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Defining the links between membrane phospholipid synthesis and cell functions. This research program is focused on identifying the cellular processes that are driven by phospholipid biosynthesis. Production of phosphatidylcholine, the most abundant phospholipid, is regulated by the CDP-choline biochemical pathway. Membranes are made up of phospholipids and proteins which quantitatively double during cell cycle progression in preparation for cell division and the formation of daughter cells. This process occurs during S phase and is regulated by the combined activities of the CDP-choline pathway and the phospholipase-mediated turnover of phosphatidylcholine. Using a series of knockout mice with deletions in the CDP-choline pathway, we found that phosphatidylcholine biosynthesis is essential for cell division at the very early stages of embryogenesis and for maintenance of gonadal responses in adult animals. Phosphatidylcholine biosynthesis is also required for the secretion of lipid surfactant from lung epithelial cells and for the secretion of cytokines from macrophages. The molecular details that link phosphatidylcholine metabolism with the dynamics of intracellular membrane formation and the trafficking of secretory vesicles are currently under investigation in B-lymphocytes and macrophages.
The importance of Coenzyme A. Mitochondrial lipid metabolism is critically dependent on coenzyme A, a central cofactor that is derived from vitamin B5. The synthesis of coenzyme A is regulated by pantothenate kinase. This research program is investigating the four active pantothenate kinases in mammals to understand the metabolic basis for the human hereditary neurodegenerative disease called PKAN. PKAN results from mutations in the pantothenate kinase 2 isoform. The different cellular locations for the pantothenate kinases, coupled with their individual sensitivities to feedback inhibition or activation, suggest multiple roles as metabolic sensors for cellular adaptation to a wide range of conditions. Derivation of a mouse model for PKAN disease and high-throughput screens for small molecule regulators of pantothenate kinase activity are in progress. Development of the bacterial pantothenate kinases as targets for novel antimicrobiol agents is also a facet of the research program. The structures of the three types of bacterial pantothenate kinases guide the rational design of inhibitors.