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Information on EC 1.5.1.15 - methylenetetrahydrofolate dehydrogenase (NAD+)
for references in articles please use BRENDA:EC1.5.1.15Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
1.5.1.15 methylenetetrahydrofolate dehydrogenase (NAD+)Specify your search results
Word Map
- 1.5.1.15
- homocysteine
- women
-
case-control
- hyperhomocysteinemia
- leiden
- thrombosis
- artery
-
folic
- prothrombin
-
meta-analysis
- cardiovascular
- pregnancy
- thrombophilias
- venous
- children
-
homozygote
-
ethnic
- stroke
- coronary
-
caucasian
-
pcr-rflp
-
smoking
-
homozygosity
- thromboembolism
-
one-carbon
-
prothrombotic
- methotrexate
- thymidylate
-
anticoagulant
-
pubmed
-
thermolabile
-
embase
-
hypercoagulable
- pai-1
-
remethylation
- 5-methyltetrahydrofolate
-
gene-gene
- antithrombin
-
pharmacogenetic
- cystathionine
- beta-synthase
-
antiphospholipid
-
reaction-restriction
- miscarriage
- medicine
-
fxiii
-
hypofibrinolysis
- homocystinuria
-
anticardiolipin
-
folate-dependent
- hinfi
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
mthfr, methylenetetrahydrofolate reductase, nmdmc, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase, mthfr1, mthfr2, methylenetetrahydrofolate dehydrogenase-cyclohydrolase, msmeg_6596, msmeg_6649, nad-dependent dehydrogenase-cyclohydrolase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
bifunctional N5,N10-methylene-H4F dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase
FolD
methylenetetrahydrofolate dehydrogenase-cyclohydrolase
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
methylenetetrahydrofolate reductase
MSMEG_6596
MSMEG_6649
MTHFD2
MTHFR
MTHFR1
MTHFR2
NADH-oxidizing methylenetetrahydrofolate reductase
NMDMC
bifunctional N5,N10-methylene-H4F dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase
bifunctional enzyme EC 1.5.1.15/EC 3.5.4.9
bifunctional N5,N10-methylene-H4F dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase
bifunctional enzyme EC 1.5.1.15/EC 3.5.4.9
-
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
-
-
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
-
-
NADH-oxidizing methylenetetrahydrofolate reductase
-
NADH-oxidizing methylenetetrahydrofolate reductase
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5,10-methylenetetrahydrofolate + NAD+ = 5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
-
5,10-methylenetetrahydrofolate + NAD+ = 5,10-methenyltetrahydrofolate + NADH + H+
the reaction catalyzed by Escherichia coli MTHFR can be divided into a reductive half-reaction and an oxidative half-reaction, respectively, in which the FAD cofactor acts as an intermediate electron acceptor and donor. The enzyme employs a ping-pong bi-bi kinetic mechanism, in which the release of NAD+, the product of the first half-reaction, precedes binding of the substrate CH2-H4folate in the second half-reaction. Rapid-reaction kinetic studies have established that the enzyme catalyzes these half-reactions at rates consistent with the observed rate of overall turnover. Proposed mechanism for the oxidative half-reaction, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
5,10-methylenetetrahydrofolate:NAD+ oxidoreductase
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CAS REGISTRY NUMBER
COMMENTARY
82062-90-6
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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
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
5,10-methenyltetrahydrofolate + NADH + H+
5,10-methylenetetrahydrofolate + NAD+
-
-
-
ir
5,10-methenyltetrahydrofolate + NADH + H+
5,10-methylenetetrahydrofolate + NAD+
-
-
-
ir
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
-
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
-
-
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
-
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
enzyme provides one-carbon units for purine synthesis during embryogenesis, metabolism overview
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
N-terminal catalytic domain
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
-
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
enzyme binding structure analysis, overview
-
-
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
the bifunctional enzyme also shows N5,N10-methenyltetrahydrofolate cyclohydrolase activity EC 3.5.4.9. with NADP+ (1 mM), the enzyme shows less than 0.1% of the activity obtained with NAD+ (1 mM). The purified enzyme shows no activity with methylene-tetrahydromethanopterin or with 5,10-methylenetetrahydrosarcinapterin either in the presence of NAD+ or NADP+ or in the presence of F420
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
the bifunctional enzyme also shows N5,N10-methenyltetrahydrofolate cyclohydrolase activity EC 3.5.4.9. with NADP+ (1 mM), the enzyme shows less than 0.1% of the activity obtained with NAD+ (1 mM). The purified enzyme shows no activity with methylene-tetrahydromethanopterin or with 5,10-methylenetetrahydrosarcinapterin either in the presence of NAD+ or NADP+ or in the presence of F420
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
?
-
-
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
about 15% of the rate with NAD+
-
-
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
-
-
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
-
-
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
-
-
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
-
-
?
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
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r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
physiological direction in most organisms is the forward rection, in the acetogens the reverse reaction is the physiologically important one
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
Antheraea eucalypti
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-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
physiological direction in most organisms is the forward rection, in the acetogens the reverse reaction is the physiologically important one
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
392075, 392076, 392077, 392078, 392079, 392080, 392081, 392082, 392084, 392085, 392086, 392087, 392088, 392090, 392091, 392092, 392093
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
Antheraea eucalypti
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
392075, 392076, 392077, 392078, 392079, 392080, 392081, 392082, 392084, 392085, 392086, 392087, 392088, 392090, 392091, 392092, 392093
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
additional information
?
-
-
active only with L-5,10-methylenetetrahydrofolate, the L-isomer does not affect the reaction
-
-
?
additional information
?
-
-
the reaction catalyzed by Escherichia coli MTHFR can be divided into a reductive half-reaction and an oxidative half-reaction, respectively, in which the FAD cofactor acts as an intermediate electron acceptor and donor. For enzyme assay, menadione is used as an alternate electron acceptor, MTHFR oxidizes NADH to NAD+, and the reaction can be monitored at 343 nm by the decrease in NADH absorbance
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-
-
additional information
?
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-
key enzyme in folate metabolism playing a major role in provision of methyl groups for DNA methylation and in production of dTMP for DNA synthesis
-
-
?
additional information
?
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-
level of enzyme activity appears to be strain dependent with Swiss mice having the highest activity
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-
?
additional information
?
-
enzyme deficiency results in a number of diseases
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?
additional information
?
-
-
enzyme deficiency results in a number of diseases
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-
?
additional information
?
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
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-
-
additional information
?
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-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
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-
-
additional information
?
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identification of the reaction product of MSMEG_6596 by LC-MS/MS
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-
additional information
?
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identification of the reaction product of MSMEG_6596 by LC-MS/MS
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-
-
additional information
?
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-
identification of the reaction product of MSMEG_6596 by LC-MS/MS
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-
-
additional information
?
-
identification of the reaction product of MSMEG_6649 by LC-MS/MS
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-
-
additional information
?
-
identification of the reaction product of MSMEG_6649 by LC-MS/MS
-
-
-
additional information
?
-
-
identification of the reaction product of MSMEG_6649 by LC-MS/MS
-
-
-
additional information
?
-
identification of the reaction product of MSMEG_6596 by LC-MS/MS
-
-
-
additional information
?
-
identification of the reaction product of MSMEG_6596 by LC-MS/MS
-
-
-
additional information
?
-
identification of the reaction product of MSMEG_6649 by LC-MS/MS
-
-
-
additional information
?
-
identification of the reaction product of MSMEG_6649 by LC-MS/MS
-
-
-
additional information
?
-
-
contains 2 enzymes, monofunctional NAD+ dependent dehydrogenase EC1.5.1.15 and trifunctional NADP+ dependent dehydrogenase, EC1.5.1.5
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-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL 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
5,10-methenyltetrahydrofolate + NADH + H+
5,10-methylenetetrahydrofolate + NAD+
-
-
-
ir
5,10-methenyltetrahydrofolate + NADH + H+
5,10-methylenetetrahydrofolate + NAD+
-
-
-
ir
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
-
-
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
enzyme provides one-carbon units for purine synthesis during embryogenesis, metabolism overview
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
-
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
?
-
-
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
physiological direction in most organisms is the forward rection, in the acetogens the reverse reaction is the physiologically important one
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
Antheraea eucalypti
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
physiological direction in most organisms is the forward rection, in the acetogens the reverse reaction is the physiologically important one
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
392075, 392076, 392077, 392078, 392079, 392080, 392081, 392082, 392084, 392085, 392086, 392087, 392088, 392090, 392091, 392092, 392093
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methenyl-tetrahydrofolate + NADH
L-5,10-methylenetetrahydrofolate + NAD+
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
Antheraea eucalypti
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
392075, 392076, 392077, 392078, 392079, 392080, 392081, 392082, 392084, 392085, 392086, 392087, 392088, 392090, 392091, 392092, 392093
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
L-5,10-methylenetetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
-
-
-
r
additional information
?
-
-
key enzyme in folate metabolism playing a major role in provision of methyl groups for DNA methylation and in production of dTMP for DNA synthesis
-
-
?
additional information
?
-
enzyme deficiency results in a number of diseases
-
-
?
additional information
?
-
-
enzyme deficiency results in a number of diseases
-
-
?
additional information
?
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
additional information
?
-
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
required for enzyme stability, binding site comprises amino acid residues 95-228
FAD
-
a flavoprotein, the FAD cofactor is bound in the center of the barrel with only the si face of the isoalloxazine ring exposed to solvent
NAD+
-
Ehrlich ascites tumor cells contains 2 enzymes, NAD+ dependent and NADP+ dependent dehydrogenase
NAD+
with NADP+ (1 mM), the enzyme shows less than 0.1% of the activity obtained with NAD+ (1 mM)
NAD+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NAD+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamat is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NADP+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NADP+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
additional information
MSMEG_6596 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
additional information
MSMEG_6596 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
additional information
-
MSMEG_6596 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
additional information
MSMEG_6649 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
additional information
MSMEG_6649 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
additional information
-
MSMEG_6649 is a monomeric protein and lacks flavin coenzyme. No activity with NADP(H)
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mn2+
Mg2+
-
NAD+ dependent enzyme from Ehrlich ascites tumor cells requires Mg2+ or Mn2+ for activity
Mn2+
-
NAD+ dependent enzyme from Ehrlich ascites tumor cells requires Mg2+ or Mn2+ for activity
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[1,5-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
i.e. LY345899
5,10-methylenetetrahydrofolate
-
substrate inhibition of wild-type enzyme and mutant Q183E, no inhibition of mutant Q183A
menadione
-
substrate inhibition of wild-type enzyme and mutant Q183A, no inhibition of mutant Q183E
S-adenosyl-L-methionine
allosteric inhibitor, enzyme contains a binding site at the C-terminus
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
phosphate
-
absolute requirement, phosphate can be replaced by its analog arsenate
phosphate
absolutely required, binds in close proximity to the 2-hydroxyl of NAD through interactions with R166 and R198. Km-value of wild-type 0.412 mM
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0004
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
0.03
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, CH3-H4folate-menadione oxidoreductase assay
0.108
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-CH2-H4folate oxidoreductase assay
0.115
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183E, CH3-H4folate-menadione oxidoreductase assay
0.29
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-CH2-H4folate oxidoreductase assay
0.123
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
0.133
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
0.302
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
0.359
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
0.0035
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
0.0066
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
0.01
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-CH2-H4folate oxidoreductase assay
0.0151
NADH
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-menadione oxidoreductase assay
0.0204
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-menadione oxidoreductase assay
0.025
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-menadione oxidoreductase assay
0.29
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
additional information
5,10-methylenetetrahydrofolate
pH 6.0, 37°C, the Km-value for 5,10-methylenetetrahydrofolate in the presence of 2.7 mM NAD+ is below 0.005 mM
additional information
additional information
-
Michaelis-Menten steady-state kinetic analysis, comparisons of half-reaction kinetics of wild-type and mutant enzymes
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.15
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, CH3-H4folate-menadione oxidoreductase assay
0.29
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-CH2-H4folate oxidoreductase assay
0.47
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, CH3-H4folate-menadione oxidoreductase assay
2.2
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
2.7
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-CH2-H4folate oxidoreductase assay
1.5
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
12.4
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
6.4
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
15.4
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
0.29
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
2.2
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
2.7
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-CH2-H4folate oxidoreductase assay
14
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-menadione oxidoreductase assay
15.3
NADH
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-menadione oxidoreductase assay
18.2
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-menadione oxidoreductase assay
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.3
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183A, CH3-H4folate-menadione oxidoreductase assay
15.67
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, CH3-H4folate-menadione oxidoreductase assay
12
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
93
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
21
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
43
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
686.3
NADH
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-menadione oxidoreductase assay
728
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-menadione oxidoreductase assay
1013.3
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-menadione oxidoreductase assay
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.061
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant wild-type, NADH-CH2-H4folate oxidoreductase assay
0.094
5,10-methylenetetrahydrofolate
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-CH2-H4folate oxidoreductase assay
0.054
menadione
-
pH 7.2, 25°C, recombinant wild-type, NADH-menadione oxidoreductase assay
0.081
menadione
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-menadione oxidoreductase assay
0.0017
NADH
-
pH 7.2, 25°C, recombinant wild-type, NADH-menadione oxidoreductase assay
0.0032
NADH
-
pH 7.2, 25°C, recombinant mutant Q183A, NADH-menadione oxidoreductase assay
0.023
NADH
-
pH 7.2, 25°C, recombinant mutant Q183E, NADH-menadione oxidoreductase assay
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0002
0.0003
0.0004
0.0005
0.0012
0.0015
0.0039
0.0042
0.005
0.0055
0.0063
2.4
5
pH 6.0, 37°C, extract from Escherichia coli cells carrying the expression vector
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8
-
enzyme activity decreases approximately 2fold at pH 7.0 or pH 9.0
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45
-
activity increases to the optimum, above 45°C the enzyme begins to denature
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
spruce budworm, cell lines IPRI CF1, IPRI CF16T, IPRI CF124T, FPMI-CF-70, FPMI-CF-27 and FPMI-34
-
-
brenda
black bellied hamster, cell line HA-Py(T), a polyoma virus-transformed hamster embryo fibroblast
-
-
brenda
normal human fibroblasts MCH-39, EBV-transformed normal human lymphoblast lines TL3 and TL4, human tumor lines MNNG/HOS(TE85 clone F-5), MCF-7, CCRF-CEM, osteosarcoma MG-63(ATCC CRL 1427), human chronic myeolitic leukemia line K562, Burkitt lymphoma line Raji, human choriocarcinoma BeWo, human intestinal carcinoma HCT
-
-
brenda
bifunctional NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
-
-
brenda
C57 black mice, murine ascites tumor lines, T-cell lymphoma EL4, Moloney virus-induced lymphoma YAC, mouse melanoma M4(original designation RPMI 7272), 3T3-SV40
-
-
brenda
mouse, Ehrlich ascites tumor cells
-
-
brenda
murine cell lines NIH 3T3, Balb/C 3T3, Balb/C 3T3-SV-T2(SV40-transformed), C3H 10T1/2, YAC(Moloney virus transformed), PSI-2(a murine ecotropic packaging cell line)
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
both Mthfd2 and Mthfd2l are expressed during embryogenesis but differ in timing of expression. Mthfd2l expression is low in early developmental stages but begins to increase at embryonic day 10.5 and remains elevated through birth while Mthfd2 is expressed more abundantly during early developmental stages and begins to taper off, with little or no expression observed in most adult tissues
brenda
-
enzyme is expressed during embryogenesis and in all immortilized cells
brenda
enzyme is mainly expressed during embryogenesis for purine synthesis
brenda
additional information
upregulation and overexpression in cancer cells
brenda
additional information
-
cell growth studies, wild-type and mutant cell lines, overview
brenda
additional information
expression pattern analysis, elevated enzyme expression in tumour cells due to different folate-mediated support of purine synthesis compared to normal cells
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
-
brenda
additional information
MTHFD2 was localized to both the nucleus and mitochondria in mouse embryonic stem cell (mESCs)
-
brenda
additional information
-
MTHFD2 was localized to both the nucleus and mitochondria in mouse embryonic stem cell (mESCs)
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
the Escherichia coli enzyme differs from the characterized pig, human, and yeast MTHFRs (EC 1.5.1.5) in its preference for NADH over NADPH as substrate and by the absence of a regulatory domain. Structures of Ered(wild-type)-NADH and Eox(Glu28Gln)-CH3-H4folate complexes reveal that the ligands occupy partially overlapping sites at the si face of the FAD. Thus, the binding of one substrate to the enzyme prevents the binding of the other substrate, consistent with the ping-pong bi-bi kinetic mechanism. But the structures reveal that the active site conformations of NADH and CH3-H4folate are remarkably different
malfunction
metabolism
physiological function
additional information
-
a role for residue glutamine 183 in the folate oxidative half-reaction of methylenetetrahydrofolate reductase from Escherichia coli. Residue Gln183 may participate in NADH binding, based on the hydrogen bonding interactions between the Gln side chain and the carboxamide of NADH observed in the X-ray structure
malfunction
Mthfd2 knockdown (KD) results in loss of typical stem cell morphology with reduced alkaline phosphatase (AP) staining. Mthfd2 depletion results in differentiation of mESCs. Two MTHFD2-specific inhibitors, MIN and NIT, are used to inhibit MTHFD2 enzymatic activity in mESCs. Both MIN- and MIT-treated mESCs (MImESCs) maintain typical stem cell morphology and pluripotency-associated marker gene expression. Mthfd2 deficiency induces mitochondrial dysfunction by regulating the activity of complex III. The mitochondrial membrane potential (MMP) and ATP production are decreased and cellular ROS levels are increased in Mthfd2 KD mESCs. Mthfd2 depletion hinders DNA repair in mESCs
malfunction
the Mycobacterium smegmatis DELTAmsmeg_6596 strain is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
malfunction
-
the Mycobacterium smegmatis DELTAmsmeg_6596 strain is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
-
metabolism
the enzyme is involved in folate pathway. It is involved in mitochondrial NADPH production. It is proposed that isoenzyme MTHFD2 may be expressed to boost flux through the mitochondrial folate pathway during early periods of embryogenesis when isoenzyme MTHFD2L alone is not sufficient to support high rates of cell proliferation
metabolism
the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase(MTHFD2)-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. It is proposed that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxidized phospholipids during atherosclerosis
physiological function
Mthfd2 modulates mitochondrial function and DNA repair to maintain the pluripotency of mouse stem cells. The methylenetetrahydrofolate dehydrogenase (NAD+-dependent), methenyltetrahydrofolate cyclohydrolase (Mthfd2), plays an essential role in maintaining embryonic stem cell pluripotency and promoting complete reprogramming of induced pluripotent stem cells. Mechanistically, in mitochondria, Mthfd2 maintains the integrity of the mitochondrial respiratory chain and prevents mitochondrial dysfunction. In the nucleus, Mthfd2 stabilizes the phosphorylation of EXO1 to support DNA end resection and promote homologous recombination repair. Mthfd2 is a dual-function factor in determining the pluripotency of pluripotent stem cells through both mitochondrial and nuclear pathways, ultimately ensuring safe application of pluripotent stem cells. Key role of Mthfd2 in the maintenance of mESC self-renewal. MTHFD2 has nonenzymatic functions in mESCs. MTHFD2 interacts with CDK1 and EXO1 to regulate DNA damage level in mESCs. Mthfd2 modulates homologous recombination repair by regulating EXO1 phosphorylation via affecting the kinase activity of CDK1 to modulate homologous recombination repair and protect genomic integrity
physiological function
MTHFR/MetF is an essential enzyme in a one-carbon metabolic pathway for de novo biosynthesis of methionine. In Mycobacterium smegmatis, the catalytic efficiency (kcat/Km) in vitro of MSMEG_6596 (MTHFR1) for 5,10-CH2-THF and NADH is 13.5 and 15.3fold higher than that of MSMEG_6649 (MTHFR2). Thus, MSMEG_6596 is the major MTHFR. This interpretation is further supported by better rescue of the Escherichia coli DELTAmthfr mutant strain by MTHFR1 than by MTHFR2. The isozymes MTHFR1 and MTHFR2 are two noncanonical MTHFR proteins that are monomeric and lack flavin coenzyme. Both MTHFR1 and MTHFR2 are involved in de novo methionine biosynthesis and required for antifolate resistance in mycobacteria. MTHFR activity is required during stress from folate pathway inhibitors. The expression of MSMEG_6596 restores maximum resistance or growth, followed by MSMEG_6649, providing antifolate resistance to Mycobacterium smegmatis
physiological function
-
MTHFR/MetF is an essential enzyme in a one-carbon metabolic pathway for de novo biosynthesis of methionine. In Mycobacterium smegmatis, the catalytic efficiency (kcat/Km) in vitro of MSMEG_6596 (MTHFR1) for 5,10-CH2-THF and NADH is 13.5 and 15.3fold higher than that of MSMEG_6649 (MTHFR2). Thus, MSMEG_6596 is the major MTHFR. This interpretation is further supported by better rescue of the Escherichia coli DELTAmthfr mutant strain by MTHFR1 than by MTHFR2. The isozymes MTHFR1 and MTHFR2 are two noncanonical MTHFR proteins that are monomeric and lack flavin coenzyme. Both MTHFR1 and MTHFR2 are involved in de novo methionine biosynthesis and required for antifolate resistance in mycobacteria. MTHFR activity is required during stress from folate pathway inhibitors. The expression of MSMEG_6596 restores maximum resistance or growth, followed by MSMEG_6649, providing antifolate resistance to Mycobacterium smegmatis
-
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MTD1_DICDI
313
0
35069
Swiss-Prot
other Location (Reliability: 1)
MTD1_SCHPO
Schizosaccharomyces pombe (strain 972 / ATCC 24843)
320
0
35814
Swiss-Prot
other Location (Reliability: 3)
MTD1_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
320
0
36240
Swiss-Prot
other Location (Reliability: 2)
MTD2L_CALJA
347
0
37342
Swiss-Prot
Mitochondrion (Reliability: 1)
MTD2L_HUMAN
347
0
37315
Swiss-Prot
Mitochondrion (Reliability: 1)
MTD2L_MOUSE
338
0
36438
Swiss-Prot
Mitochondrion (Reliability: 2)
MTD2L_RAT
338
0
36426
Swiss-Prot
Mitochondrion (Reliability: 2)
MTDC_BOVIN
350
0
37767
Swiss-Prot
Mitochondrion (Reliability: 1)
MTDC_CHICK
337
0
36411
Swiss-Prot
Mitochondrion (Reliability: 1)
MTDC_DROME
309
0
33551
Swiss-Prot
other Location (Reliability: 2)
MTDC_HUMAN
350
0
37895
Swiss-Prot
Mitochondrion (Reliability: 2)
MTDC_MOUSE
350
0
37863
Swiss-Prot
Mitochondrion (Reliability: 2)
K0KLD5_WICCF
Wickerhamomyces ciferrii (strain ATCC 14091 / BCRC 22168 / CBS 111 / JCM 3599 / NBRC 0793 / NRRL Y-1031 F-60-10)
310
0
34393
TrEMBL
other Location (Reliability: 2)
A0A1S7UI93_ROSNE
329
0
36531
TrEMBL
other Location (Reliability: 2)
A0A8J5EEF3_9ASCO
326
0
36153
TrEMBL
other Location (Reliability: 2)
A0A3G2RZP1_9BASI
393
0
43096
TrEMBL
other Location (Reliability: 2)
A0A8J5BW50_9ASCO
325
0
36121
TrEMBL
other Location (Reliability: 2)
A0A0F4YN84_TALEM
336
0
37489
TrEMBL
other Location (Reliability: 2)
W1QBS2_OGAPD
Ogataea parapolymorpha (strain ATCC 26012 / BCRC 20466 / JCM 22074 / NRRL Y-7560 / DL-1)
305
0
34102
TrEMBL
other Location (Reliability: 4)
A2R8J8_ASPNC
Aspergillus niger (strain CBS 513.88 / FGSC A1513)
334
0
36984
TrEMBL
other Location (Reliability: 2)
Q4WC87_ASPFU
Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100)
298
0
33064
TrEMBL
other Location (Reliability: 2)
C1LFF7_SCHJA
333
0
35994
TrEMBL
other Location (Reliability: 4)
A1Z9B4_DROME
122
1
13353
TrEMBL
Secretory Pathway (Reliability: 1)
Q7JRN6_DROME
223
1
24828
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1Z5JE80_FISSO
364
0
40578
TrEMBL
other Location (Reliability: 2)
Q8KEH0_CHLTE
Chlorobaculum tepidum (strain ATCC 49652 / DSM 12025 / NBRC 103806 / TLS)
296
0
33244
TrEMBL
-
A0A084FY34_PSEDA
329
0
36390
TrEMBL
other Location (Reliability: 2)
A0A0B7FU61_THACB
Thanatephorus cucumeris (strain AG1-IB / isolate 7/3/14)
363
0
39334
TrEMBL
other Location (Reliability: 2)
M5BLC9_THACB
Thanatephorus cucumeris (strain AG1-IB / isolate 7/3/14)
363
0
39362
TrEMBL
other Location (Reliability: 2)
A0A1Z5K4A0_FISSO
364
1
40689
TrEMBL
other Location (Reliability: 2)
A0A0F8B4W0_CERFI
333
0
37114
TrEMBL
other Location (Reliability: 2)
C5P087_COCP7
Coccidioides posadasii (strain C735)
345
0
38401
TrEMBL
other Location (Reliability: 2)
A0A8B6ES68_MYTGA
336
0
36608
TrEMBL
Mitochondrion (Reliability: 3)
B8BT80_THAPS
266
0
29926
TrEMBL
other Location (Reliability: 1)
A0A8J8W1C6_9EURO
332
0
37067
TrEMBL
other Location (Reliability: 4)
B8Y659_LEIDO
475
0
50730
TrEMBL
Mitochondrion (Reliability: 3)
A0R6M0_MYCS2
Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155)
302
0
33311
TrEMBL
-
A0R6S0_MYCS2
Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155)
296
0
32941
TrEMBL
-
FOLD_METBF
Methanosarcina barkeri (strain Fusaro / DSM 804)
287
0
31051
Swiss-Prot
-
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
33000 - 38000
34000
34000
-
2 * 34000, native bifunctional enzyme, associated with cyclohydrolase, SDS-PAGE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
monomer
dimer
-
2 * 34000, native bifunctional enzyme, associated with cyclohydrolase, SDS-PAGE
monomer
MSMEG_6596 is a monomeric protein and lacks flavin coenzyme
monomer
MSMEG_6649 is a monomeric protein and lacks flavin coenzyme
monomer
-
MSMEG_6596 is a monomeric protein and lacks flavin coenzyme
-
monomer
-
MSMEG_6649 is a monomeric protein and lacks flavin coenzyme
-
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of the enzyme (MTHFD2) in complex with a substrate-based inhibitor and the enzyme cofactors NAD+ and inorganic phosphate
protein crystallized from 7% PEG 8000 in 50 mM Tris-HCl, pH 8.2 at 4°C in both hanging and sitting drop conditions, space group P4212 with cell constants a/b/c 75.9/75,9/160.0 A, crystals diffract to 2.9 A resolution, crystals form as tetragonal bipyramids and may grow as large as 0.45 mm on a side
-
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Q183A
-
site-directed mutagenesis, the Gln183Ala variant exhibits a 6-10fold lower rate of folate reduction and bound CH2-H4folate with 7-fold lower affinity compared to wild-type enzyme. The oxidative half-reaction of the Gln183Ala mutant is considered reversible, and the enzyme can catalyze either of two half reactions involving folate: reduction of CH2-H4folate as part of the physiological oxidoreductase reaction or oxidation of CH3-H4folate as part of the CH3-H4folate-menadione oxidoreductase reaction, comparisons of half-reaction kinetics of wild-type and mutant enzymes
Q183E
-
site-directed mutagenesis, comparisons of half-reaction kinetics of wild-type and mutant enzymes, the Gln183Glu mutant displays catalytic constants within 3fold of the wild-type enzyme enzyme
C677T
-
one of several polymorphisms, leads to increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis, determination of genotypes in liver transplant patients with cirrhosis with and without hepatocellular carcinoma and in healthy persons
D133A
cosubstrate NAD+, 1.7% of wild-type activity, cosubstrate NADP+, 5.5% of wild-type activity
D133N
cosubstrate NAD+, 20.4% of wild-type activity, cosubstrate NADP+, 82.2% of wild-type activity
D133S
cosubstrate NAD+, 17.8% of wild-type activity, cosubstrate NADP+, 34.5% of wild-type activity
R198A
cosubstrate NAD+, 0.7% of wild-type activity, cosubstrate NADP+, 5.3% of wild-type activity
R198K
cosubstrate NAD+, 56% of wild-type activity, cosubstrate NADP+, 42% of wild-type activity
R198S
cosubstrate NAD+, 0.9% of wild-type activity, cosubstrate NADP+, 53% of wild-type activity
K56Q
-
inactivation of methenyltetrahydrofolate cyclohydrolase activity of bifunctional enzyme. Transfection with mutant enzyme rescues auxotrophy of enzyme-deficient fibroblasts, but only poorly. Rescued cells demonstrate a decrease in the ratio of incorporation of exogenous formate to serine
additional information
additional information
construction of a gene deletion mutant cell line, the cells can survive in liver and other tissues because the null defect is rescued by metabolites supplied by surrounding normal cells
additional information
-
primary fibroblasts from embryo of knock-out mice, spontaneous immortalization, the mutant cells require methionine and glycine for growth, glycine auxotrophy, replacement of mehtionine by homocysteine results in much lower enzyme activity, metabolism overview
additional information
short hairpin RNAs (shRNAs) suppression of expression of Mthfd2 gene in E14 mouse embryonic stem cells (mESCs). Mthfd2 knockdown (KD) results in loss of typical stem cell morphology, with reduced alkaline phosphatase (AP) staining. The expression of pluripotency marker genes is downregulated and that of lineage marker genes upregulated, showing that Mthfd2 depletion results in differentiation of mESCs. Knockdown of Mthfd2 in another G4 mESC line shows results consistent with those in Mthfd2 KD E14 mESCs. Additionally, homozygous Mthfd2 knockout (KO) mESCs are characterized by the loss of typical mESC morphology, abnormal expression of marker genes, and compromised cell proliferation. Forced expression of Mthfd2 rescues the Mthfd2 KO-induced differentiation and compromised cell proliferation. In addition, MTHFD2 protein expression is gradually silenced during the differentiation of mESCs into embryoid bodies (EBs). Expression of Mthfd2 facilitates mouse induced pluripotent stem cells (iPSCs)induction, Mthfd2 promotes complete reprogramming of iPSCs and improves the quality of iPSCs. All iPSCs induced with Mthfd2 (OSKM2 iPSCs) show typical mESC-like morphology and express Oct4-driven GFP. Analysis of changes in the transcriptome due to suppression of Mthfd2. Mthfd2 depletion hinders DNA repair in mESCs
additional information
-
short hairpin RNAs (shRNAs) suppression of expression of Mthfd2 gene in E14 mouse embryonic stem cells (mESCs). Mthfd2 knockdown (KD) results in loss of typical stem cell morphology, with reduced alkaline phosphatase (AP) staining. The expression of pluripotency marker genes is downregulated and that of lineage marker genes upregulated, showing that Mthfd2 depletion results in differentiation of mESCs. Knockdown of Mthfd2 in another G4 mESC line shows results consistent with those in Mthfd2 KD E14 mESCs. Additionally, homozygous Mthfd2 knockout (KO) mESCs are characterized by the loss of typical mESC morphology, abnormal expression of marker genes, and compromised cell proliferation. Forced expression of Mthfd2 rescues the Mthfd2 KO-induced differentiation and compromised cell proliferation. In addition, MTHFD2 protein expression is gradually silenced during the differentiation of mESCs into embryoid bodies (EBs). Expression of Mthfd2 facilitates mouse induced pluripotent stem cells (iPSCs)induction, Mthfd2 promotes complete reprogramming of iPSCs and improves the quality of iPSCs. All iPSCs induced with Mthfd2 (OSKM2 iPSCs) show typical mESC-like morphology and express Oct4-driven GFP. Analysis of changes in the transcriptome due to suppression of Mthfd2. Mthfd2 depletion hinders DNA repair in mESCs
additional information
construction of the Mycobacterium smegmatis DELTAmsmeg_6596 strain. The mutant is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
additional information
construction of the Mycobacterium smegmatis DELTAmsmeg_6596 strain. The mutant is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
additional information
-
construction of the Mycobacterium smegmatis DELTAmsmeg_6596 strain. The mutant is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
additional information
-
construction of the Mycobacterium smegmatis DELTAmsmeg_6596 strain. The mutant is partially auxotrophic for methionine and grows only poorly without methionine or without being complemented with a functional copy of MTHFR1 or MTHFR2. Furthermore, the DELTAmsmeg_6596 strain is more sensitive to folate pathway inhibitors (sulfachloropyridazine, p-aminosalicylic acid, sulfamethoxazole, and trimethoprim)
-
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8
-
enzyme activity decreases approximately 2fold at pH 7.0 or pH 9.0
392083
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50
-
stable for 30 min at temperatures below, loses 25% of its activity during incubation
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, enzyme is stable in 20-30% glycerol buffer and can be frozen for months without loss of activity
-
4°C, can be stored dissolved in 0.1 M potassium maleate, pH 7.0 for at least 1 month without significant loss of activity
-
4°C, enzyme activity is stable for several weeks after storage in the final elution buffer
-
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
native enzyme from yeast as well as recombinant yest enzyme expressed in Escherichia coli
-
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain AB1909
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene MSMEG_6596, DNA and amino acid sequence determination and analysis, sequence comparisons
gene MSMEG_6649, DNA and amino acid sequence determination and analysis, sequence comparisons
heterologously overproduced in Escherichia coli with a C-terminal His6-tag
isolation of cDNA and the gene encoding the murine cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (DCS)
-
recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain AB1909
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
enzyme distribution suggests it can be useful as an oncodevelopmental marker
medicine
-
enzyme distribution suggests it can be useful as an oncodevelopmental marker
medicine
-
NAD+ dependent isoenzyme is genuinely tumor-specific, it may provide a novel therapeutic target for cancer therapy and/or an important diagnostic tool
medicine
-
NAD+ dependent isoenzyme is genuinely tumor-specific, it may provide a novel therapeutic target for cancer therapy and/or an important diagnostic tool
-
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Moore, M.R.; O'Brien, W.E.; Ljungdahl, L.G.
Purification and characterisation of nicotinamide adenine dinucleotide-dependent methylenetetrahydrofolate dehydrogenase from Clostridium formicoaceticum
J. Biol. Chem.
249
5250-5253
1974
Saccharomyces cerevisiae, Gottschalkia acidurici, Clostridium formicaceticum, Mus musculus
brenda
Ragsdale, S.W.; Ljungdahl, L.G.
Purification and properties of NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Acetobacterium woodii
J. Biol. Chem.
259
3499-3503
1984
Acetobacterium woodii, Saccharomyces cerevisiae, Clostridium formicaceticum, Mus musculus
brenda
Mejia, N.; Mackenzie, R.E.
NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells
J. Biol. Chem.
260
14616-14620
1985
Cricetulus griseus, Cricetus cricetus, Homo sapiens, Mesocricetus auratus, Mus musculus, Rattus norvegicus
brenda
Mejia, N.; Rios-Orlandi, E.M.; Mackenzie, R.E.
NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase from ascites tumor cells. Purification and properties
J. Biol. Chem.
261
9509-9513
1986
Acetobacterium woodii, Clostridium formicaceticum, Mus musculus
brenda
Mackenzie, R.E.; Mejia, N.; Yang, X.M.
Methylenetetrahydrofolate dehydrogenases in normal and transformed mammalian cells
Adv. Enzyme Regul.
27
31-39
1988
Saccharomyces cerevisiae, Homo sapiens, Mus musculus
brenda
Mejia, N.; Mackenzie, R.E.
NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase in transformed cells is a mitochondrial enzyme
Biochem. Biophys. Res. Commun.
155
1-6
1988
Mus musculus
brenda
Rios-Orlandi, E.M.; Mackenzie, R.E.
The activities of the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase from ascites tumor cells are kinetically independent
J. Biol. Chem.
263
4662-4667
1988
Mus musculus
brenda
Belanger, C.; Mackenzie, R.E.
Isolation and characterization of cDNA clones encoding the murine NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
J. Biol. Chem.
264
4837-4843
1989
Mus musculus
brenda
Barlowe, C.K.; Appling, D.R.
Isolation and characterization of a novel eukaryotic monofunctional NAD+-dependent 5,10-methylenetetrahydrofolate dehydrogenase
Biochemistry
29
7089-7094
1990
Acetobacterium woodii, Saccharomyces cerevisiae, Clostridium formicaceticum, Homo sapiens, Rattus norvegicus, Saccharomyces cerevisiae KSY8
brenda
Smith, G.K.; Banks, S.D.; Monaco, T.J.; Rigual, R.; Duch, D.S.; Mullin, R.J.; Huber, B.E.
Activity of an NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase in normal tissue, neoplastic cells, and oncogene-transformed cells
Arch. Biochem. Biophys.
283
367-371
1990
Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus, Rattus norvegicus Fischer
brenda
Peri, K.G.; Mackenzie, R.E.
NAD(+)-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase: detection of the mRNA in normal murine tissues and transcriptional regulation of the gene in cell lines
Biochim. Biophys. Acta
1171
281-287
1993
Homo sapiens, Mus musculus, Rattus norvegicus
brenda
Price, B.D.; Laughon, A.
The isolation and characterization of a Drosophila gene encoding a putative NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
Biochim. Biophys. Acta
1173
94-98
1993
Drosophila melanogaster, Homo sapiens, Mus musculus
brenda
Yang, X.M.; Mackenzie, R.E.
NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is the mammalian homolog of the mitochondrial enzyme encoded by the yeast MIS1 gene
Biochemistry
32
11118-11123
1993
Saccharomyces cerevisiae, Homo sapiens, Mus musculus
brenda
Tremblay, G.B.; Sohi, S.S.; Retnakaran, A.; Mackenzie, R.E.
NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is targeted to the cytoplasm in insect cell lines
FEBS Lett.
368
177-182
1995
Antheraea eucalypti, Choristoneura fumiferana, Drosophila melanogaster, Homo sapiens, Malacosoma disstria, Mus musculus, Spodoptera frugiperda
brenda
Monzingo, A.F.; West, M.G.; Schelp, E.; Appling, D.R.; Robertus, J.D.
Crystallization of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae
Proteins
26
481-482
1996
Acetobacterium woodii, Saccharomyces cerevisiae
brenda
Appling, D.R.; West, M.G.
Monofunctional NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae
Methods Enzymol.
281
178-188
1997
Acetobacterium woodii, Saccharomyces cerevisiae, Clostridium formicaceticum, Drosophila melanogaster, Homo sapiens, Mus musculus
brenda
Mackenzie, R.E.
Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
Methods Enzymol.
281
171-177
1997
Drosophila melanogaster, Homo sapiens, Mus musculus, Saccharomyces cerevisiae, Spodoptera frugiperda
brenda
Di Pietro, E.; Sirois, J.; Trenblay, M.L.; Mackenzie, R.E.
Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is essential for embryonic development
Mol. Cell. Biol.
22
4158-4166
2002
Saccharomyces cerevisiae, Cricetulus griseus, Mus musculus
brenda
Patel, H.; Christensen, K.E.; Mejia, N.; Mackenzie, R.E.
Mammalian mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase
Arch. Biochem. Biophys.
403
145-148
2002
Drosophila melanogaster, Homo sapiens, Mus musculus
brenda
Takeya, C.; Esumi, M.; Shiroishi, T.; Hishida, R.; Yamamoto, T.
Multiple single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase and its truncated pseudogene of 23 inbred strains of mice
Biochem. Biophys. Res. Commun.
312
480-486
2003
Mus musculus (Q9WU20), Mus musculus
brenda
Di Pietro, E.; Wang, X.L.; MacKenzie, R.E.
The expression of mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase supports a role in rapid cell growth
Biochim. Biophys. Acta
1674
78-84
2004
Mus musculus (P18155)
brenda
Saffroy, R.; Pham, P.; Chiappini, F.; Gross-Goupil, M.; Castera, L.; Azoulay, D.; Barrier, A.; Samuel, D.; Debuire, B.; Lemoine, A.
The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis
Carcinogenesis
25
1443-1448
2004
Homo sapiens
brenda
Patel, H.; Pietro, E.D.; MacKenzie, R.E.
Mammalian fibroblasts lacking mitochondrial NAD+-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase are glycine auxotrophs
J. Biol. Chem.
278
19436-19441
2003
Mus musculus
brenda
Patel, H.; Di Pietro, E.; Mejia, N.; MacKenzie, R.E.
NAD- and NADP-dependent mitochondrially targeted methylenetetrahydrofolate dehydrogenase-cyclohydrolases can rescue mthfd2 null fibroblasts
Arch. Biochem. Biophys.
442
133-139
2005
Mus musculus
brenda
Christensen, K.E.; Mirza, I.A.; Berghuis, A.M.; Mackenzie, R.E.
Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
J. Biol. Chem.
280
34316-34323
2005
Homo sapiens (P13995), Homo sapiens
brenda
Buchenau, B.; Thauer, R.K.
Tetrahydrofolate-specific enzymes in Methanosarcina barkeri and growth dependence of this methanogenic archaeon on folic acid or p-aminobenzoic acid
Arch. Microbiol.
182
313-325
2004
Methanosarcina barkeri (Q46A53), Methanosarcina barkeri DSM 804 (Q46A53)
brenda
Shin, M.; Momb, J.; Appling, D.R.
Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
Cancer Metab.
5
11
2017
Homo sapiens (P13995), Homo sapiens (Q9H903)
brenda
Gustafsson, R.; Jemth, A.S.; Gustafsson, N.M.; Faernegardh, K.; Loseva, O.; Wiita, E.; Bonagas, N.; Dahllund, L.; Llona-Minguez, S.; Haeggblad, M.; Henriksson, M.; Andersson, Y.; Homan, E.; Helleday, T.; Stenmark, P.
Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitor
Cancer Res.
77
937-948
2017
Homo sapiens (P13995)
brenda
Hitzel, J.; Lee, E.; Zhang, Y.; Bibli, S.I.; Li, X.; Zukunft, S.; Pflueger, B.; Hu, J.; Schuermann, C.; Vasconez, A.E.; Oo, J.A.; Kratzer, A.; Kumar, S.; Rezende, F.; Josipovic, I.; Thomas, D.; Giral, H.; Schreiber, Y.; Geisslinger, G.; Fork, C.; Yang, X.; Sigala, F.; Romanoski, C.E.; Kroll, J.; Jo, H.; Lan, L.a.n.d.
Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
Nat. Commun.
9
2292
2018
Homo sapiens (P13995)
brenda
Zuo, C.; Jolly, A.L.; Nikolova, A.P.; Satzer, D.I.; Cao, S.; Sanchez, J.S.; Ballou, D.P.; Trimmer, E.E.
A role for glutamine 183 in the folate oxidative half-reaction of methylenetetrahydrofolate reductase from Escherichia coli
Arch. Biochem. Biophys.
642
63-74
2018
Escherichia coli
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Sah, S.; Lahry, K.; Talwar, C.; Singh, S.; Varshney, U.
Monomeric NADH-oxidizing methylenetetrahydrofolate reductases from Mycobacterium smegmatis lack flavin coenzyme
J. Bacteriol.
202
e00709-19
2020
no activity by Mycobacterium smegmatis MSMEG_6664, no activity by Mycobacterium smegmatis MSMEI_6484, Mycolicibacterium smegmatis (A0R6M0), Mycolicibacterium smegmatis (A0R6S0), Mycolicibacterium smegmatis, Mycolicibacterium smegmatis ATCC 700084 (A0R6M0), Mycolicibacterium smegmatis ATCC 700084 (A0R6S0)
brenda
Yue, L.; Pei, Y.; Zhong, L.; Yang, H.; Wang, Y.; Zhang, W.; Chen, N.; Zhu, Q.; Gao, J.; Zhi, M.; Wen, B.; Zhang, S.; Xiang, J.; Wei, Q.; Liang, H.; Cao, S.; Lou, H.; Chen, Z.; Han, J.
Mthfd2 modulates mitochondrial function and DNA repair to maintain the pluripotency of mouse stem cells
Stem Cell Reports
15
529-545
2020
Mus musculus (P18155), Mus musculus
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Release 2023.1 (January 2023)
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