Folic acid is a precursor of folylpolyglutamates, which are coenzymes in, and potential regulators of, a large number of reactions known as one carbon metabolism. These reactions, which include metabolic cycles for the synthesis of thymidylate, purines and amino acids, are compartmentalized in the mitochondria and cytosol of tissues. This proposal is for the continuation of a series of studies aimed at investigating the role that mitochondrial folate metabolism plays in one carbon metabolism in cells and tissues. A number of approaches will be used. 1. Model cell systems defective in cytosolic and/or mitochondrial folate metabolism, cells over expressing serine hydroxymethyltransferase (SHMT) in the cytosol and mitochondria will be developed. 2. The regulation of one carbon entry into the folate pool via mitochondrial and cytosolic SHMT and the synthesis and fate of cytosolic and mitochondrial serine and glycine will be studied. The role of formate as a one carbon shuttle linking mitochondrial and cytosolic one carbon metabolism will be investigated. 3. The human cytosolic and mitochondrial SHMT genes will be characterized and nutritional factors regulating the expression of these genes identified. 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. A methionine synthase cDNA will be cloned and the regulation of the synthase investigated. The long term goals of the project are to understand the basic mechanisms by which folate homeostasis and one carbon metabolism are regulated. The metabolic cycles under study play a central role in the de novo synthesis of the methyl group of methionine and in precursor availability for DNA and protein synthesis. Disturbances in these cycles result in megaloblastic anemia, homocysteinemia and may also be involved in the etiology of neural tube defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK042033-06
Application #
2142058
Study Section
Nutrition Study Section (NTN)
Project Start
1990-01-01
Project End
1999-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Schaevitz, Laura R; Picker, Jonathan D; Rana, Jasmine et al. (2012) Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders. Dev Neurobiol 72:891-905
MacFarlane, Amanda J; Perry, Cheryll A; Girnary, Hussein H et al. (2009) Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. J Biol Chem 284:1533-9
Lawrance, Andrea K; Deng, Liyuan; Brody, Lawrence C et al. (2007) Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. J Nutr Biochem 18:305-12
O'Leary, Valerie B; Mills, James L; Pangilinan, Faith et al. (2005) Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab 85:220-7
Davis, Steven R; Quinlivan, Eoin P; Shelnutt, Karla P et al. (2005) Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C->T polymorphism and by dietary folate restriction in young women. J Nutr 135:1045-50
Lim, Unhee; Peng, Kun; Shane, Barry et al. (2005) Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men. J Nutr 135:1989-94
Quinlivan, Eoin P; Davis, Steven R; Shelnutt, Karla P et al. (2005) Methylenetetrahydrofolate reductase 677C->T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosides. J Nutr 135:389-96
Dayal, Sanjana; Devlin, Angela M; McCaw, Ryan B et al. (2005) Cerebral vascular dysfunction in methionine synthase-deficient mice. Circulation 112:737-44
Davis, Steven R; Stacpoole, Peter W; Williamson, Jerry et al. (2004) Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am J Physiol Endocrinol Metab 286:E272-9
Prasannan, Priya; Pike, Schuyler; Peng, Kun et al. (2003) Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. J Biol Chem 278:43178-87

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