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IUBMB CommentsA 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).
Synonyms
respiratory nitrate reductase, 10-methylenetetrahydrofolate reductase, napab, met13, n5,n10-methylenetetrahydrofolate reductase, n5,10-methylenetetrahydrofolate reductase, methylenetetrahydrofolate reductase (nadph), atmthfr-1, 5,10-ch2-h4folate reductase, 5,10-methylenetetrahydrofolate reductase (nadph),
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methylenetetrahydrofolate reductase
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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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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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methylenetetrahydrofolate reductase
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MTHFR
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A23187
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treatment of cells results in increase in enzyme mRNA and protein
homocysteine
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treatment of cells results in increase in enzyme mRNA and protein
inositol-requiring enzyme-1
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the induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1
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thapsigargin
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treatment of cells results in increase in enzyme mRNA and protein
tunicamycin
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treatment of cells results in increase in enzyme mRNA and protein
Valproic acid
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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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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
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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
brenda
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
brenda
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
brenda
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)
brenda
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
brenda
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
brenda
Lawrance, A.K.; Deng, L.; Rozen, R.
Methylenetetrahydrofolate reductase deficiency and low dietary folate reduce tumorigenesis in Apc min/+ mice
Gut
58
805-811
2009
Mus musculus
brenda