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Information on EC 1.5.1.20 - methylenetetrahydrofolate reductase [NAD(P)H] and Organism(s) Mus musculus and UniProt Accession Q9WU20
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1.5.1.20 methylenetetrahydrofolate reductase [NAD(P)H]IUBMB Comments
A flavoprotein (FAD). The enzyme catalyses the reversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, playing an important role in folate metabolism by regulating the distribution of one-carbon moieties between cellular methylation reactions and nucleic acid synthesis. This enzyme, characterized from Protozoan parasites of the genus Leishmania, is unique among similar characterized eukaryotic enzymes in that it lacks the C-terminal allosteric regulatory domain (allowing it to catalyse a reversible reaction) and uses NADH and NADPH with equal efficiency under physiological conditions. cf. EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); and EC 1.5.7.1, methylenetetrahydrofolate reductase (ferredoxin).
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Word Map
- 1.5.1.20
- nitrite
- homocysteine
- medicine
- paracoccus
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assimilatory
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denitrification
- chlorate
- narghi
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resde
- napc
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molybdoenzyme
- pantotrophus
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ammonification
- nutrition
- analysis
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
respiratory nitrate reductase, 10-methylenetetrahydrofolate reductase, napab, met13, n5,n10-methylenetetrahydrofolate reductase, n5,10-methylenetetrahydrofolate reductase, atmthfr-1, methylenetetrahydrofolate reductase (nadph), 5,10-ch2-h4folate reductase, 5,10-methylenetetrahydrofolate reductase (nadph), 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5,10-CH2-H4folate reductase
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5,10-methylenetetrahydrofolate reductase
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5,10-methylenetetrahydrofolate reductase (NADPH)
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5,10-methylenetetrahydrofolic acid reductase
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5,10-methylenetetrahydropteroylglutamate reductase
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5-methyltetrahydrofolate:NAD oxidoreductase
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5-methyltetrahydrofolate:NAD+ oxidoreductase
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5-methyltetrahydrofolate:NADP+ oxidoreductase
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methylenetetrahydrofolate (reduced riboflavin adenine dinucleotide) reductase
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methylenetetrahydrofolate reductase
methylenetetrahydrofolate reductase (NADPH)
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methylenetetrahydrofolic acid reductase
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MTHFR
MTHFR2
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N5,10-methylenetetrahydrofolate reductase
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N5,N10-methylenetetrahydrofolate reductase
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reductase, methylenetetrahydrofolate (reduced nicotinamide adenine dinucleotide phosphate)
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reductase, methylenetetrahydrofolate (reduced riboflavin adenine dinucleotide)
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methylenetetrahydrofolate reductase
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MTHFR
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
5-methyltetrahydrofolate:NAD(P)+ oxidoreductase
A flavoprotein (FAD). The enzyme catalyses the reversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, playing an important role in folate metabolism by regulating the distribution of one-carbon moieties between cellular methylation reactions and nucleic acid synthesis. This enzyme, characterized from Protozoan parasites of the genus Leishmania, is unique among similar characterized eukaryotic enzymes in that it lacks the C-terminal allosteric regulatory domain (allowing it to catalyse a reversible reaction) and uses NADH and NADPH with equal efficiency under physiological conditions. cf. EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); and EC 1.5.7.1, methylenetetrahydrofolate reductase (ferredoxin).
CAS REGISTRY NUMBER
COMMENTARY
71822-25-8
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9028-69-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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ir
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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inhibited by a dominant-negative mutant of inositol-requiring enzyme-1, a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduce MTHFR activation
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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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thapsigargin
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treatment of cells results in increase in enzyme mRNA and protein
Valproic acid
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300 mg/kg treatment increases MTHFR promoter activity 2.5fold and MTHFR mRNA and protein 3.7fold
additional information
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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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additional information
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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
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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). MTHR_MOUSE
654
0
74580
Swiss-Prot
other Location (Reliability: 3)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
nutrition
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mice carrying a mutation in the adenomatous polyposis coli gene Apc, a model for intestinal polyposis, fed with high folate diets from weaning develop more adenomas than those fed the folic acid deficient diet or the control diet. Mthfr deficiency does not affect adenoma number. When the folic acid deficient diet and control diet are administered to dams prior to conception, throughout pregnancy and continued in offspring post-weaning, Apc -/+ offspring fed folic acid deficient diet develop fewer adenomas than those fed control diet. Mthfr+/- genotype of the mother or of the offspring also reduces adenoma numbers in the Apc -/+ offspring. Adenoma number is inversely correlated with plasma homocysteine, intestinal dUTP/dTTP ratios, and levels of intestinal apoptosis
medicine
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MTHFR deficiency in mice is accompanied with hyperhomocysteinemia and decreased hematocrit, hemoglobin, and red blood cell numbers, increased nephrotoxicity und hepatotoxicity compared to wild type animals
medicine
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maternal MTHFR and dietary folate deficiencies in Mthfr +/- mice result in increased developmental delays and smaller embryos. Folate-deficient mice also have increased embryonic losses and severe placental defects, including placental abruption and disturbed patterning of placental layers. Folate-deficient placentae have decreased ApoA-I expression, and there is a trend toward a negative correlation between ApoA-I expression with maternal homocysteine concentrations
medicine
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mice carrying a mutation in the adenomatous polyposis coli gene Apc, a model for intestinal polyposis, fed with high folate diets from weaning develop more adenomas than those fed the folic acid deficient diet or the control diet. Mthfr deficiency does not affect adenoma number. When the folic acid deficient diet and control diet are administered to dams prior to conception, throughout pregnancy and continued in offspring post-weaning, Apc -/+ offspring fed folic acid deficient diet develop fewer adenomas than those fed control diet. Mthfr+/- genotype of the mother or of the offspring also reduces adenoma numbers in the Apc -/+ offspring. Adenoma number is inversely correlated with plasma homocysteine, intestinal dUTP/dTTP ratios, and levels of intestinal apoptosis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Chwatko, G.; Boers, G.H.; Strauss, K.A.; Shih, D.M.; Jakubowski, H.
Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice
FASEB J.
21
1707-1713
2007
Homo sapiens, Mus musculus
Leclerc, D.; Rozen, R.
Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer
J. Biol. Chem.
283
3151-3160
2008
Mus musculus
Roy, M.; Leclerc, D.; Wu, Q.; Gupta, S.; Kruger, W.D.; Rozen, R.
Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency
J. Cell. Biochem.
105
467-476
2008
Mus musculus
Kasap, M.; Sazci, A.; Ergul, E.; Akpinar, G.
Molecular phylogenetic analysis of methylenetetrahydrofolate reductase family of proteins
Mol. Phylogenet. Evol.
42
838-846
2007
Agrobacterium tumefaciens (Q7CXU3), Aquifex aeolicus (O67422), Arabidopsis thaliana (O80585), Aspergillus nidulans (Q5B0P7), Aspergillus oryzae (Q2UEQ8), Bacteroides thetaiotaomicron (Q8A146), Bifidobacterium longum (Q8G652), Bordetella bronchiseptica (A0A0H3LLF9), Bordetella parapertussis, Bos taurus (Q5I598), Bradyrhizobium japonicum (Q89UJ7), Brucella suis (A0A0H3G3R1), Caenorhabditis elegans (Q17693), Candida albicans (Q5AEI0), Candidatus Blochmannia floridanus (Q7VRL4), Caulobacter vibrioides (Q9A6F4), Chromobacterium violaceum (Q7NZF6), Collimonas fungivorans (Q6J6A1), Corynebacterium diphtheriae (Q6NGB6), Corynebacterium glutamicum (Q8NNM2), Coxiella burnetii (Q83A63), Desulfovibrio vulgaris (Q72DD2), Dictyostelium discoideum (Q54X84), Escherichia coli, Fusarium graminearum, Gloeobacter violaceus (Q7NMH7), Homo sapiens (P42898), Leptospira interrogans (Q9L5C1), Macaca fascicularis (Q60HE5), Macaca mulatta, Mesorhizobium loti (Q98K87), Methanosarcina mazei (Q8PZQ4), Mus musculus (Q9WU20), Oryza sativa (Q10BJ7), Pasteurella multocida (Q9CP31), Photorhabdus luminescens (Q7MYD0), Prochlorococcus marinus (Q7VE38), Pseudomonas syringae (Q87V72), Pyricularia grisea, Ralstonia solanacearum (Q8Y389), Rattus norvegicus, Rhodopirellula baltica (Q7UNJ7), Rhodopseudomonas palustris (Q6N3J2), Saccharomyces cerevisiae (P53128), Schizosaccharomyces pombe (Q10258), Shigella flexneri (Q0SY49), Sinorhizobium meliloti (Q92NK1), Streptococcus pneumoniae (Q8DQT1), Tetraodon nigroviridis (Q4T956), Thermus thermophilus (Q72H39), Vibrio cholerae (Q9KNP6), Vibrio parahaemolyticus (Q87L52), Vibrio vulnificus (Q7MH66), Wolinella succinogenes (Q7M8S8), Xenopus laevis (Q7ZWU2), Xylella fastidiosa (Q9PEA7), Zea mays (Q9SE94), [Candida] glabrata (Q6FU20)
Celtikci, B.; Leclerc, D.; Lawrance, A.K.; Deng, L.; Friedman, H.C.; Krupenko, N.I.; Krupenko, S.A.; Melnyk, S.; James, S.J.; Peterson, A.C.; Rozen, R.
Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice
Pharmacogenet. Genomics
18
577-589
2008
Mus musculus
Pickell, L.; Li, D.; Brown, K.; Mikael, L.G.; Wang, X.L.; Wu, Q.; Luo, L.; Jerome-Majewska, L.; Rozen, R.
Methylenetetrahydrofolate reductase deficiency and low dietary folate increase embryonic delay and placental abnormalities in mice
Birth Defects Res. Part A Clin. Mol. Teratol.
85
531-541
2009
Mus musculus
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