fiona et al. (2005) The unusual mitochondrial compartment of Cryptosporidium parvum. Trends Parasitol 21:68-74
Mui, Ernest J; Jacobus, David; Milhous, Wilbur K et al. (2005) Triazine Inhibits Toxoplasma gondii tachyzoites in vitro and in vivo. Antimicrob Agents Chemother 49:3463-7

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