Folic acid is metabolized in tissues to folypolyglutamates, which are coenzymes in, and potential regulators of, metabolic cycles involving the syntheses of thymidylate, purines and amino acids. The nutritional and physiological relevance of potential regulatory features that control folate accumulation by tissues and control one carbon availability for folate-dependent reactions will be investigated in the rat and in mammalian cell culture. Several approaches will be used. 1. Model cell systems defective in cytosolic and/or mitochondrial folate metabolism will be developed by transfecting mutant mammalian cells with the folypoly- glutamate synthetase gene. 2.Mitochondrial folates and folate-dependent enzymes will be identified and the metabolism of one carbon precursors studied. The role of the mitochondria in providing one carbon units for mitochondrial and cytosolic folate-dependent reactions will be assessed using mammalian cell transfectants as model systems. 3.The regulation of one carbon entry into the folate pool and the synthesis and fate of cytosolic and mitochondrial glycine will be studied in model cells. 4.The regulation of folate-dependent methionine synthesis and the role of the methionine cycle in sparing the nutritional need for methionine and in the retention of absorbed folate by tissues will be investigated. The long term goals of the project are to understand the basic mechanisms by which folate homeostasis and one carbon metabolism are regulated and to develop models explaining how these important physiological processes are disturbed under a number of nutritional conditions. The metabolic cycles under study play a central role in the de novo synthesis of the methyl group of methionine, a group that is used extensively in metabolic control processes, and in precursor availability for DNA and protein synthesis. An understanding of how these cycles are regulated should also provide information on rate limiting steps in one carbon metabolism and suggest target enzymes for anitmetabolite intervention.
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