Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate (PubMed:1881876, PubMed:10828945, PubMed:18767138). These derivatives of tetrahydrofolate are differentially required in nucleotide and amino acid biosynthesis, (6S)-10-formyltetrahydrofolate being required for purine biosynthesis while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine and methionine biosynthesis for instance (PubMed:25633902, PubMed:18767138). (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = 5,10-methenyltetrahydrofolate + NADPH 5,10-methenyltetrahydrofolate + H2O = (6S)-10-formyltetrahydrofolate + H(+) (6S)-5,6,7,8-tetrahydrofolate + ATP + formate = (6S)-10-formyltetrahydrofolate + ADP + phosphate One-carbon metabolism; tetrahydrofolate interconversion. Homodimer. Ubiquitous. The N-terminal methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (D/C) domain carries both the methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The larger C-terminal formyltetrahydrofolate synthetase domain carries a third formyltetrahydrofolate synthetase activity. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Susceptibility to colorectal cancer may be associated with the missense variant p.Arg134Lys, which has been observed in about 16% of the human population. The sequence shown in this entry represents the minor allele, as it is reported in the reference genome. The disease is caused by variants affecting the gene represented in this entry. In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family. In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.