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Information on EC 1.5.1.15 - methylenetetrahydrofolate dehydrogenase (NAD+) and Organism(s) Mus musculus and UniProt Accession P18155
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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
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caucasian
-
pcr-rflp
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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 taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
mthfr, methylenetetrahydrofolate reductase, nmdmc, methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase, mthfr2, mthfr1, methylenetetrahydrofolate dehydrogenase-cyclohydrolase, msmeg_6596, msmeg_6649, nad-dependent dehydrogenase-cyclohydrolase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
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
-
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-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
-
-
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-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
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
-
-
-
-
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH
N-terminal catalytic domain
-
-
?
additional information
?
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
additional information
?
-
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
additional information
?
-
-
level of enzyme activity appears to be strain dependent with Swiss mice having the highest activity
-
-
?
additional information
?
-
enzyme deficiency results in a number of diseases
-
-
?
additional information
?
-
-
enzyme deficiency results in a number of diseases
-
-
?
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-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
-
-
-
-
?
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-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
additional information
?
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
additional information
?
-
-
MTHFD2 interacts with mitochondrial ETC complex III in mitochondria, mechanism
-
-
-
additional information
?
-
enzyme deficiency results in a number of diseases
-
-
?
additional information
?
-
-
enzyme deficiency results in a number of diseases
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
required for enzyme stability, binding site comprises amino acid residues 95-228
NAD+
-
Ehrlich ascites tumor cells contains 2 enzymes, NAD+ dependent and NADP+ dependent dehydrogenase
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
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
S-adenosyl-L-methionine
allosteric inhibitor, enzyme contains a binding site at the C-terminus
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0004
0.0039
0.0042
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
enzyme is mainly expressed during embryogenesis for purine synthesis
additional information
additional information
expression pattern analysis, elevated enzyme expression in tumour cells due to different folate-mediated support of purine synthesis compared to normal cells
additional information
-
cell growth studies, wild-type and mutant cell lines, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
-
additional information
additional information
MTHFD2 was localized to both the nucleus and mitochondria in mouse embryonic stem cell (mESCs)
-
additional information
-
MTHFD2 was localized to both the nucleus and mitochondria in mouse embryonic stem cell (mESCs)
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
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). MTDC_MOUSE
350
0
37863
Swiss-Prot
Mitochondrion (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
34000
34000
-
2 * 34000, native bifunctional enzyme, associated with cyclohydrolase, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
dimer
-
2 * 34000, native bifunctional enzyme, associated with cyclohydrolase, SDS-PAGE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
-
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
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
isolation of cDNA and the gene encoding the murine cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (DCS)
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
enzyme distribution suggests it can be useful as an oncodevelopmental marker
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Mackenzie, R.E.
Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase
Methods Enzymol.
281
171-177
1997
Saccharomyces cerevisiae, Drosophila melanogaster, Homo sapiens, Mus musculus, Spodoptera frugiperda
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
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
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
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)
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
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
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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