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.

R01AI043228

1997-09-30

2008-03-31