Phosphatidic Acid Biosynthesis and Signalling in Eukaryotes

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Phosphatidic acid is not only the precursor for the biosynthesis of all glycerolipids but is also a key signaling lipid. The mechanisms of the regulation of phosphatidic acid biosynthesis, the rate limiting glycerol 3-phosphate acyltransferase (GPAT) step, as well as lipid metabolic pathway partitioning, are just emerging. Overcoming this gap in knowledge is a central issue in cell biology. Exploiting the molecular and genetic advantages of Saccharomyces cerevisiae, we plan to identify molecular events that regulate GPATs and how they affect specific lipid metabolic, lipid signaling and lipid mediated transport processes. We have initiated a comprehensive biochemical, molecular and biological characterization of the yeast GPATs, Gat1 and Gat2. Our studies indicated these enzymes are microsomal phosphoproteins with differential contributions to specific lipid pools. We plan to investigate ***i) the role that phosphorylation plays in regulating GPAT activity, localization, and protein-protein interactions; ***ii) the contribution of Gat1 and Gat2 to the synthesis of the mitochondrial lipids phosphatidylglycerol and cardiolipin.***iii) the distribution of diacylglycerol pools in yeast and the identification of pathways that maintain these pools.***In addition, yeast genetic approaches will be used in order to further characterize the inter-conversion of phosphatidic acid to diacylglycerol and the cell anatomy of their lipid traffic, trading and signaling. Lipid metabolism is conserved in eukaryotes, from yeast to humans. Due to its fundamental nature, our research is relevant to understand how organisms control lipid metabolism in relation to the availability of nutrients in the environment. The outcome of our investigations could have a significant impact in the exploitation of lipid metabolism for industrial production of oils, which includes biofuels. In addition, it could also provide insights into understanding how loss of lipid homeostasis due to alterations of the regulatory circuits that control lipid synthesis and signalling contributes to the development of diseases such as obesity, diabetes, and cancer in humans.**