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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kamynina, Elena Lamarre, Simon G. Agunloye, Olufunmilayo C. Brosnan, John T. Stover, Patrick J. Brosnan, Margaret E. Field, Martha S. Liebenthal, Rebecca P. |
| Description | Author Affiliation: Field MS ( From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 and.); Kamynina E ( From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 and.); Agunloye OC ( From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 and.); Liebenthal RP ( From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 and.); Lamarre SG ( Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada.); Brosnan ME ( Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada.); Brosnan JT ( Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada.); Stover PJ ( From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 and pjs13@cornell.edu.) |
| Abstract | Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 43 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-10-24 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Nucleus Metabolism Coenzymes Folic Acid Deficiency Enzymology Folic Acid Methylenetetrahydrofolate Dehydrogenase (NADP) Thymidine Monophosphate Biosynthesis Animals Cell Cycle Checkpoints Cell Line DNA Diet Pathology Formates Blood Gene Knockdown Techniques Glycine Hydroxymethyltransferase Liver Methionine Mice Mice, Inbred C57BL Protein Transport Purines S Phase Uracil Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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