Abstract
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.
Highlights
The regulation of total cellular folate concentrations is complex because it is influenced by uptake, polyglutamylation, export, and turnover [15]
The results presented in this study demonstrate that methenyltetrahydrofolate synthetase (MTHFS) activity regulates intracellular folate concentrations by accelerating rates of folate catabolism, and that newly imported folate, which is in the monoglutamate form and not protein-bound, is vulnerable to turnover resulting from increased MTHFS activity
The correlation among MTHFS message levels and rates of folate catabolism in tissues indicates that MTHFS may play a key role in determining cellular folate concentrations in a tissue-specific manner
Summary
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 which is a cofactor and one-carbon donor for numerous cellular methylation reactions [3,4,5]. Carrier proteins [16] and folate receptors [17] transport folate monoglutamates into cells, but folate monoglutamates do not accumulate unless they are converted to folate polyglutamates in the cytoplasm or mitochonfolate 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. Elucidating the mechanisms that regulate systemic folate concentrations as well as the folate content of individual tissues is critical to understanding the complex relationships among folate status, folate metabolism, and disease
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