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Information on EC 1.5.1.20 - methylenetetrahydrofolate reductase [NAD(P)H]
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1.5.1.20 methylenetetrahydrofolate reductase [NAD(P)H]IUBMB Comments
A flavoprotein (FAD). The enzyme catalyses the reversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, playing an important role in folate metabolism by regulating the distribution of one-carbon moieties between cellular methylation reactions and nucleic acid synthesis. This enzyme, characterized from Protozoan parasites of the genus Leishmania, is unique among similar characterized eukaryotic enzymes in that it lacks the C-terminal allosteric regulatory domain (allowing it to catalyse a reversible reaction) and uses NADH and NADPH with equal efficiency under physiological conditions. cf. EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); and EC 1.5.7.1, methylenetetrahydrofolate reductase (ferredoxin).
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Word Map
- 1.5.1.20
- nitrite
- homocysteine
- medicine
- paracoccus
-
assimilatory
-
denitrification
- chlorate
- narghi
-
resde
- napc
-
molybdoenzyme
- pantotrophus
-
ammonification
- nutrition
- analysis
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
respiratory nitrate reductase, 10-methylenetetrahydrofolate reductase, napab, met13, n5,n10-methylenetetrahydrofolate reductase, n5,10-methylenetetrahydrofolate reductase, methylenetetrahydrofolate reductase (nadph), atmthfr-1, 5,10-methylenetetrahydrofolate reductase (nadph), methylenetetrahydrofolic acid reductase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5,10-CH2-H4folate reductase
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5,10-methylenetetrahydrofolate reductase
5,10-methylenetetrahydrofolate reductase (NADPH)
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5,10-methylenetetrahydrofolic acid reductase
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5,10-methylenetetrahydropteroylglutamate reductase
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5-methyltetrahydrofolate:NAD oxidoreductase
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5-methyltetrahydrofolate:NAD+ oxidoreductase
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5-methyltetrahydrofolate:NADP+ oxidoreductase
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EC 1.1.1.171
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formerly
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EC 1.1.1.68
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formerly
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EC 1.1.99.15
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formerly
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EC 1.7.99.5
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formerly
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MET13
methylenetetrahydrofolate (reduced riboflavin adenine dinucleotide) reductase
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methylenetetrahydrofolate reductase
methylenetetrahydrofolate reductase (NADPH)
methylenetetrahydrofolic acid reductase
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MetVF-type methylenetetrahydrofolate reductase
MTHFR
MTHFR2
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N5,10-methylenetetrahydrofolate reductase
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N5,N10-methylenetetrahydrofolate reductase
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NADH:CH2-H4folate oxidoreductase
reductase, methylenetetrahydrofolate (reduced nicotinamide adenine dinucleotide phosphate)
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reductase, methylenetetrahydrofolate (reduced riboflavin adenine dinucleotide)
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type II-MTHFR
5,10-methylenetetrahydrofolate reductase
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5,10-methylenetetrahydrofolate reductase
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methylenetetrahydrofolate reductase
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methylenetetrahydrofolate reductase
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654163, 684273, 684274, 684291, 684295, 684298, 684314, 684428, 684441, 684442, 684465, 684738, 684805, 685493, 685860, 685894, 685917, 685988, 685990, 685995, 686128, 686133, 686144, 686149, 686185, 686240, 686310, 686329, 686343, 686497, 686513, 686515, 686540, 686572, 686590, 686592, 686633, 686835, 686994, 687023, 687066, 687152, 687167, 687174, 687359, 687832, 687894, 687946, 687957, 688129, 688140, 688142, 688184, 688476, 688554, 688562, 688565, 688704, 688709, 688710, 688715, 688756, 688778, 689031, 689103, 689111, 689282, 689284, 689298, 689333, 689366, 689729, 689833, 689836, 690042, 690049, 690083, 690112, 690122, 690124, 690181, 690199
methylenetetrahydrofolate reductase (NADPH)
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MTHFR
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MTHFR
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654163, 684226, 684273, 684274, 684280, 684291, 684295, 684297, 684298, 684314, 684428, 684441, 684442, 684465, 684469, 684473, 684738, 684805, 685493, 685860, 685862, 685893, 685894, 685895, 685917, 685988, 685990, 685995, 686128, 686133, 686144, 686149, 686158, 686185, 686240, 686310, 686329, 686343, 686497, 686513, 686515, 686517, 686540, 686572, 686589, 686590, 686592, 686633, 686829, 686835, 686994, 687023, 687066, 687152, 687167, 687170, 687174, 687359, 687832, 687894, 687946, 687957, 688057, 688129, 688135, 688140, 688142, 688184, 688476, 688554, 688562, 688565, 688688, 688704, 688709, 688710, 688715, 688756, 688778, 689009, 689031, 689103, 689111, 689166, 689282, 689284, 689298, 689329, 689330, 689333, 689366, 689729, 689833, 689836, 690042, 690049, 690083, 690112, 690122, 690124, 690162, 690181, 690199, 690212, 702155, 724809
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
mechanism
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
mechanism, acceptor is free FAD, stereochemistry
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
ping-pong bi-bi mechanism, in which NAD(P)+ release precedes the binding of methylenetetrahydrofolate
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
substrate binding and catalyic mechanism involve Asp120, half-reaction mechanisms
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
NADH adopts a hairpin conformation and is sandwiched between a conserved phenylalanine, F223, and the isoalloxazine ring of FAD, resulting in a complex competent for hydride transfer. The binding sites of the two substrates overlap. Pinog-pong reaction is facilitated by motions of loops L2, L3, L4
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5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
MTHFR is proposed to use the mechanism of flavin-based electron bifurcation
5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
MTHFR is proposed to use the mechanism of flavin-based electron bifurcation
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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redox reaction
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reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
5-methyltetrahydrofolate:NAD(P)+ oxidoreductase
A flavoprotein (FAD). The enzyme catalyses the reversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, playing an important role in folate metabolism by regulating the distribution of one-carbon moieties between cellular methylation reactions and nucleic acid synthesis. This enzyme, characterized from Protozoan parasites of the genus Leishmania, is unique among similar characterized eukaryotic enzymes in that it lacks the C-terminal allosteric regulatory domain (allowing it to catalyse a reversible reaction) and uses NADH and NADPH with equal efficiency under physiological conditions. cf. EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); and EC 1.5.7.1, methylenetetrahydrofolate reductase (ferredoxin).
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CAS REGISTRY NUMBER
COMMENTARY
71822-25-8
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9028-69-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(6R)-5,10-methylenetetrahydrofolate + NAD(P)H + H+
(6S)-5-methyltetrahydrofolate + NAD(P)+
5,10-methylene-5,6,7,8-tetrahydropteroylpentaglutamate + reduced acceptor
(+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate + oxidized acceptor
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equilibrium lies far in favor of 5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate formation, pentaglutamate form binds to the same enzyme site as monoglutamate form
menadione as acceptor for 5,10-methylene-5,6,7,8-tetrahydropteroylpentaglutamate formation
?
5,10-methylenetetrahydrofolate + NAD(P)H
5-methyltetrahydrofolate + NAD(P)+
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NADH is the preferred cofactor of the plant enzyme
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r
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
5,10-methylenetetrahydrofolate + reduced ferredoxin
5-methyltetrahydrofolate + oxidized ferredoxin
5-methyltetrahydrofolate + oxidized menadione
5,10-methylenetetrahydrofolate + reduced menadione
5-methyltetrahydropteroylmonoglutamate + 5,10-methylenetetrahydropteroylhexaglutamate
5,10-methylenetetrahydropteroylmonoglutamate + 5-methyltetrahydropteroylhexaglutamate
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r
(6R)-5,10-methylenetetrahydrofolate + NAD(P)H + H+
(6S)-5-methyltetrahydrofolate + NAD(P)+
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r
(6R)-5,10-methylenetetrahydrofolate + NAD(P)H + H+
(6S)-5-methyltetrahydrofolate + NAD(P)+
Thermus thermophilus HB8 / ATCC 27634 / DSM 579
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r
5,10-methylenetetrahydrofolate + acceptor
5-methyltetrahydrofolate + reduced acceptor
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?
5,10-methylenetetrahydrofolate + acceptor
5-methyltetrahydrofolate + reduced acceptor
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ir
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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enzyme in pathway of synthesis of acetate from CO2 via formate and a series of reactions involving tetrahydrofolate and a corrinoid, FADH2 and reduced ferredoxin may serve as natural reductants for 5,10-methylenetetrahydrofolate
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?
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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?
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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biosynthesis of 5-methyltetrahydrofolate, a donor of methyl groups of methionine
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?
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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?
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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biosynthesis of 5-methyltetrahydrofolate, a donor of methyl groups of methionine
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?
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
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first step of conversion of 5,10-methylenetetrahydrofolate to methionine
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?
5,10-methylenetetrahydrofolate + ferredoxin
5-methyltetrahydrofolate + reduced ferredoxin
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r
5,10-methylenetetrahydrofolate + ferredoxin
5-methyltetrahydrofolate + reduced ferredoxin
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r
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
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?
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
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?
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
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?
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
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?
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
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?
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
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folate-mediated one-carbon metabolism
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r
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
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?
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
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?
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
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physiological direction is the 5-methyltetrahydrofolate formation by transfer of reducing equivalents from NADH to the enzyme-bound FAD and from reduced FAD to methylenetetrahydrofolate
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?
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
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physiological direction: 5-methyltetrahydrofolate formation, inhibition by S-adenosylmethionine functions as a feedback-type metabolic regulation in vivo
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?
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
folate-mediated one-carbon metabolism
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r
5,10-methylenetetrahydrofolate + NADH + H+
5-methyltetrahydrofolate + NAD+
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r
5,10-methylenetetrahydrofolate + NADH + H+
5-methyltetrahydrofolate + NAD+
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r
5,10-methylenetetrahydrofolate + NADH + H+
5-methyltetrahydrofolate + NAD+
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-
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r
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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-
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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physiological NADPH-CH2-H4folate oxidoreductase activity
5-methyltetrahydrofolate is the major methyl donor for the conversion of homocysteine to methionine
?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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equilibrium far on the side of methyltetrahydrofolate formation
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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specific for (+)-diastereoisomer
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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r
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme encoded by MET13 produces 5-methyltetrahydrofolate used for methylation of homocysteine for methionine biosynthesis in vivo, NADPH is the likely natural reductant
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme encoded by MET13 produces 5-methyltetrahydrofolate used for methylation of homocysteine for methionine biosynthesis in vivo, NADPH is the likely natural reductant
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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-
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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-
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ir
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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ping pong bi bi mechanism
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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ferricyanide, dichlorophenolindophenol and cytochrome c can act as electron acceptors
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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equilibrium far on the side of methyltetrahydrofolate formation
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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ping pong kinetics
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme catalyzes the reduction of quinoid dihydropterins without a 5-substituent
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme also catalyzes the NADPH-linked reduction of quinoid dihydrofolate and dihydropterin derivates
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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specific for (+)-diastereoisomer
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?
5,10-methylenetetrahydrofolate + NADPH
?
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first step in biosynthesis of methyl groups
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?
5,10-methylenetetrahydrofolate + NADPH
?
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branch point in folate metabolism
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?
5,10-methylenetetrahydrofolate + NADPH
?
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initial enzyme in pathway leading to synthesis of S-adenosylmethionine
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?
5,10-methylenetetrahydrofolate + NADPH
?
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overview: role in incorporation of methyltetrahydrofolate into cellular metabolism
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?
5,10-methylenetetrahydrofolate + NADPH + H+
5-methyltetrahydrofolate + NADP+
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-
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r
5,10-methylenetetrahydrofolate + NADPH + H+
5-methyltetrahydrofolate + NADP+
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-
-
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?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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reverse reaction: menadione as electron acceptor
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r
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
forward reaction: strong preference of NADH over NADPH
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r
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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forward reaction: reduced acceptor is FADH2