Information on EC 1.5.1.20 - methylenetetrahydrofolate reductase [NAD(P)H]

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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea

EC NUMBER
COMMENTARY hide
1.5.1.20
-
RECOMMENDED NAME
GeneOntology No.
methylenetetrahydrofolate reductase [NAD(P)H]
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
5-methyltetrahydrofolate + NAD(P)+ = 5,10-methylenetetrahydrofolate + NAD(P)H + H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
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redox reaction
-
-
-
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reduction
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
folate transformations I
-
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folate transformations II
-
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N10-formyl-tetrahydrofolate biosynthesis
-
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reductive acetyl coenzyme A pathway I (homoacetogenic bacteria)
-
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sulfopterin metabolism
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tetrahydrofolate metabolism
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One carbon pool by folate
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Carbon fixation pathways in prokaryotes
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Metabolic pathways
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Microbial metabolism in diverse environments
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SYSTEMATIC NAME
IUBMB Comments
5-methyltetrahydrofolate:NAD(P)+ oxidoreductase
A flavoprotein (FAD). Menadione can also serve as an electron acceptor.
CAS REGISTRY NUMBER
COMMENTARY hide
71822-25-8
-
9028-69-7
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
animal
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Automatic Mining of ENzyme DAta
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UniProt
Manually annotated by BRENDA team
ecotype Columbia, expression in Saccharomyces cerevisiae
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Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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-
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Automatic Mining of ENzyme DAta
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Q7WQX3
UniProt
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
USDA110
-
-
Manually annotated by BRENDA team
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Q8FZN0
UniProt
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
guinea pig
-
-
Manually annotated by BRENDA team
Cercocebus sp.
monkey
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-
Manually annotated by BRENDA team
strain ATCC 23439
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
denitrifying bacterium
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-
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Automatic Mining of ENzyme DAta
strain 113-3
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Manually annotated by BRENDA team
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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Manually annotated by BRENDA team
formerly Mesorhizobium loti
UniProt
Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
plant
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-
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
strain DAY4, two isoenzymes, encoded by the genes MET12 and MET13
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
synonym Sinorhizobium meliloti
UniProt
Manually annotated by BRENDA team
-
-
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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Automatic Mining of ENzyme DAta
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-
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Automatic Mining of ENzyme DAta
-
-
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Automatic Mining of ENzyme DAta
-
UniProt
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
-
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
-
mutations in the enzyme lead to hyperhomocysteinemia. A C677T polymorphism is associated with an increased risk for the development of cardiovascular disease, Alzheimer's disease, and depression in adults and of neural tube defects in the fetus
metabolism
-
the enzyme plays a key role in folate metabolism and in the homeostasis of homocysteine
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(6R)-5,10-methylenetetrahydrofolate + NAD(P)H + H+
(6S)-5-methyltetrahydrofolate + NAD(P)+
show the reaction diagram
-
-
-
r
(6R,S)-5,10-methylenetetrahydrofolate + ?
?
show the reaction diagram
5,10-methylene-5,6,7,8-tetrahydropteroylpentaglutamate + reduced acceptor
(+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate + oxidized acceptor
show the reaction diagram
-
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 + acceptor
5-methyltetrahydrofolate + reduced acceptor
show the reaction diagram
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
show the reaction diagram
5,10-methylenetetrahydrofolate + NAD(P)H
5-methyltetrahydrofolate + NAD(P)+
show the reaction diagram
-
NADH is the preferred cofactor of the plant enzyme
-
-
r
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH
?
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH + H+
5-methyltetrahydrofolate + NADP+
show the reaction diagram
-
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
show the reaction diagram
5,10-methylenetetrahydrofolate + reduced ferredoxin
5-methyltetrahydrofolate + oxidized ferredoxin
show the reaction diagram
5-methyltetrahydrofolate + NAD+
5,10-methylenetetrahydrofolate + NADH
show the reaction diagram
5-methyltetrahydrofolate + NADP+
5,10-methylenetetrahydrofolate + NADPH
show the reaction diagram
5-methyltetrahydrofolate + oxidized menadione
5,10-methylenetetrahydrofolate + reduced menadione
show the reaction diagram
5-methyltetrahydropteroylmonoglutamate + 5,10-methylenetetrahydropteroylhexaglutamate
5,10-methylenetetrahydropteroylmonoglutamate + 5-methyltetrahydropteroylhexaglutamate
show the reaction diagram
-
-
-
r
NADH + menadione
NAD+ + reduced menadione
show the reaction diagram
-
-
-
-
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NADPH + H+ + menadione
NADP+ + menadiol
show the reaction diagram
nitrate + reduced acceptor
nitrite + acceptor
show the reaction diagram
nitrate + reduced benzyl viologen
nitrite + benzyl viologen
show the reaction diagram
nitrate + reduced methyl viologen
nitrite + methyl viologen
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(6R)-5,10-methylenetetrahydrofolate + NAD(P)H + H+
(6S)-5-methyltetrahydrofolate + NAD(P)+
show the reaction diagram
Q5SLG6
-
-
-
r
5,10-methylenetetrahydrofolate + FADH2
5-methyltetrahydrofolate + FAD
show the reaction diagram
5,10-methylenetetrahydrofolate + NAD(P)H + H+
5-methyltetrahydrofolate + NAD(P)+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADH
5-methyltetrahydrofolate + NAD+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH
?
show the reaction diagram
5,10-methylenetetrahydrofolate + NADPH + H+
5-methyltetrahydrofolate + NADP+
show the reaction diagram
-
-
-
-
?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
show the reaction diagram
5,10-methylenetetrahydrofolate + reduced ferredoxin
5-methyltetrahydrofolate + oxidized ferredoxin
show the reaction diagram
5-methyltetrahydrofolate + NAD+
5,10-methylenetetrahydrofolate + NADH
show the reaction diagram
-
-
-
-
r
5-methyltetrahydrofolate + NADP+
5,10-methylenetetrahydrofolate + NADPH
show the reaction diagram
-
-
-
-
?
nitrate + reduced acceptor
nitrite + acceptor
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
FADH2
flavin
-
flavin-dependent enzyme
NADP+
additional information
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
iron-sulfur centre
-
enzyme contains 15.2 molecules iron and 19.5 molecules acid-labile sulfur as iron-sulfur clusters
Molybdenum
Zinc
-
2.3 molecules zinc per enzyme molecule
additional information
-
no evidence for participation of heavy metals ions in catalytic process
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate
-
inhibits at high concentrations
2,4-dihydroxyphenylacetic acid
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at 0.01 M
5,10-methylenetetrahydrofolate
dicoumarol
-
inhibits menadione reductase activity only
diethyldicarbonate
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20 mM NADP+ and 20 mM NAD+ partially protected the enzyme against inactivation whereas 20 mM nicotinamide gives complete protection
dihydrofolate
dihydropteroylhexaglutamate
-
-
dihydropteroylpolyglutamate
-
folylpolyglutamate
-
overview
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LY309887
-
i.e. 6R-2,5-thienyl-5,10-dideazatetrahydrofolate monoglutamate
menadione
-
inhibits enzyme activity in yeast extracts
Mersalyl
-
80% inhibition at 1 mM
methylenetetrahydrofolate
-
-
N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamyl-gamma-glutamyl-gamma-glutamylglutamic acid
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N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamylglutamic acid
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N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)glutamic acid
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N-([5-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2,3-dihydrothiophen-2-yl]carbonyl)-4-methylideneglutamic acid
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N-bromosuccinimide
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inactivates the enzyme by modification of tryptophan
N-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-4-methylideneglutamic acid
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N-[4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid
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N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2-fluorobenzoyl]-4-methylideneglutamic acid
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N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid
-
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N-[4-[2-(2-amino-4-methylquinazolin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid
-
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NADPH
-
100 mM
p-chloromercuribenzoate
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60% inhibition of the methylenetetrahydrofolate reductase activity at 0.04 mM, 83% inhibition of the menadione reductase activity at 0.04 mM
Phenylglyoxal
-
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Polyglutamate analogues
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S-adenosyl-L-methionine
S-adenosylmethionine
tetrahydrofolate
-
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
A23187
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treatment of cells results in increase in enzyme mRNA and protein
homocysteine
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treatment of cells results in increase in enzyme mRNA and protein
inositol-requiring enzyme-1
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the induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1
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S-adenosylmethionine
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stimulates
thapsigargin
-
treatment of cells results in increase in enzyme mRNA and protein
tunicamycin
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treatment of cells results in increase in enzyme mRNA and protein
Valproic acid
-
300 mg/kg treatment increases MTHFR promoter activity 2.5fold and MTHFR mRNA and protein 3.7fold
additional information
-
induction of MTHFR is observed after overexpression of inositol-requiring enzyme IRE1 and is inhibited by a dominant-negative mutant of IRE1. Tranfection of c-Jun and its activators LiCl and sodium valproate increase MTHFR expression, whereas inhibitor of c-Jun SP600125 reduces activation; transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increase MTHFR expression, MTHFR mRNA is up-regulated by endoplasmic reticulum stress
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.003
(+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate
-
-
0.023
(+)-5-methyltetrahydrofolate
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-
0.18
(6R)-5,10-methylenetetrahydrofolate
at pH 7.0 and 50C
0.0005 - 0.287
5,10-methylenetetrahydrofolate
0.019 - 0.16
5-methyltetrahydrofolate
0.0019
5-methyltetrahydropteroylhexaglutamate
-
-
0.033
5-methyltetrahydropteroylmonoglutamate
-
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11.1
benzyl viologen
-
-
0.12
DL-5-methyltetrahydrofolate
-
-
0.0004 - 0.187
methylenetetrahydrofolate
0.0027 - 0.585
NADH
0.0073 - 0.049
NADPH
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.007 - 50
methylenetetrahydrofolate
10.4 - 160
NADH
26.7 - 160
NADPH
additional information
additional information
Escherichia coli
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-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.04 - 0.051
(+)-5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate
-
-
0.16 - 0.873
5,10-methylenetetrahydrofolate
0.0065
dihydrofolate
-
-
0.000013
dihydropteroylhexaglutamate
-
-
0.061
methylenetetrahydrofolate
-
recombinant wild-type enzyme, pH 7.2, 4C
0.014
NADH
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recombinant wild-type enzyme, pH 7.2, 4C, the mutant enzymes all show a Km below 0.0035 mM
0.2
S-adenosylmethionine
-
-
additional information
additional information
-
dihydropteroylpolyglutamate inhibitors with different numbers of glutamyl residues
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0007
N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamyl-gamma-glutamyl-gamma-glutamylglutamic acid
Homo sapiens
-
-
0.0022
N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)-gamma-glutamyl-gamma-glutamylglutamic acid
Homo sapiens
-
-
0.033
N-(4-[[(2,4-diaminopteridin-6-yl)methyl](methyl)amino]benzoyl)glutamic acid
Homo sapiens
-
-
0.0018
N-([5-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2,3-dihydrothiophen-2-yl]carbonyl)-4-methylideneglutamic acid
Homo sapiens
-
-
0.0035
N-[4-[2-(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid
Homo sapiens
-
-
0.0012
N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]-2-fluorobenzoyl]-4-methylideneglutamic acid
Homo sapiens
-
-
0.0016
N-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-4-methylideneglutamic acid
Homo sapiens
-
-
additional information
N-[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-4-methylideneglutamic acid
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0000424
-
liver homogenate
0.000094
-
wild-type, cell extract
0.00022
Cercocebus sp.
-
reverse reaction
0.000231
-
brain homogenate
0.00029
Cercocebus sp.
-
forward reaction
0.00071
-
forward reaction
0.001
-
reverse reaction
0.0017
-
muscle
0.0045
-
brain
0.0048
-
intestine
0.0082
-
kidney
0.0089
-
pancreas
0.0106
-
liver
6.92
-
recombinant enzyme
12.4
-
recombinant enzyme
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.3 - 6.4
-
formation of 5-methyltetrahydrofolate
6.3 - 6.9
-
-
6.5
-
NADPH-tetrahydrofolate oxidoreductase activity
6.6
-
methyltetrahydrofolate-menadione oxidoreductase activity
6.6 - 6.7
-
methylenetetrahydrofolate reductase reaction
7
-
assay at
7.1
-
menadione reductase reaction
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.8 - 8.6
-
about 60% of activity maximum at pH 5.8, about 50% of activity maximum at pH 8.6, menadione reductase activity
6 - 8
-
pH 6: about 70% of activity maximum, pH 8: about 35% of activity maximum with 5-methyl-5,6,7,8-tetrahydropteroylmonoglutamate, about 65% of activity maximum with 5-methyl-5,6,7,8-tetrahydropteroylpentaglutamate
6.2 - 7.3
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half-maximal activity at pH 6.2 and pH 7.3, methylenetetrahydrofolate reductase reaction
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
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assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25 - 45
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methylenetetrahydrofolate reductase reaction, slow increase of activity between 25C and 45C