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J. Biol. Chem., Vol. 278, Issue 32, 29856-29862, August 8, 2003

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Methenyltetrahydrofolate Synthetase Regulates Folate Turnover and Accumulation^*

Montserrat C. Anguera , Jae Rin Suh , Haifa Ghandour ¶, Ilya M. Nasrallah , Jacob Selhub ¶ and Patrick J. Stover   ||

From the Cornell University Division of Nutritional Sciences and Graduate Field of Biochemistry, Molecular and Cellular Biology, Ithaca, New York 14853 and the ^¶Vitamin Metabolism Laboratory, Jean Mayer United States Department of Agriculture, Human Nutrition Research on Aging, Tufts University, Boston, Massachusetts 02111

Cellular folate deficiency impairs one-carbon metabolism, resulting in decreased fidelity of DNA synthesis and inhibition of numerous S-adenosylmethionine-dependent methylation reactions including protein and DNA methylation. Cellular folate concentrations are influenced by folate availability, cellular folate transport efficiency, folate polyglutamylation, and folate turnover specifically through degradation. Folate cofactors are highly susceptible to oxidative degradation in vitro with the exception of 5-formyltetrahydrofolate, which may be a storage form of folate. In this study, we determined the effects of depleting cytoplasmic 5-formyltetrahydrofolate on cellular folate concentrations and folate turnover rates in cell cultures by expressing the human methenyltetrahydrofolate synthetase cDNA in human MCF-7 cells and SH-SY5Y neuroblastoma. Cells with increased methenyltetrahydrofolate synthetase activity exhibited: 1) increased rates of folate turnover, 2) elevated generation of p-aminobenzoylglutamate in culture medium, 3) depressed cellular folate concentrations independent of medium folic acid concentrations, and 4) increased average polyglutamate chain lengths of folate cofactors. These data indicate that folate catabolism and folate polyglutamylation are competitive reactions that influence cellular folate concentrations, and that increased methenyltetrahydrofolate synthetase activity accelerates folate turnover rates, depletes cellular folate concentrations, and may account in part for tissue-specific differences in folate accumulation.

Received for publication, March 20, 2003 , and in revised form, May 20, 2003.

^* This work was supported by United States Public Health Service Grant HD35687 (to P. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Cornell University, 315 Savage Hall, Ithaca, NY 14853. Tel.: 607-255-9751; Fax: 607-255-9751; E-mail: PJS13{at}cornell.edu.

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