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Information on EC 1.5.7.1 - methylenetetrahydrofolate reductase (ferredoxin)
for references in articles please use BRENDA:EC1.5.7.1
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EC Tree 1 Oxidoreductases
1.5 Acting on the CH-NH group of donors
1.5.7 With an iron-sulfur protein as acceptor
1.5.7.1 methylenetetrahydrofolate reductase (ferredoxin)
IUBMB Comments
An iron-sulfur flavoprotein that also contains zinc. The enzyme from Clostridium formicoaceticum catalyses the reduction of methylene blue, menadione, benzyl viologen, rubredoxin or FAD with 5-methyltetrahydrofolate and the oxidation of reduced ferredoxin or FADH2 with 5,10-methylenetetrahydrofolate. However, unlike EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); or EC 1.5.1.20, methylenetetrahydrofolate reductase [NAD(P)H], there is no activity with either NADH or NADP+.
The enzyme appears in viruses and cellular organisms
Reaction Schemes
showSynonyms
methylene-tetrahydrofolate reductase, metvf-type mthfr, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
metF
methylene-H4F reductase
methylenetetrahydrofolate reductase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5-methyltetrahydrofolate + oxidized ferredoxin = 5,10-methylenetetrahydrofolate + reduced ferredoxin + 2 H+
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PATHWAY SOURCE
PATHWAYS
MetaCyc
folate transformations I, reductive acetyl coenzyme A pathway I (homoacetogenic bacteria)
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SYSTEMATIC NAME
IUBMB Comments
5-methyltetrahydrofolate:ferredoxin oxidoreductase
An iron-sulfur flavoprotein that also contains zinc. The enzyme from Clostridium formicoaceticum catalyses the reduction of methylene blue, menadione, benzyl viologen, rubredoxin or FAD with 5-methyltetrahydrofolate and the oxidation of reduced ferredoxin or FADH2 with 5,10-methylenetetrahydrofolate. However, unlike EC 1.5.1.53, methylenetetrahydrofolate reductase (NADPH); EC 1.5.1.54, methylenetetrahydrofolate reductase (NADH); or EC 1.5.1.20, methylenetetrahydrofolate reductase [NAD(P)H], there is no activity with either NADH or NADP+.
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CAS REGISTRY NUMBER
COMMENTARY
9028-69-7
cf. EC 1.7.99.5
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + FADH2
5,10-methylenetetrahydrofolate + FAD
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Substrates: -
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5,10-methylenetetrahydrofolate + reduced ferredoxin
5-methyltetrahydrofolate + ferredoxin
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Substrates: -
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5-methyltetrahydrofolate + 2 benzyl viologen
5,10-methylenetetrahydrofolate + 2 reduced benzyl viologen + 2 H+
5-methyltetrahydrofolate + 2 oxidized ferredoxin
5,10-methylenetetrahydrofolate + 2 reduced ferredoxin + 2 H+
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Substrates: -
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r
5-methyltetrahydrofolate + benzyl viologen
5,10-methylenetetrahydrofolate + reduced benzyl viologen
5-methyltetrahydrofolate + FAD
5,10-methylenetetrahydrofolate + FADH2
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Substrates: 11% of the activity with methylene blue
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5-methyltetrahydrofolate + menadione
5,10-methylenetetrahydrofolate + reduced menadiol
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Substrates: 25% of the activity with methylene blue
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5-methyltetrahydrofolate + rubredoxin
5,10-methylenetetrahydrofolate + reduced rubredoxin
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Substrates: 11% of the activity with methylene blue
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5-methyltetrahydrofolate + 2 benzyl viologen
5,10-methylenetetrahydrofolate + 2 reduced benzyl viologen + 2 H+
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Substrates: -
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r
5-methyltetrahydrofolate + 2 benzyl viologen
5,10-methylenetetrahydrofolate + 2 reduced benzyl viologen + 2 H+
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Substrates: -
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r
5-methyltetrahydrofolate + benzyl viologen
5,10-methylenetetrahydrofolate + reduced benzyl viologen
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Substrates: -
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5-methyltetrahydrofolate + benzyl viologen
5,10-methylenetetrahydrofolate + reduced benzyl viologen
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Substrates: 11% of the activity with methylene blue
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additional information
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Substrates: no activity with pyridine nucleotides
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additional information
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Substrates: reduced ferredoxin cannot be the physiological electron donor in vivo, since growth by acetogenesis from H2 + CO2 has a negative ATP yield. Reduced methyl viologen is used as electron donor for following the MVred:methylene-THF oxidoreductase activity during the purification procedure. With ethanol as product and Fdred as electron donor for the MetVF-type MTHFR, the ATP yield becomes slightly positive (0.14 ATP/ethanol). But since only minor amounts of ethanol are produced, this does not result in an overall positive ATP yield
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additional information
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Substrates: the enzyme catalyzes reduction of methylenetetrahydrofolate with reduced benzyl viologen but not with NAD(P)H in either the absence or presence of oxidized ferredoxin. The enzyme also catalyzes the reversible reduction of benzyl viologen with NADH (diaphorase activity) at 48 U/mg
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additional information
?
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Substrates: the enzyme catalyzes reduction of methylenetetrahydrofolate with reduced benzyl viologen but not with NAD(P)H in either the absence or presence of oxidized ferredoxin. The enzyme also catalyzes the reversible reduction of benzyl viologen with NADH (diaphorase activity) at 48 U/mg
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ferredoxin
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the dimer consisting of two of MetVF heterodimers contains 1.87 mol FMN per mol dimeric heterodimer. Reduced ferredoxin cannot be the physiological electron donor in vivo, since growth by acetogenesis from H2 + CO2 has a negative ATP yield
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FMN
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the enzyme contains 3.4 nmol FAD per mg of enzyme protein, the purified recombinant MetF contains FMN rather than FAD
FAD
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the enzyme contains 3.1 nmol FAD per mg of enzyme protein. In the absence of FAD, the enzyme is still active, the purified recombinant MetF contains FMN rather than FAD
additional information
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The enzyme complex does not catalyze the reduction of methylene-H4F with NADH or NADPH. The enzyme complex subunit HdrA contains iron-sulfur clusters and 2 FADs and catalyzes the reduction of benzyl viologen with NADH. But the physiological electron donor for methylenetetrahydrofolate reduction in Moorella thermoacetica is NADH, and the exergonic reduction of methylenetetrahydrofolate with NADH is coupled via flavin-based electron bifurcation with the endergonic reduction of an yet unknown electron acceptor
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additional information
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NADH and NADPH are not used as electron donor. MTHFR is able to use artificial electron donors for the reduction of methylene-THF
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Iron
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iron-sulfur protein, contains 15.2 iron and 19.5 acid labile sulfide per 237000 Da enzyme
additional information
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the dimer consisting of two of MetVF heterodimers has 16.2 mol acid-labile sulfur per mol enzyme
Fe2+
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the dimer consisting of two of MetVF heterodimers has 14.9 mol iron per mol enzyme
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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the reduction of benzyl viologen with NADH is competitively inhibited by NADP+
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
MetV
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the enzyme complex subunit MetV, an iron-sulfur zinc protein, is required by MetF for full activity, and activates the enzyme 70fold with benzyl viologen
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Abortion, Habitual
Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Acquired Immunodeficiency Syndrome
[Superior mesenteric venous thrombosis. Report of 2 cases and review of the literature]
Cardiovascular Diseases
Polymorphic methyl group metabolism genes in patients with transitional cell carcinoma of the urinary bladder.
Colorectal Neoplasms
Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis.
Coronary Artery Disease
Association of the methylene-tetrahydrofolate reductase gene rs1801133 C677T variant with serum homocysteine levels, and the severity of coronary artery disease.
Coronary Artery Disease
Relationship of the 1793G-A and 677C-T polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene to coronary artery disease.
Diabetes Mellitus
Association of ACE and MTHFR genetic polymorphisms with type 2 diabetes mellitus: Susceptibility and complications.
Diabetes Mellitus, Type 2
Association of ACE and MTHFR genetic polymorphisms with type 2 diabetes mellitus: Susceptibility and complications.
Down Syndrome
[Mutations in the methylene-tetrahydrofolate reductase gene and Down syndrome]
Folic Acid Deficiency
Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR.
Hyperhomocysteinemia
Congenital MTHFR deficiency causing early-onset cerebral stroke in a case homozygous for MTHFR thermolabile variant.
Hyperhomocysteinemia
Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon.
Hyperhomocysteinemia
Hyperhomocysteinemia and MTHFR C677T and A1298C polymorphisms are associated with chronic allograft nephropathy in renal transplant recipients.
Hyperhomocysteinemia
Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion.
Hyperhomocysteinemia
Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Hyperhomocysteinemia
Role of Genetic Background in Cardiovascular Risk Markers Changes in Water Polo Players.
Hypertension
Genotype of the CYBA promoter -930A/G, polymorphism C677T of the MTHFR and APOE genotype in patients with hypertensive disorders of pregnancy: An observational study.
Ischemic Stroke
Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke.
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Association between methylene-tetrahydrofolate reductase gene polymorphisms and chronic myeloid leukemia.
Leukoencephalopathies
Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings.
Lung Neoplasms
Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study.
Lung Neoplasms
Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms.
Lung Neoplasms
The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.
methylenetetrahydrofolate reductase (ferredoxin) deficiency
Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings.
methylenetetrahydrofolate reductase (ferredoxin) deficiency
Genetic defects of folate and cobalamin metabolism.
Neoplasms
Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes.
Neoplasms
Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors.
Neoplasms
Polymorphic methyl group metabolism genes in patients with transitional cell carcinoma of the urinary bladder.
Nijmegen Breakage Syndrome
Polymorphisms in DNA repair and metabolic genes in bladder cancer.
Obesity
Are genetic variants of the methyl group metabolism enzymes risk factors predisposing to obesity?
Osteonecrosis
The 677C-->T mutation of the methylene-tetrahydrofolate reductase gene in the pathogenesis of osteonecrosis of the femoral head.
Osteoporosis
Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Pre-Eclampsia
Genotype of the CYBA promoter -930A/G, polymorphism C677T of the MTHFR and APOE genotype in patients with hypertensive disorders of pregnancy: An observational study.
Scleroderma, Systemic
Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon.
Small Cell Lung Carcinoma
Prognostic significance of folate metabolism polymorphisms for lung cancer.
Stroke
Ischaemic stroke following tranexamic acid in young patients carrying heterozygosity of MTHFR C677T.
Stroke
The plasminogen activator inhibitor (PAI)-1 promoter 4G/4G genotype is not associated with ischemic stroke in a population of German children. Childhood Stroke Study Group.
Thrombophilia
Embryo implantation after assisted reproductive procedures and maternal thrombophilia.
Thrombophilia
Factor v Leiden and antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke.
Thrombophilia
The frequency of factor V Leiden and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey.
Thrombophilia
[Successful direct thrombin inhibitor treatment of a left atrial appendage thrombus developed under rivaroxaban therapy].
Thrombosis
Hyperhomocysteinemia and the MTHFR C677T mutation in central retinal vein occlusion.
Thrombosis
Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.
Thrombosis
[Superior mesenteric venous thrombosis. Report of 2 cases and review of the literature]
Thrombotic Stroke
Neonatal stroke associated with de novo antiphospholipid antibody and homozygous 1298C/C methylenetetrahydrofolate reductase mutation.
Urinary Bladder Neoplasms
Genetic variation in Glutathione S-Transferase Omega-1, Arsenic Methyltransferase and Methylene-tetrahydrofolate Reductase, arsenic exposure and bladder cancer: a case-control study.
Urinary Bladder Neoplasms
Polymorphisms in DNA repair and metabolic genes in bladder cancer.
Uterine Cervical Neoplasms
Polymorphism in folate- and methionine-metabolizing enzyme and aberrant CpG island hypermethylation in uterine cervical cancer.
Vascular Diseases
Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon.
Vascular Diseases
Hyperhomocysteinemia and Dementia Associated With Severe Cortical Atrophy, but No Amyloid Burden.
Vascular Diseases
Hyperhomocysteinemia and MTHFR C677T and A1298C polymorphisms are associated with chronic allograft nephropathy in renal transplant recipients.
Venous Thromboembolism
The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism.
Vitamin B 6 Deficiency
[Deregulation of homocysteine metabolism and consequences for the vascular system]
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.8
5-methyltetrahydrofolate
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pH 7.5, 45°C, recombinant enzyme, with benzyl viologen
0.1
benzyl viologen
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pH 7.5, 45°C, recombinant enzyme, with 5-methyltetrahydrofolate
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
16
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purified enzyme, substrate 5-methyltetrahydrofolate, pH 7.5, 45°C
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
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optimum growth temperature of Moorella thermoacetica is 55°C
brenda
additional information
-
optimum growth temperature of Moorella thermoacetica is 55°C
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brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
metabolism
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type I- and III-MTHFRs are neither involved directly (as terminal electron acceptor) nor indirectly (by producing the fuel for the respiratory enzymes, reduced ferredoxin, by electron bifurcation) in energy conservation. Type IV-MTHFR may be coupled to energy conservation, either directly or indirectly. Modeling of cofactor dependence of enzyme MTHFR, detailed overview
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterohexamer
tetramer
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(1 * 23000, MetV + 1 * 33000, MetF)2, SDS-PAGE, a dimer consisting of two of MetVF heterodimers
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5 - 9
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enzyme MTHFR shows maximal activity at pH 7.0 and is significantly less active with only 2% activity left at pH 5.0 and 6% activity left at pH 9.0
764936
7.1 - 7.6
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the enzyme is more stable in Tris/HCl than in triethanolamine/HCl or phosphate buffer
437714
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37 - 80
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enzyme activity is relatively stable between 37°C and 50°C but decreases to 56% at 20°C and 23% at 80°C
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme loses 50% of the activity within 2 h in aerobic buffer (0.1 M Tris/HCl buffer, pH 7.4) with or without a reducing agent and in anaerobic buffer without a reducing agent
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437714
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
10°C, pH 7.4, 50 mM Tris/HCl containing 20% glycerol and 2 mM dithionite in an anaerobic chamber
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
native enzyme 57.6fold from cytoplasm by anion exchange chromatography, hydrophobic interaction chromatography, ultrafiltration, and gel filtration, to homogeneity
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native enzyme aerobically 40fold by ultracentrifugation, anion exchange chromatography, gel filtration, ultrafiltration, hydroxyapatite chromatography, followed by again ultrafiltration and gel filtration, enzyme MetF copurifies with the other five proteins encoded in the unit in a hexaheteromeric complex with an apparent molecular mass in the 320-kDa range. Recombinant Strep-tagged enzyme MetF anaerobically from Escherichia coli strain C41(DE3) by avidine affinity chromatography and ultrafiltration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene metF, which is part of a transcription unit also containing the genes hdrCBA, mvhD, and metV, genetic structure, recombinant expression of Strep-tagged enzyme MetF in Escherichia coli strain C41(DE3) harboring pCodonPlus and pRKISC, the recombinant MetF contains FMN rather than FAD
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Clark, J.E.; Ljungdahl, L.G.
Purification and properties of 5,10-methylenetetrahydrofolate reductase, an iron-sulfur flavoprotein from Clostridium formicoaceticum
J. Biol. Chem.
259
10845-10849
1984
Clostridium formicaceticum
brenda
Mock, J.; Wang, S.; Huang, H.; Kahnt, J.; Thauer, R.K.
Evidence for a hexaheteromeric methylenetetrahydrofolate reductase in Moorella thermoacetica
J. Bacteriol.
196
3303-3314
2014
Moorella thermoacetica, Moorella thermoacetica DSM 521
brenda
Oeppinger, C.; Kremp, F.; Mueller, V.
Is reduced ferredoxin the physiological electron donor for MetVF-type methylenetetrahydrofolate reductases in acetogenesis? a hypothesis
Int. Microbiol.
25
75-88
2021
Clostridium ljungdahlii
brenda
EXTERNAL LINKS (specific for EC-Number 1.5.7.1)
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Release 2023.1 (January 2023)
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