Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine (PubMed:29891918). Represents a key regulatory connection between the folate and methionine cycles (Probable). (6S)-5-methyl-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + H(+) + NADPH (6S)-5-methyl-5,6,7,8-tetrahydrofolate + NAD(+) = (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + H(+) + NADH Allosterically regulated by S-adenosylmethionine (SAM). kcat is 40.7 sec(-1). One-carbon metabolism; tetrahydrofolate interconversion. Homodimer. Contains a serine-rich phosphorylation region at the N-terminal and an eukaryote-only S-adenosylmethionine (SAM)-binding domain at the C-terminal. Through asymmetric homodimerization, the two regions are positioned next to each other and N-terminal phosphorylation increases sensitivity to SAM binding and inhibition. Phosphorylation of an N-terminal serine-rich phosphorylation region increases sensitivity to S-adenosylmethionine and inhibition. Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. Belongs to the methylenetetrahydrofolate reductase family. Methylenetetrahydrofolate reductase entry