EC 1.5.1.53     
Accepted name: methylenetetrahydrofolate reductase (NADPH)
Reaction: 5-methyltetrahydrofolate + NADP+ = 5,10-methylenetetrahydrofolate + NADPH + H+
Other name(s): MTHFR (gene name); methylenetetrahydrofolate (reduced nicotinamide adenine dinucleotide phosphate) reductase; 5,10-methylenetetrahydrofolate reductase (NADPH); 5,10-methylenetetrahydrofolic acid reductase (ambiguous); 5,10-CH2-H4folate reductase (ambiguous); methylenetetrahydrofolate reductase (NADPH2); 5,10-methylenetetrahydrofolate reductase (ambiguous); methylenetetrahydrofolate reductase (ambiguous); N5,10-methylenetetrahydrofolate reductase (ambiguous); 5,10-methylenetetrahydropteroylglutamate reductase (ambiguous); N5,N10-methylenetetrahydrofolate reductase (ambiguous); methylenetetrahydrofolic acid reductase (ambiguous); 5-methyltetrahydrofolate:(acceptor) oxidoreductase (incorrect); 5,10-methylenetetrahydrofolate reductase (FADH2) (ambiguous)
Systematic name: 5-methyltetrahydrofolate:NADP+ oxidoreductase
Comments: A flavoprotein (FAD). The enzyme from yeast and mammals catalyses a physiologically irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH as the electron donor. It plays an important role in folate metabolism by regulating the distribution of one-carbon moieties between cellular methylation reactions and nucleic acid synthesis. The enzyme contains an N-terminal catalytic domain and a C-terminal allosteric regulatory domain that binds S-adenosyl-L-methionine, which acts as an inhibitor. cf. EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); EC 1.5.1.20, methylenetetrahydrofolate reductase [NAD(P)H]; and EC 1.5.7.1, methylenetetrahydrofolate reductase (ferredoxin).
References:
1.  Donaldson, K.O. and Keresztesy, J.C. Naturally occurring forms of folic acid. I. J. Biol. Chem. 234 (1959) 3235–3240. [PMID: 13817476]
2.  Kutzbach, C. and Stokstad, E.L.R. Mammalian methylenetetrahydrofolate reductase. Partial purification, properties, and inhibition by S-adenosylmethionine. Biochim. Biophys. Acta 250 (1971) 459–477. [PMID: 4399897]
3.  Daubner, S.C. and Matthews, R.T. Purification and properties of methylenetetrahydrofolate reductase from pig liver. J. Biol. Chem. 257 (1982) 140–145. [PMID: 6975779]
4.  Zhou, J., Kang, S.S., Wong, P.W., Fournier, B. and Rozen, R. Purification and characterization of methylenetetrahydrofolate reductase from human cadaver liver. Biochem Med Metab Biol 43 (1990) 234–242. [PMID: 2383427]
5.  Roje, S., Chan, S.Y., Kaplan, F., Raymond, R.K., Horne, D.W., Appling, D.R. and Hanson, A.D. Metabolic engineering in yeast demonstrates that S-adenosylmethionine controls flux through the methylenetetrahydrofolate reductase reaction in vivo. J. Biol. Chem. 277 (2002) 4056–4061. [PMID: 11729203]
6.  Froese, D.S., Kopec, J., Rembeza, E., Bezerra, G.A., Oberholzer, A.E., Suormala, T., Lutz, S., Chalk, R., Borkowska, O., Baumgartner, M.R. and Yue, W.W. Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nat. Commun. 9:2261 (2018). [PMID: 29891918]
[EC 1.5.1.53 created 2021]