Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase derived from a trifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase.

We have isolated the cDNA and the gene encoding the murine cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (DCS). Comparison of these sequences with the 3'-untranslated region of the mitochondrial NAD(+)-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase (mt-DC) revealed areas of significant homology. Both exon and intron sequences of the synthetase domain of DCS are homologous to sequences in the untranslated region of mt-DC. A similar comparison between the mt-DC and the DCS sequences of humans as well as Drosophila supports the conclusion that in higher eukaryotes the bifunctional mt-DC replaced a trifunctional precursor through inactivation of the synthetase domain. The mt-DC should be considered in models of one-carbon folate fluxes in mammals.