Investigating Trypanosoma brucei's unusual inositol metabolism. (360G-Wellcome-093228_Z_10_Z)

In this proposal we will use multi-disciplinary approaches to investigate myo-inositol phospholipid biosynthesis and catabolism in Trypanosoma brucei. Emphasis will be on extending our understanding of myo-inositol metabolic pathways both in bloodstream and procyclic form T.brucei, allowing us to genetically and chemically validated the biosynthetic steps as potential drug targets. This project aims to answer four key questions: Are T.brucei auxotrophic for myo-inositol? Is de novo synthesised myo-inositol central to other cellular processes? Does the catabolism of inositol phosphoceramide in the procylic form, determine carbon source usage? Are T.brucei vulnerable to inhibition of de novo myo-inositol synthesis? Consequently our key goals are to: understand the uptake and subsequent usage of the separate pools of myo-inositol validate enzymes involved in myo-inositol uptake and metabolism as drug targets understand the role of inosit ol-phospholipid catabolism. develop and carry out high-throughput assays for enzymes involved in myo-inositol metabolism. obtain kinetic, substrate specificity and structural information about the enzymes involved in inositol metabolism, thus allowing construction of structure-activity relationships to facilitate the design of potent parasite-specific inhibitors.