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Information on EC 1.5.1.20 - methylenetetrahydrofolate reductase [NAD(P)H] and Organism(s) Saccharomyces cerevisiae and UniProt Accession P53128
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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
-
assimilatory
-
denitrification
- chlorate
- narghi
-
resde
- napc
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molybdoenzyme
- pantotrophus
-
ammonification
- nutrition
- analysis
The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
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
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methylenetetrahydrofolate reductase (NADPH)
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methylenetetrahydrofolic acid reductase
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MTHFR
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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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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 + NADH + H+
5-methyltetrahydrofolate + NAD+
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r
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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r
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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?
5,10-methylenetetrahydrofolate + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme encoded by MET13 produces 5-methyltetrahydrofolate used for methylation of homocysteine for methionine biosynthesis in vivo, NADPH is the likely natural reductant
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?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
additional information
?
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reverse reaction: menadione and 2,6-dichlorophenolindophenol and NADP+ are not effective as electron acceptor
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?
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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equilibrium lies far in favor of 5-methyltetrahydrofolate formation
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r
5,10-methylenetetrahydrofolate + reduced acceptor
5-methyltetrahydrofolate + oxidized acceptor
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forward reaction: NADPH as reduced acceptor
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r
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 + NADPH
5-methyltetrahydrofolate + NADP+
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enzyme encoded by MET13 produces 5-methyltetrahydrofolate used for methylation of homocysteine for methionine biosynthesis in vivo, NADPH is the likely natural reductant
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
only active with the chimeric mutant enzyme, not with the wild-type
NADH
only active with the chimeric mutant enzyme, not with the wild-type
additional information
wild-type shows no activity with NADH/NAD+
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additional information
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wild-type shows no activity with NADH/NAD+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
S-adenosyl-L-methionine
feed-back regulation of the methyl group biosynthesis pathway in vivo, the chimeric mutant enzyme is insensitive to inhibition by S-adenosyl-L-methionine
additional information
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gene contains a putative S-adenosylmethionione binding sequence, that is inhibitory in eukaryotic MTHFR
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.011
5,10-methylenetetrahydrofolate
recombinant enzyme, with NADPH, pH 7.2
0.106
5,10-methylenetetrahydrofolate
recombinant chimeric mutant enzyme, with NADH, pH 7.2
0.152
5,10-methylenetetrahydrofolate
recombinant chimeric mutant enzyme, with NADPH, pH 7.2
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.455
5,10-methylenetetrahydrofolate
recombinant enzyme, with NADPH, pH 7.2
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
construction of a chimeric enzyme comprising the yeast N-terminal domain and the Arabidopsis thaliana C-terminal domain, recombinant expression in and complementation of an enzyme-deficient mutant strain with altered sensitivity to S-adenosyl-L-methionine and altered cofactor specifcity
additional information
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construction of a chimeric enzyme comprising the yeast N-terminal domain and the Arabidopsis thaliana C-terminal domain, recombinant expression in and complementation of an enzyme-deficient mutant strain with altered sensitivity to S-adenosyl-L-methionine and altered cofactor specifcity
additional information
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mutant strain RRY1 with single disruption of MET13 and strain RRY3 with double disruption of both MET12 and MET13, but not strain RRY2 with single disruption of MET12, result in loss of MTHFR activity and methionine auxothrophy, they can be complemented by overexpression of the human enzyme, but not by overexpression of the Escherichia coli metF gene
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of chimeric mutant in an enzyme-deficient strain, overexpression of the plant enzyme from Arabidopsis thaliana in an enzyme-deficient strain can complement the mutant and results in 8fold increased accumulation of S-adenosyl-L-methionine, mechanism overview
cloning, disruption and expression of the two genes MET12 and MET13 encoding isoenzymes of MTHFR, MET12 is located on chromosome XVI and encodes a 657 amino acids protein, MET13 is located on chromosome VII, encodes a 599 amino acids protein and is responsible for most of the activity in cell, expression in Escherichia coli BL21
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Raymond, R.K.; Kastanos, E.K.; Appling, D.R.
Saccharomyces cerevisiae expresses two genes encoding isoenzymes of methylenetetrahydrofolate reductase
Arch. Biochem. Biophys.
372
300-308
1999
Saccharomyces cerevisiae, Saccharomyces cerevisiae DAY4, Schizosaccharomyces pombe
Roje, S.; Chan, S.Y.; Kaplan, F.; Raymond, R.K.; Horne, D.W.; Appling, D.R.; Hanson, A.D.
Metabolic endineering in yeast demonstrates that S-adenosylmethionine controls flux through the methylenetetrahydrofolate reductase reaction in vivo
J. Biol. Chem.
277
4056-4061
2002
Arabidopsis thaliana, Saccharomyces cerevisiae (P53128), Saccharomyces cerevisiae
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)
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