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Information on EC 1.5.1.5 - methylenetetrahydrofolate dehydrogenase (NADP+)
for references in articles please use BRENDA:EC1.5.1.5
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EC Tree 1 Oxidoreductases
1.5 Acting on the CH-NH group of donors
1.5.1 With NAD+ or NADP+ as acceptor
1.5.1.5 methylenetetrahydrofolate dehydrogenase (NADP+)
IUBMB Comments
In eukaryotes, occurs as a trifunctional enzyme also having methenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9) and formate—tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes occurs as a bifunctional enzyme also having methenyltetrahydrofolate cyclohydrolase activity (EC 3.5.4.9).
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
- 1.5.1.5
-
one-carbon
-
cyclohydrolase
- thymidylate
-
trifunctional
- methenyltetrahydrofolate
- 5,10-methenyltetrahydrofolate
- 10-formyltetrahydrofolate
- mthfd1l
-
folate-dependent
- formyltetrahydrofolate
-
folate-mediated
-
c1-tetrahydrofolate
-
3.5.4.9
-
transcobalamin
-
10-formyl-thf
-
6.3.4.3
-
remethylation
-
5,10-methenyl-thf
-
1-carbon
-
dehydrogenase-cyclohydrolase
-
megaloblastic
- medicine
Reaction Schemes
showSynonyms
methylenetetrahydrofolate dehydrogenase, 5,10-methylenetetrahydrofolate dehydrogenase, mthfd2 protein, ch2-thf dehydrogenase, mthfd1 protein, mitochondrial methylenetetrahydrofolate dehydrogenase, methylenetetrahydrofolate dehydrogenase (nadp+ dependent), bmmthfd, n5,n10-methylenetetrahydrofolate dehydrogenase, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5,10-CH2-THF dehydrogenase
5,10-methenyltetrahydrofolate cyclohydrolase/5,10-methylene tetrahydrofolate dehydrogenase
-
-
5,10-methylenetetrahydrofolate dehydrogenase
5,10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
CH2-THF dehydrogenase
DHCH
DHCH1
FolD
methylenetetrahydrofolate dehydrogenase
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
MTHFD1
MTHFD1 protein
-
trifunctional cytosolic NADP(+)-dependent methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase
MTHFD2
MTHFD2 protein
-
bifunctional mitochondrial NAD(+)-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase, derived from trifunctional precursor by loss of the formyltetrahydrofolate synthetase domain, unique in mammals
MTHFD2L
MTHFDC
N5,N10-methylenetetrahydrofolate dehydrogenase
-
-
-
-
N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
NADP-dependent 5,10-methylene-THF dehydrogenase
-
folD encodes a monofunctional enzyme
5,10-methylenetetrahydrofolate dehydrogenase
-
-
-
-
5,10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
bifunctional enzyme
DHCH1
-
bifuntional enzyme with 5,10-mehtylene tetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activity in Leishmania major
methylenetetrahydrofolate dehydrogenase
-
-
-
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
bifunctional enzyme
N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
bifunctional enzyme
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5,10-methylenetetrahydrofolate + NADP+ = 5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
redox reaction
-
-
-
-
reduction
-
-
-
-
oxidation
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
KEGG
MetaCyc
folate transformations I, folate transformations II (plants), folate transformations III (E. coli), formaldehyde oxidation VII (THF pathway), formate assimilation into 5,10-methylenetetrahydrofolate, purine nucleobases degradation II (anaerobic), reductive acetyl coenzyme A pathway I (homoacetogenic bacteria), reductive glycine pathway of autotrophic CO2 fixation
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SYSTEMATIC NAME
IUBMB Comments
5,10-methylenetetrahydrofolate:NADP+ oxidoreductase
In eukaryotes, occurs as a trifunctional enzyme also having methenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9) and formate---tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes occurs as a bifunctional enzyme also having methenyltetrahydrofolate cyclohydrolase activity (EC 3.5.4.9).
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CAS REGISTRY NUMBER
COMMENTARY
9029-14-5
-
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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
(6R,S)-5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: monofunctional enzyme, no methenyltetrahydrofolate cyclohydrolase activity
Products: -
Products: -
?
5,10-methylene tetrahydrofolate + NAD+
5,10-methenyl tetrahydrofolate + NADH + H+
-
Substrates: bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH
-
Substrates: trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH
Substrates: dehydrogenase activity of MTHFD1
Products: -
Products: -
r
5,10-methylene-tetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
Substrates: combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
Products: 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
Products: 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
r
5,10-methylenetetrahydropteroate + NADP+
5,10-methenyltetrahydropteroate + NADPH
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
5,10-methylenetetrahydropteroylpoly-L-glutamate + NADP+
5,10-methenyltetrahydropteroylpoly-L-glutamate + NADPH + H+
5,10-methylenetetrahydropteroyltriglutamate + NADP+
5,10-methenyltetrahydropteroyltriglutamate + NADPH
tetrahydropteroylglutamic acid + NADP+
?
-
Substrates: -
Products: -
Products: -
?
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
Substrates: trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
Substrates: DH activity
Products: -
Products: -
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
Substrates: -
Products: the cyclohydrolase forms formyltetrahydrofolate
Products: the cyclohydrolase forms formyltetrahydrofolate
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
Substrates: -
Products: 10-formyl tetrahydrofolate (10-CHO-THF)is the product of subsequently active methenyltetrahydrofolate cyclohydrolase, ATP-dependent formate-tetrahydrofolate ligase catalyzes an alternative one step reaction from tetrahydrofolate + format to 10-formyl tetrahydrofolate
Products: 10-formyl tetrahydrofolate (10-CHO-THF)is the product of subsequently active methenyltetrahydrofolate cyclohydrolase, ATP-dependent formate-tetrahydrofolate ligase catalyzes an alternative one step reaction from tetrahydrofolate + format to 10-formyl tetrahydrofolate
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: the enzyme is involved in the folate recycling pathway
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Escherichia coli B / ATCC 11303
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: the enzyme is involved in the folate recycling pathway
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: deuterated folate substrate also
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
Products: -
Products: -
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
Products: -
Products: -
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
Products: -
Products: -
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
Substrates: NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpoly-L-glutamate + NADP+
5,10-methenyltetrahydropteroylpoly-L-glutamate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydropteroylpoly-L-glutamate + NADP+
5,10-methenyltetrahydropteroylpoly-L-glutamate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydropteroyltriglutamate + NADP+
5,10-methenyltetrahydropteroyltriglutamate + NADPH
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydropteroyltriglutamate + NADP+
5,10-methenyltetrahydropteroyltriglutamate + NADPH
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: the recombinant Bombyx mori MTHFD (bmMTHFD) recognizes 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate as substrates in the presence of NADP+ as well as NAD+
Products: -
Products: -
?
additional information
?
-
Substrates: (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
Products: -
Products: -
?
additional information
?
-
-
Substrates: dehydrogenase and cyclohydrogenase activities are contained in the single bifunctional protein DHCH1
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
Substrates: enzyme MTHFD2Luses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies
Products: -
Products: -
?
additional information
?
-
-
Substrates: enzyme MTHFD2Luses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
Substrates: enzyme MTHFD2Luses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
Substrates: enzyme MTHFD2L uses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies
Products: -
Products: -
?
additional information
?
-
-
Substrates: the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,10-methylene tetrahydrofolate + NAD+
5,10-methenyl tetrahydrofolate + NADH + H+
-
Substrates: bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH
-
Substrates: trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH
Substrates: dehydrogenase activity of MTHFD1
Products: -
Products: -
r
5,10-methylene-tetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
Substrates: combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
Products: 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
Products: 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
Substrates: trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
Products: -
Products: -
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
Substrates: DH activity
Products: -
Products: -
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
Substrates: -
Products: the cyclohydrolase forms formyltetrahydrofolate
Products: the cyclohydrolase forms formyltetrahydrofolate
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
Substrates: -
Products: 10-formyl tetrahydrofolate (10-CHO-THF)is the product of subsequently active methenyltetrahydrofolate cyclohydrolase, ATP-dependent formate-tetrahydrofolate ligase catalyzes an alternative one step reaction from tetrahydrofolate + format to 10-formyl tetrahydrofolate
Products: 10-formyl tetrahydrofolate (10-CHO-THF)is the product of subsequently active methenyltetrahydrofolate cyclohydrolase, ATP-dependent formate-tetrahydrofolate ligase catalyzes an alternative one step reaction from tetrahydrofolate + format to 10-formyl tetrahydrofolate
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NAD+
5,10-methenyltetrahydrofolate + NADH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: the enzyme is involved in the folate recycling pathway
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Escherichia coli B / ATCC 11303
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: the enzyme is involved in the folate recycling pathway
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
Substrates: -
Products: -
Products: -
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
Substrates: -
Products: -
Products: -
?
additional information
?
-
Substrates: (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
Products: -
Products: -
?
additional information
?
-
-
Substrates: dehydrogenase and cyclohydrogenase activities are contained in the single bifunctional protein DHCH1
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
Substrates: MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9
Products: -
Products: -
?
additional information
?
-
-
Substrates: the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
Products: -
Products: -
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
-
instead of NADP as in cytosolic dehydrogenase precursor (higher Km and lower Vmax with NADP)
NAD+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NAD+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamat is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NADP+
-
no dependence on NAD+ in presence of K3PO4 and MgCl2 (required for human mitochondrial NAD+ dependent activity of bifunctional dehydrogenase cyclase)
NADP+
-
reverse cyclohydrolase activity is stimulated by the NADP analog 2',5'-ADP twofold
NADP+
-
the hydrogenase can also us NADP+ but with a higher Km value and lower Vmax than NAD+
NADP+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2 with the substrate 5,10-methylenetetrahydropteroylglutamate is 8.5fold higher than its NADP+-dependent activity. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
NADP+
the enzyme exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+. NAD+-dependent dehydrogenase activity of MTHFD2L with the substrate 5,10-methylenetetrahydropteroylglutamate is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions. While the NAD+-dependent activity of MTHFD2 slightly decreases, its maximal NADP+-dependent activity considerably increases with 5,10-methylenetetrahydropteroylpentaglutamate compared to 5,10-methylenetetrahydropteroylglutamate
additional information
the enzyme MTHFD2L uses both NAD+ and NADP+ for methylenetetrahydrofolate dehydrogenase activity but requires both phosphate and Mg2+ when using NAD+
-
additional information
-
the enzyme MTHFD2L uses both NAD+ and NADP+ for methylenetetrahydrofolate dehydrogenase activity but requires both phosphate and Mg2+ when using NAD+
-
additional information
enzyme MTHFD2L uses both NAD+ and NADP+ for methylenetetrahydrofolate dehydrogenase activity but requires both phosphate and Mg2+ when using NAD+
-
additional information
-
the recombinant Bombyx mori MTHFD (bmMTHFD) recognizes 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate as substrates in the presence of NADP+ as well as NAD+
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K+
Mg2+
phosphate
additional information
Mg2+
required for methylenetetrahydrofolate dehydrogenase activity with NADH
Mg2+
required for methylenetetrahydrofolate dehydrogenase activity with NADH
phosphate
required for methylenetetrahydrofolate dehydrogenase activity with NADH
phosphate
required for methylenetetrahydrofolate dehydrogenase activity with NADH
additional information
phosphate appears to counteract the Mg2+ effect with NADP+
additional information
-
phosphate appears to counteract the Mg2+ effect with NADP+
additional information
phosphate appears to counteract the Mg2+ effect with NADP+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioate
-
-
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
-
5,10-formyltetrahydrofolate substrate analogue inhibits dehydrogenase activity
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
-
competitive substrate analogue
potassium phosphate
-
effect on NADP+-dependent dehydrogenase activity
potassium sulfate
-
effect on NADP+-dependent dehydrogenase activity
additional information
-
no inhibition by pteridine analogues, such as methotrexate, or by hydrophobic diamino-quinazoline, -pyrimidine or -pteridine analogues, such as 2,4-diamino-6-(3,4-dichlorophenoxy)-quinazoline, or 2,4-diamino-6-benzyl-5-(3-phenylpropyl)-pyrimidine, or 2,4-diamino-6,7-diisopropylpteridine
-
phosphate
the NADP+-dependent methylenetetrahydrofolate dehydrogenase activity is inhibited by phosphate, competitive inhibition
phosphate
the NADP+-dependent methylenetetrahydrofolate dehydrogenase activity is inhibited by phosphate, competitive inhibition
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Anemia, Megaloblastic
Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency.
Anemia, Megaloblastic
Update and new concepts in vitamin responsive disorders of folate transport and metabolism.
Anencephaly
Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.
Angina, Stable
Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial).
Atherosclerosis
[Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries]
Atypical Hemolytic Uremic Syndrome
Update and new concepts in vitamin responsive disorders of folate transport and metabolism.
Breast Neoplasms
Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy.
Breast Neoplasms
Increased MTHFD2 expression is associated with poor prognosis in breast cancer.
Carcinogenesis
Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation.
Carcinoma
High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and its Clinical Prognostic Significance.
Carcinoma
Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) is Underexpressed in Clear Cell Renal Cell Carcinoma Tissue and Transfection and Overexpression in Caki-1 Cells Inhibits Cell Proliferation and Increases Apoptosis.
Carcinoma
MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion.
Carcinoma
The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma.
Carcinoma, Hepatocellular
Methylenetetrahydrofolate dehydrogenase 2 overexpression is associated with tumor aggressiveness and poor prognosis in hepatocellular carcinoma.
Carcinoma, Hepatocellular
[The preliminary study on the function of methylenetetrahydrofolate dehydrogenase 2 in hepatocellular carcinoma].
Carcinoma, Non-Small-Cell Lung
Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation.
Carcinoma, Renal Cell
Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) is Underexpressed in Clear Cell Renal Cell Carcinoma Tissue and Transfection and Overexpression in Caki-1 Cells Inhibits Cell Proliferation and Increases Apoptosis.
Carcinoma, Renal Cell
MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion.
Carcinoma, Squamous Cell
The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma.
Colorectal Neoplasms
The importance of mitochondrial folate enzymes in human colorectal cancer.
Congenital Abnormalities
Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects.
Down Syndrome
Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China.
Down Syndrome
Methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study.
Esophageal Squamous Cell Carcinoma
High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and its Clinical Prognostic Significance.
Glioma
Expression and Prognostic Value Identification of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Brain Low-Grade Glioma.
Heart Defects, Congenital
Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect.
Heart Diseases
MTHFR c.1793G>A polymorphism is associated with congenital cardiac disease in a Chinese population.
Hypertension
Investigation of homocysteine-pathway-related variants in essential hypertension.
Hypertension
Significant Association of Methylenetetrahydrofolate dehydrogenase 1 Promoter Hypomethylation with Stroke in a Chinese Population with Primary Hypertension.
Laryngeal Neoplasms
Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer.
Leukemia, Myeloid, Acute
miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia.
Lung Neoplasms
Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation.
Lung Neoplasms
Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer.
Meningomyelocele
Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.
Myocardial Infarction
Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial).
Neoplasms
Association of methylenetetrahydrofolate dehydrogenase 1 polymorphisms with cancer: a meta-analysis.
Neoplasms
Detection and characterisation of novel alternative splicing variants of the mitochondrial folate enzyme MTHFD2.
Neoplasms
Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2.
Neoplasms
High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and its Clinical Prognostic Significance.
Neoplasms
KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in Non Small Cell Lung Cancer cells.
Neoplasms
Methylenetetrahydrofolate dehydrogenase 2 overexpression is associated with tumor aggressiveness and poor prognosis in hepatocellular carcinoma.
Neoplasms
Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development.
Neoplasms
Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer.
Neoplasms
MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3?/?-catenin signalling.
Neoplasms
mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle.
Neoplasms
NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview.
Neoplasms
NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase from ascites tumor cells. Purification and properties.
Neoplasms
p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage.
Neoplasms
Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.
Neoplasms
The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation.
Neoplasms
The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation.
Neural Tube Defects
Association between MTHFD1 G1958A polymorphism and neural tube defects susceptibility: a meta-analysis.
Neural Tube Defects
MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis.
Neural Tube Defects
Paternal transmission of MTHFD1 G1958A variant predisposes to neural tube defects in the offspring.
Neural Tube Defects
Polymorphisms in MTHFD1 Gene and Susceptibility to Neural Tube Defects: A Case-Control Study in a Chinese Han Population with Relatively Low Folate Levels.
Ovarian Neoplasms
Lack of association between MTHFD1 G401A polymorphism and ovarian cancer susceptibility.
Pregnancy Complications
Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.
Prostatic Neoplasms
Lack of association between methylenetetrahydrofolate dehydrogenase 1 G1958A polymorphism and prostate cancer risk: a meta-analysis.
Severe Combined Immunodeficiency
Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency.
Severe Combined Immunodeficiency
Update and new concepts in vitamin responsive disorders of folate transport and metabolism.
Small Cell Lung Carcinoma
Prognostic significance of folate metabolism polymorphisms for lung cancer.
Spinal Dysraphism
The methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G>A variant is not associated with spina bifida risk in the Dutch population.
Squamous Cell Carcinoma of Head and Neck
The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma.
Stroke
A comprehensive association analysis between homocysteine metabolic pathway gene methylation and ischemic stroke in a Chinese hypertensive population.
Stroke
Significant Association of Methylenetetrahydrofolate dehydrogenase 1 Promoter Hypomethylation with Stroke in a Chinese Population with Primary Hypertension.
Urinary Bladder Neoplasms
Expression and Role of Methylenetetrahydrofolate Dehydrogenase 1 Like (MTHFD1L) in Bladder Cancer.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.228
(6R,S)-5,10-methylenetetrahydrofolate
pH 7.6, temperature not specified in the publication
0.068
5,10-methenyltetrahydrofolate
pH 7.6, 30°C, mutant enzyme G122D
0.104
5,10-methenyltetrahydrofolate
pH 7.6, 30°C, mutant enzyme D121A
0.12
5,10-methylene-tetrahydrofolate
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 1 mM NADP+, 30 mM 2-mercaptoethanol, 27°C
0.008
5,10-methylenetetrahydrofolate
-
deuterated, NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
0.009
5,10-methylenetetrahydrofolate
-
NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
0.01
5,10-methylenetetrahydrofolate
-
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase enzyme
0.012
5,10-methylenetetrahydrofolate
-
NAD+-M2+-phopsphate-dependent mitochondrial dehydrogenase-cyclohydrolase enzyme
0.024
5,10-methylenetetrahydrofolate
-
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase enzyme
0.045
5,10-methylenetetrahydrofolate
-
-
0.228
5,10-methylenetetrahydrofolate
pH 7.6, temperature not specified in the publication
0.123
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
0.133
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
0.302
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
0.359
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
0.04
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NAD+
0.042
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NADP+
0.13
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NAD+
0.153
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NADP+
0.507
NAD+
-
NAD+-M2+-phopsphate-dependent mitochondrial dehydrogenase-cyclohydrolase enzyme
0.022
NADP+
-
NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
0.038
NADP+
-
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase enzyme
0.038
NADP+
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 30 mM 2-mercaptoethanol, 27°C, with 250 microM 5,10-methylene-tetrahydrofolate
0.085
NADP+
pH 7.6, temperature not specified in the publication
0.13
NADP+
-
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase enzyme
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
-
Michaelis-Menten kinetics
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
NADP+
-
mutation of Arg173 causes a 500fold increase in the Km value for NADP+, while mutation of Ser197 causes a 20fold increase
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
14
5,10-methylene-tetrahydrofolate
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 1 mM NADP+, 30 mM 2-mercaptoethanol, 27°C
3.2
5,10-methylenetetrahydrofolate
-
deuterated, NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
9.4
5,10-methylenetetrahydrofolate
-
NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
1.5
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
12.4
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
6.4
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
15.4
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
1.3
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NADP+
2.7
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NAD+
7.2
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NADP+
8.8
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NAD+
3.8
NADP+
-
substrate constant: methylenetetrahydrofolate, deuterated, NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
10
NADP+
-
NADP+-dependent bifunctional dehydrogenase-cyclohydrolase domain of the cytoplasmic trifunctional enzyme
10
NADP+
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 30 mM 2-mercaptoethanol, 27°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
120
5,10-methylene-tetrahydrofolate
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 1 mM NADP+, 30 mM 2-mercaptoethanol, 27°C
0.096
5,10-methenyltetrahydrofolate
pH 7.6, 30°C, mutant enzyme D121A
12
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
93
5,10-methylenetetrahydropteroylglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
21
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NADP+ (6.0 mM)
43
5,10-methylenetetrahydropteroylpentaglutamate
pH 8.0, 30°C, at saturating concentrations of NAD+ (1.0 mM)
30.95
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NADP+
47.06
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NADP+
67.5
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, monoglutamylated substrate, with NAD+
67.69
5,10-methylenetetrahydropteroylpoly-L-glutamate
pH 8.0, 30°C, polyglutamylated substrate, with NAD+
260
NADP+
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 30 mM 2-mercaptoethanol, 27°C, with 250 microM 5,10-methylene-tetrahydrofolate
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000105
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioate
-
-
0.000105
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
-
pH 7.3, 27°C, Leishmania wild-type growth is inhibited with an EC50 of 1.1 microM, DHCH1 or formate-tetrahydrofolate ligase overexpressing (FTL) Leishmania transfectants show 4-5fold or 3fold resistance, respectively
0.035
dihydropteroylmonoglutamate
-
varying concentration of tetrahydropteroylmonoglutamate
0.003
dihydropteroylpentaglutamate
-
varying concentration of tetrahydropteroylmonoglutamate
0.000105
LY354899
pH and temperature not specified in the publication
0.61
pteroylglutamate
-
varying concentration of tetrahydropteroylmonoglutamate
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0011 - 0.0051
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
0.0011 - 0.0051
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
0.0011
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
wild type enzyme
0.0045
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
dhch1-/pXNG4-DHCH1 mutant, FV1 line
0.0051
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazol[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
WT/pXNG4-DHCH mutant, FV1 line
0.0011
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
50% growth inhibition of wild-type cell line
0.0033
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
50% growth inhibition of null mutant with plasmid expressing formate-tetrahydrofolate ligase
0.0037
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
50% growth inhibition of wild-type with plasmid expressing formate-tetrahydrofolate ligase
0.0045
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
50% growth inhibition of null mutant with plasmid expressing the enzyme
0.0051
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[3,4-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
Leishmania major
-
50% growth inhibition of wild-type with plasmid expressing the enzyme (overexpressing it as a result)
0.00076
2,4-diamino-6-(3,4-dichlorophenoxy)-quinazoline
Leishmania major
-
dhch1-/pXNG4-DHCH1 mutant, FV1 line
0.0004
2,4-diamino-6-benzyl-5-(3-phenylpropyl)-pyrimidine
Leishmania major
-
dhch1-/pXNG4-DHCH1 mutant, FV1 line
0.00044
2,4-diamino-6-benzyl-5-(3-phenylpropyl)-pyrimidine
Leishmania major
-
wild type enzyme
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
additional information
22
-
25 mM MOPS pH 7.3, 2.5 mM formaldehyde, 1 mM NADP+, 30 mM 2-mercaptoethanol, 27°C, 6.3 microM/min/mg activity of the methenyltetrahydrofolate cyclohydrolase
22
-
dehydrogenase activity is measured by following the conversion of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
monofunctional methylenetetrahydrofolate dehydrogenase. No methenyltetrahydrofolate cyclohydrolase activity
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
HNSCC cell carcinoma, a total of 121 significantly altered IRMEs are identified between HNSCC and normal tissues, and 21 IRMEs are found to be strongly associated with overall survival of HNSCC. THe expression level of MTHFD1 is significantly overexpressed in tumor tissues compared to the normal controls in both GSE6631 and TCGA HNSCC cohort
brenda
additional information
both Mthfd2 and Mthfd2l are expressed during embryogenesis but differ in timing of expression. Mthfd2l expression is low in early developmental stages but begins to increase at embryonic day 10.5 and remains elevated through birth while Mthfd2 is expressed more abundantly during early developmental stages and begins to taper off, with little or no expression observed in most adult tissues
brenda
enzyme MTHFD2L is expressed in embryonic tissues during neural tube closure. Expression of the MTHFD2L transcript is low in early mouse embryos but begins to increase at embryonic day 10.5 and remains elevated through birth, in situ hybridization of whole mouse embryos
brenda
additional information
-
the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells
brenda
additional information
-
the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues
brenda
additional information
MTHFD1 is positively correlated with NK cells resting, mast cells activated, and eosinophils, while negatively associated with NK cells activated, mast cells resting, and dendritic cells resting
brenda
additional information
in adults, MTHFD2L is expressed in all tissues examined, with the highest levels observed in brain and lung
brenda
additional information
-
in adults, MTHFD2L is expressed in all tissues examined, with the highest levels observed in brain and lung
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme behaves as a tightly associated peripheral membrane protein of the mitochondrial inner membrane
brenda
-
the enzyme behaves as a tightly associated peripheral membrane protein of the mitochondrial inner membrane
brenda
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
evolution
metabolism
physiological function
additional information
evolution
the redox cofactor requirements of the isozymes from Mus musculus and Rattus norvegicus are quite similar, both exhibit lower Km values for NAD+ than for NADP+, their NAD+-dependent activities require phosphate and Mg2+, and their NADP+-dependent activities are inhibited by phosphate
evolution
the redox cofactor requirements of the isozymes from Mus musculus and Rattus norvegicus are quite similar, both exhibit lower Km values for NAD+ than for NADP+, their NAD+-dependent activities require phosphate and Mg2+, and their NADP+-dependent activities are inhibited by phosphate
evolution
-
the redox cofactor requirements of the isozymes from Mus musculus and Rattus norvegicus are quite similar, both exhibit lower Km values for NAD+ than for NADP+, their NAD+-dependent activities require phosphate and Mg2+, and their NADP+-dependent activities are inhibited by phosphate
-
metabolism
-
product of the bifuncional enzyme, 10-formyl tetrahydrofolate, is not essential for de novo purine synthesis in Leishmania and other parasitic protozoans contrary to other organisms, it is utilized for methionyl-tRNA formulation in mitochondria, the bifunctional enzyme product is essential for Leishmania major and may even reveal novel pathways
metabolism
-
mitochondrial protein with role in cytosolic purine synthesis (main switch for format production in mitochondria) during embryonic development and in cells undergoing rapid growth, not expressed in differentiated cells
metabolism
-
cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells
metabolism
the dehydrogenase activity of FolD catalyses NADP+-dependent oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate. The 5,10-methenyltetrahydrofolate cyclohydrolase activity in Clostridium perfringens is provided by another protein, the 5,10-methylenetetrahydrofolate cyclohydrolase FchA, whose cyclohydrolase activity is 10 times more efficient than that of Eco FolD. Both Clostridium perfringens FolD and FchA are required to substitute for the single bifunctional FolD in Escherichia coli. The simultaneous presence of Clostridium perfringens FolD and FchA is also necessary to rescue an Escherichia coli K16 folD deletion strain for its formate and glycine auxotrophies, and to alleviate its susceptibility to trimethoprim (an antifolate drug) or UV light
metabolism
the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase(MTHFD2)-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. It is proposed that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxidized phospholipids during atherosclerosis
metabolism
the enzyme is involved in folate pathway. It is involved in mitochondrial NADPH production. It is proposed that isoenzyme MTHFD2 may be expressed to boost flux through the mitochondrial folate pathway during early periods of embryogenesis when isoenzyme MTHFD2L alone is not sufficient to support high rates of cell proliferation
metabolism
the enzyme plays a central role in folate homeostasis and serve as targets for antibacterials
physiological function
MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. The cofactor specificity allows for rapid response to changing metabolic conditions. MTHFD2 uses Mg2+ and phosphate to convert an NADP+ binding site into an NAD+ binding site. Phosphate binds in close proximity to the 2'-hydroxyl of NAD+ and competes with NADP+ binding. Mg2 plays a role in positioning phosphatei and NAD+
physiological function
MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. The cofactor specificity allows for rapid response to changing metabolic conditions. MTHFD2 uses Mg2+ and phosphate to convert an NADP+ binding site into an NAD+ binding site. Phosphate binds in close proximity to the 2'-hydroxyl of NAD+ and competes with NADP+ binding. Mg2 plays a role in positioning phosphatei and NAD+
physiological function
unlike the bifunctional enzyme FolD of Escherichia coli, and contrary to its annotated bifunctional nature, Clostridium perfringens FolD is a monofunctional 5,10-CH2-THF dehydrogenase. The dehydrogenase activity of Clostridium perfringens FolD is about five times more efficient than that of Escherichia coli FolD. FolD plays an important role in maintaining the NADP+/NADPH ratio
physiological function
enzyme is part of MTHFD1, a trifunctional protein containing 10-formyltetrahydrofolate synthetase, 5,10-methenyltetrahydrofolate cyclohydrolase and 5,10-methylenetetrahydrofolate dehydrogenase
physiological function
methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (i.e. the enzymatic activities of MTHFD1) are a suppressor of anoikis. MTHFD1 binds the protein arginine methyltransferase 5 (PRMT5) and then undergoes symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 is strengthened, which increases the symmetric dimethylation of MTHFD1 and in turn largely augments its metabolic activity to generate NADPH, leading to anoikis resistance and distant organ metastasis. Genetic depletion or pharmacological inhibition of PRMT5 declines tumor distant metastasis
physiological function
-
MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. The cofactor specificity allows for rapid response to changing metabolic conditions. MTHFD2 uses Mg2+ and phosphate to convert an NADP+ binding site into an NAD+ binding site. Phosphate binds in close proximity to the 2'-hydroxyl of NAD+ and competes with NADP+ binding. Mg2 plays a role in positioning phosphatei and NAD+
-
additional information
MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax
additional information
-
MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax
additional information
MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax
additional information
-
the amino acid residue Tyr49 contributes to its catalytic activity
additional information
-
MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax
-
Show AA Sequence and Transmembrane Helices (25463 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
100000
101000
-
trifunctional enzyme: 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase, transcription-translation of a cDNA clone
108000
-
2 * 108000, 1 * 218000 intramolecular cross-linked with dimethylsuberimidate, SDS-PAGE
150000
-
methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, gel filtration
201000
218000
-
2 * 108000, 1 * 218000 intramolecular cross-linked with dimethylsuberimidate, SDS-PAGE
226000
-
methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, gel filtration
228000
-
methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, gel filtration
31000
33000
-
x * 33000, fragment has methylenetetrahydrofolate dehadrogenase and methenyltetrahydrofolate cyclohydrase activity, proteolysis, SDS-PAGE
34000
-
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function
55000
-
methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase combined, equilibrium ultracentrifugation
57000
-
1 * 57000, bifunctional protein: methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase, SDS-PAGE
58000
-
methylenetetrahydrofolate dehydrogenase-methyltetrahydrofolate cyclohydrolase protein, gel filtration
60000
-
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase protein, gel filtration
100000
-
1 * 100000, methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, SDS-PAGE
201000
-
methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, gel filtration
201000
-
formyltetrahydrofolate synthetase, methenyltetrahydrofolate cyclohydrolase and methylenetetrahydrofolate dehydrogenase combined, gel filtration
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
homodimer
monomer
?
x * 33000, recombinant His6-tagged truncated enzyme mutant rMTHFD2LDELTA1-40, SDS-PAGE
?
-
x * 33000, fragment has methylenetetrahydrofolate dehadrogenase and methenyltetrahydrofolate cyclohydrase activity, proteolysis, SDS-PAGE
dimer
-
2 * 108000, 1 * 218000 intramolecular cross-linked with dimethylsuberimidate, SDS-PAGE
monomer
-
1 * 57000, bifunctional protein: methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase, SDS-PAGE
monomer
-
1 * 100000, methylenetetrahydrofolate dehydrogenase, formyltetrahydrofolate synthetase and methenyltetrahydrofolate cyclohydrolase combined, SDS-PAGE
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
MTHFD1 binds the protein arginine methyltransferase 5 (PRMT5) and then undergoes symmetric dimethylation on R173 by PRMT5. R173 symmetric dimethylation status is associated with metastasis and prognosis of esophageal squamous cell carcinoma patients
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant bmMTFDH in complex with, X-ray diffraction structure determination and analysis at 1.75 A resolution
-
three ternary complex structures of human methylenetetrahydrofolate dehydrogenase/cyclohydrolase, models are deposited in PDB following further refinement and with interpretation of the data
hanging drop vapor diffusion method, using 20% (w/v) PEG 3350 and 0.2 M ammonium acetate
hanging drop vapour diffusion method, in the presence of its cofactor NADP+, at 22°C using polyethylene glycol 4000 as a precipitant
-
native form and as a NADP complex, hanging drop vapor diffusion method, at 22°C in 18% PEG 4000, 400 mM NaCl, and 100 mM Tris-HCl (pH 8.0)
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C58Y
kcat/Km for 5,10-methenyltetrahydrofolate is 8.4fold lower than wild-type value
D121A
kcat/Km for 5,10-methenyltetrahydrofolate is 600fold lower than wild-type value
G122D
kcat/Km for 5,10-methenyltetrahydrofolate is 84fold lower than wild-type value
K54S
kcat/Km for 5,10-methenyltetrahydrofolate is identical to wild-type value
C58Y
-
kcat/Km for 5,10-methenyltetrahydrofolate is 8.4fold lower than wild-type value
-
D121A
-
kcat/Km for 5,10-methenyltetrahydrofolate is 600fold lower than wild-type value
-
G122D
-
kcat/Km for 5,10-methenyltetrahydrofolate is 84fold lower than wild-type value
-
K54S
-
kcat/Km for 5,10-methenyltetrahydrofolate is identical to wild-type value
-
D133E
K56Q/Q100K
R173C
mutation identified in a patient with megaloblastic anemia. MTHFD1 protein expression in fibroblast extracts is markedly decreased compared to expression in wild type cells. There is no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts
R653Q
mutant enzyme has normal substrate affinity but a 36% reduction in half-life at 42°C
S49F/E225*
mutation identified in a patient with megaloblastic anemia. MTHFD1 protein expression in fibroblast extracts is markedly decreased compared to expression in wild type cells. There is no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts
S49F/G276R
mutation identified in a patient with megaloblastic anemia. MTHFD1 protein expression in fibroblast extracts is markedly decreased compared to expression in wild type cells. There is no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts
T269I
mutation identified in a patient with megaloblastic anemia. MTHFD1 protein expression in fibroblast extracts is markedly decreased compared to expression in wild type cells. There is no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts
additional information
K56Q/Q100K
-
retaines two-third of dehydrogenase activity but no cyclohydrolase activity
K56Q/Q100K
-
site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity
additional information
-
mutation of arginine-166 leads to complete loss of dehydrogenase activity, is critically responsible for binding of the inorganic phosphate, with arginine-198 mutation some dehydrogenase activity is retained, it probably only assists in phosphate binding
additional information
-
knockout mutant of MTHFD2 is embryonic lethal in mice at about 12 days gestation, no normal development of hematogenesis in the liver
additional information
-
asparagine-125 is required for folate-substrate binding, arginine-173 mutation causes 500fold increase in the Km for NADP, serine-197 mutation a 20fold increase
additional information
-
successful double replacement of the DHCH1 gene is a result of double electroporation with two replacement fragments but an intact gene copy is retained (probably aneuploidy), additional metabolic complementation to bypass the requirement for DHCH1 is not successful either, ectopic addition of DHCH1 or formate-tetrahydrofolate ligase before the second replacement step finally results in a null mutant without chromosomal DHCH1 gene (dhch1-/pXNG4-DHCH1 or dhch1-/pXNG4-FTL) or addition to wild-type in overexpressing transfectants (WT/pXNG4-DHCH1 or WT/pXNG4-FTL)
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
frozen stable for 12 days, loss of activity upon repeated freezing and thawing
-
highly instable, partial protection against inactivation by thiol compounds, glycerol, serum albumin and EDTA, freezing inactivates purified enzyme
-
highly unstable, can be preserved as suspension in ammonium sulfate at 50% saturation
-
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-17°C, partially purified enzyme after second ammonium sulphate fractionation stable for 2 weeks, 1 mM mercaptoethanol,
-
-20°C, purified MTHFD2L in 25 mM Tris-Cl, 10 mM 2-mercaptoethanol, 100mM KCl, and 50% v/v glycerol at pH 7.5. The purified enzyme retains about 75% of initial 5,10-CH2THF dehydrogenase activity after 1 week of storage
-20°C, stable for at least 2 months at diluted protein concentration
-
0-4°C, after 1 month retains 75% of the methylenetetrahydrofolate dehydrogenase activity
-
5°C, stable for several weeks in ammonium sulfate at 50% saturation
-
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase
co-purification of 5,10-methylenetetrahydrofolate dehydrogenase and 5,10-methenyltetrahydrofolate cyclohydrolase
-
complex of N5,N10-methylenetetrahydrofolate dehydrogenase and N5,N10-methenyltetrahydrofolate cyclohydrolase
-
formyltetrahydrofolate synthetase, methenyltetrahydrofolate cyclohydrolase and methylenetetrahydrofolate dehydrogenase combined
-
heat treatment, Ni-affinity column chromatography, and Superdex-200 gel filtration
in vitro transcription-translation of cDNA clone, trifunctional enzyme: 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrase and 10-formyltetrahydrofolate synthetase
-
methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase combined
-
partial
recombinant His-tagged truncated enzyme mutant rMTHFD2LDELTA1-40 from Saccharomyces cerevisiae strain MWY4.4 by nickel affinity chromatography, sodium carbonate in the extraction buffer is used to release MTHFD2L from membranes
trifunctional enzyme: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrase, formyltetrahydrofolate synthetase
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase
-
bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase
-
trifunctional enzyme: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrase, formyltetrahydrofolate synthetase
-
trifunctional enzyme: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrase, formyltetrahydrofolate synthetase
-
trifunctional enzyme: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrase, formyltetrahydrofolate synthetase
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
bmMTHFD, DNA and amino acid sequence determination and analysis, recombinant expression in Escherichia coli
-
expressed in Escherichia coli
expressed in Escherichia coli BL21(DE3) cells
expressed in Saccharomyces cerevisiae strain MWY4.4 and in CHO cells
gene folD, recombinant coexpression with Clostridium perfringens FchA in Escherichia coli strain K16 DELTA foldD mutants and functional complementation, overview
gene MTHFD2L, DNA and amino acid sequence determination and analysis, quantitative real-time PCR enzyme expression analysis, the truncated enzyme mutant rMTHFD2LDELTA1-40 is cloned into vector YEp24-based yeast expression vector containing the Saccharomyces cerevisiae MET6 promoter and expressed in Saccharomyces cerevisiae strain MWY4.4 as N-terminally His6-tagged protein, replacment of the mitochondrial targeting sequence of the rat MTHFD2L with an N-terminal His tag for localization in the yeast cytosol
gene Mthfd2l, MTHFD2L is alternatively spliced at exons 2 and 8, quantitative real-time PCR enzyme expression analysis, gene expression profiling of the MTHFD gene family in mouse embryos and adult organs
hexa-His tagged DHCH1 is expressed in Escherichia coli, production of a genetic knock-out
-
null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis
-
PCR-amplification, expressed in Escherichia coli, overexpression and null-mutant production
-
the wild type and R653Q mutant pBKeDCS constructs are transformed into Escherichia coli BL21 DE3 to express the full-length protein
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
the expression level of MTHFD1 is significantly overexpressed in tumor tissues compared to the normal controls in both GSE6631 and TCGA HNSCC cohort. A total of 121 significantly altered IRMEs are identified between head and neck squamous cell carcinoma (HNSCC) and normal tissues, and 21 IRMEs are found to be strongly associated with overall survival of HNSCC. Upregulation of MTHFD1 is positively correlated with adverse clinicopathological factors in TCGA HNSCC cohort. Increased MTHFD1 expression is negatively associated with NK cells activation, while positively correlated with mast cells activation
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
prognostic significance of MTHFD1 in head and neck squamous cell carcinoma (HNSCC) as well as the association between MTHFD1 and immune cell infiltration. MTHFD1 overexpression is closely correlated with unfavorable prognosis of HNSCC, and it might play an important role in modulating the tumor immune microenvironment
medicine
medicine
-
Leishmania major is shown to require 10-formyl tetrahydrofolate metabolism, thus this is a possible target for chemotherapy in Leishmania major and potential other protozoan parasites
medicine
-
MTHFD1 G1958A polymorphism might be a weak risk factor for early onset Alzheimers disease in the age group below 65 years
medicine
methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (i.e. the enzymatic activities of MTHFD1) is a suppressor of anoikis. MTHFD1 depletion restrains the capacity of cellular antioxidant defense and inhibits tumor distant metastasis. Genetic depletion or pharmacological inhibition of PRMT5 declines tumor distant metastasis. R173 symmetric dimethylation status is associated with metastasis and prognosis of esophageal squamous cell carcinoma patients
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Paukert, J.L.; Rabinowitz, J.C.
Formyl-methenyl-methylenetetrahydrofolate synthetase (combined): a multifunctional protein in eukaryotic folate metabolism
Methods Enzymol.
66
616-626
1980
Saccharomyces cerevisiae, Sus scrofa, Ovis aries
brenda
Cossins, E.A.; Kirk, C.D.; Imeson, H.C.; Zheng, L.l.
Enzymes for synthesis of 10-formyltetrahydrofolate in plants. Characterization of a monofunctional 10-formyltetrahydrofolate synthetase and copurification of 5,10-methylenetetrahydrofolate dehydrogenase and 5,10-methenyltetrahydrofolate cyclohydrolase activities
Adv. Exp. Med. Biol.
338
707-710
1993
Lathyrus oleraceus
brenda
Villar, E.; Schuster, B.; Peterson, D.; Schirch, V.
C1-Tetrahydrofolate synthase from rabbit liver. Structural and kinetic properties of the enzyme and its two domains
J. Biol. Chem.
260
2245-2252
1985
Oryctolagus cuniculus
brenda
Cohen, L.; MacKenzie, R.E.
Methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase from porcine liver. Interaction between the dehydrogenase and cyclohydrolase activities of the multifunctional enzyme
Biochim. Biophys. Acta
522
311-317
1978
Sus scrofa
brenda
Tan, L.U.L.; Drury, E.J.; MacKenzie, R.E.
Methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. A multifunctional protein from porcine liver
J. Biol. Chem.
252
1117-1122
1977
Sus scrofa
brenda
Kirk, C.D.; Chen, L.; Imeson, H.C.; Cossins, E.A.
A 5,10-methylenetetrahydrofolate dehydrogenase: 5,10-methenyltetrahydrofolate cyclohydrolase protein from Pisum sativum
Phytochemistry
39
1309-1317
1995
Lathyrus oleraceus
-
brenda
Pawelek, P.D.; MacKenzie, R.E.
Methylenetetrahydrofolate dehydrogenase-cyclohydrolase from Photobacterium phosphoreum shares properties with a mammalian mitochondrial homologue
Biochim. Biophys. Acta
1296
47-54
1996
Photobacterium phosphoreum
brenda
Mackenzie, R.E.; Mejia, N.; Yang, X.M.
Methylenetetrahydrofolate dehydrogenases in normal and transformed mammalian cells
Adv. Enzyme Regul.
27
31-39
1988
Homo sapiens, Mus musculus
brenda
Albrecht, A.M.; Pearce, F.K.; Hutchinson, D.J.
Methylenetetrahydrofolate dehydrogenase of the amethopterin-resistant strain Streptococcus faecium var. durans A and its repressibility by serine
J. Bacteriol.
95
1779-1789
1968
Enterococcus faecium
brenda
Dev, I.K.; Harvey, R.J.
A complex of N5,N10-methylenetetrahydrofolate dehydrogenase and N5,N10-methenyltetrahydrofolate cyclohydrolase in Escherichia coli. Purification, subunit structure, and allosteric inhibition by N10-formyltetrahydrofolate
J. Biol. Chem.
253
4245-4253
1978
Escherichia coli, Escherichia coli B / ATCC 11303
brenda
Harvey, R.J.; Dev, I.K.
Regulation in the folate pathway of Escherichia coli
Adv. Enzyme Regul.
13
99-124
1975
Escherichia coli, Escherichia coli B / ATCC 11303
brenda
Ljungdahl, L.G.; O'Brien, W.E.; Moore, M.R.; Liu, M.T.
Methylenetetrahydrofolate dehydrogenase from Clostridium formicoaceticum and methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase (combined) from Clostridium thermoaceticum
Methods Enzymol.
66
599-609
1980
Neomoorella thermoacetica
brenda
Uyeda, K.; Rabinowitz, J.C.
Enzymes of clostridial purine fermentation. Methylenetetrahydrofolate dehydrogenase
J. Biol. Chem.
242
4378-4385
1967
Clostridium cylindrosporum
brenda
O'Brien, W.E.; Brewer, J.M.; Ljungdahl, L.G.
Purification and characterization of thermostable 5,10-methylenetetrahydrofolate dehydrogenase from Clostridium thermoaceticum
J. Biol. Chem.
248
403-408
1973
Neomoorella thermoacetica
brenda
Dalal, F.R.; Gots, J.S.
Purification of 5,10-methylenetetrahydrofolate dehydrogenase from Salmonella typhimurium and its inhibition by purine nucleotides
J. Biol. Chem.
242
3636-3640
1967
Salmonella enterica subsp. enterica serovar Typhimurium
brenda
Ramasastri, B.V.; Blakley, R.L.
5,10-Methylenetetrahydrofolic dehydrogenase from bakers'yeast
J. Biol. Chem.
237
1982-1988
1962
Saccharomyces cerevisiae
brenda
Paukert, J.L.; Williams, G.R.; Rabinowitz, J.C.
Formyl-methenyl-methylenetetrahydrofolate synthetase (combined); correlation of enzymic activities with limited proteolytic degradation of the protein from yeast
Biochem. Biophys. Res. Commun.
77
147-154
1977
Saccharomyces cerevisiae
brenda
Hum, D.W.; Bell, A.W.; Rozen, R.; MacKenzie, R.E.
Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
J. Biol. Chem.
263
15946-15950
1988
Homo sapiens
brenda
Yeh, Y.C.; Greenberg, D.M.
Purification and properties of N5, N10-Methylenetetra-hydrofolate dehydrogenase of calf thymus
Biochim. Biophys. Acta
105
279-291
1965
Bos taurus
brenda
MacKenzie, R.E.; Tan, L.U.L.
Methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase: a multifunctional protein from porcine liver
Methods Enzymol.
66
609-615
1980
Sus scrofa
brenda
MacKenzie, R.E.
Co-purification of three folate enzymes from porcine liver
Biochem. Biophys. Res. Commun.
53
1088-1095
1973
Sus scrofa
brenda
Ross, J.; Green, J.; Baugh, C.M.; MacKenzie, R.E.; Matthews, R.G.
Studies on the polyglutamate specificity of methylenetetrahydrofolate dehydrogenase from pig liver
Biochemistry
23
1796-1801
1984
Sus scrofa
brenda
Gardam, M.A.; Mejia, N.R.; MacKenzie, R.E.
The NADP-dependent trifunctional methylenetetrahydrofolate dehydrogenase purified from mouse liver is immunologically distinct from the mouse NAD-dependent [corrected] bifunctional enzyme [published erratum appears in Biochem Cell Biol 1988 May;66(5):459]
Biochem. Cell Biol.
66
66-70
1988
Mus musculus
brenda
Paukert, J.L.; D'Ari Straus, L.; Rabinowitz, J.C.
Formyl-methyl-methylenetetrahydrofolate synthetase-(combined). An ovine protein with multiple catalytic activities
J. Biol. Chem.
251
5104-5111
1976
Ovis aries
brenda
Cossins, E.A.; Wong, K.F.; Roos, A.J.
Plant N5,N10-methylenetetrahydrofolate dehydrogenase: partial purification and some general properties of the enzyme from germinating pea seedlings
Phytochemistry
9
1463-1471
1970
Lathyrus oleraceus
-
brenda
Yoshida, T.; Kikuchi, G.
Comparative study on major pathways of glycine and serine catabolism in vertebrate livers
J. Biochem.
72
1503-1516
1972
Bos taurus, Ovis aries, Gallus gallus bankiva, Elaphe quadrivirgata
brenda
Pelletier J.N.; MacKenzie, E.
Binding and interconversion of tetrahydrofolates at a single site in the bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase
Biochemistry
34
12673-12680
1995
Homo sapiens
brenda
Pawelek, P.D.; MacKenzie, R.E.
Methenyltetrahydrofolate cyclohydrolase is rate limiting for the enzymatic conversion of 10-formyltetrahydrofolate to 5,10-methylenetetrahydrofolate in bifunctional dehydrogenase-cyclohydrolase enzymes
Biochemistry
37
1109-1115
1998
Homo sapiens, Photobacterium phosphoreum
brenda
Goenrich, M.; Bursy, J.; Hubner, E.; Linder, D.; Schwartz, A.C.; Vorholt, J.A.
Purification and characterization of the methylene tetrahydromethanopterin dehydrogenase MtdB and the methylene tetrahydrofolate dehydrogenase FolD from Hyphomicrobium zavarzinii ZV580
Arch. Microbiol.
177
299-303
2002
Hyphomicrobium zavarzinii, Hyphomicrobium zavarzinii ZV580, no activity in Methylobacterium extorquens
brenda
Casaite, V.; Meskiene, R.; Meskys, R.
Elucidation of enzymatic function encoded by folD and fic genes from dimethylglycine operon
Biologia (Bratisl. )
2
1-4
2004
Arthrobacter globiformis
-
brenda
Kim, J.H.; Sung, M.W.; Lee, E.H.; Nam, K.H.; Hwang, K.Y.
Crystallization and preliminary X-ray diffraction analysis of 5,10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase from Thermoplasma acidophilum DSM 1728
J. Microbiol. Biotechnol.
18
283-286
2008
Thermoplasma acidophilum
brenda
Christensen, K.E.; Rohlicek, C.V.; Andelfinger, G.U.; Michaud, J.; Bigras, J.L.; Richter, A.; Mackenzie, R.E.; Rozen, R.
The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects
Hum. Mutat.
30
212-220
2009
Homo sapiens (P11586)
brenda
Murta, S.M.; Vickers, T.J.; Scott, D.A.; Beverley, S.M.
Methylene tetrahydrofolate dehydrogenase/cyclohydrolase and the synthesis of 10-CHO-THF are essential in Leishmania major
Mol. Microbiol.
71
1386-1401
2009
Leishmania major
brenda
Christensen, K.E.; Mackenzie, R.E.
Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases
Vitam. Horm.
79
393-410
2008
Homo sapiens, Saccharomyces cerevisiae
brenda
Bi, X.H.; Zhao, H.L.; Zhang, Z.X.; Liu, Q.; Zhang, J.W.
Association analysis of CbetaS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimers disease in Chinese
J. Neural Transm.
117
499-503
2010
Homo sapiens
brenda
Lee, W.H.; Sung, M.W.; Kim, J.H.; Kim, Y.K.; Han, A.; Hwang, K.Y.
Crystal structure of bifunctional 5,10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase from Thermoplasma acidophilum
Biochem. Biophys. Res. Commun.
406
459-463
2011
Thermoplasma acidophilum (Q05213)
brenda
Eadsforth, T.C.; Cameron, S.; Hunter, W.N.
The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target
Mol. Biochem. Parasitol.
181
178-185
2012
Leishmania major (Q4Q9F9), Leishmania major Fridlin (Q4Q9F9)
brenda
Bolusani, S.; Young, B.A.; Cole, N.A.; Tibbetts, A.S.; Momb, J.; Bryant, J.D.; Solmonson, A.; Appling, D.R.
Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues
J. Biol. Chem.
286
5166-5174
2011
Homo sapiens, Rattus norvegicus
brenda
Shin, M.; Bryant, J.D.; Momb, J.; Appling, D.R.
Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues
J. Biol. Chem.
289
15507-15517
2014
Mus musculus (D3YZG8), Mus musculus, Rattus norvegicus (D3ZUA0), Mus musculus C57BL/6 (D3YZG8)
brenda
Aluri, S.; Sah, S.; Miryala, S.; Varshney, U.
Physiological role of FolD (methylenetetrahydrofolate dehydrogenase), FchA (methenyltetrahydrofolate cyclohydrolase) and Fhs (formyltetrahydrofolate synthetase) from Clostridium perfringens in a heterologous model of Escherichia coli
Microbiology
162
145-155
2016
Clostridium perfringens, Clostridium perfringens (Q0TPD4)
brenda
Sah, S.; Varshney, U.
Impact of mutating the key residues of a bifunctional 5,10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase from Escherichia coli on its activities
Biochemistry
54
3504-3513
2015
Escherichia coli (P24186), Escherichia coli K12 (P24186)
brenda
Bueno, R.; Dawson, A.; Hunter, W.N.
An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement
Acta Crystallogr. Sect. F
75
148-152
2019
Homo sapiens (P11586)
brenda
Shin, M.; Momb, J.; Appling, D.R.
Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
Cancer Metab.
5
11
2017
Homo sapiens (P13995), Homo sapiens (Q9H903)
brenda
Sah, S.; Shah, R.; Govindan, A.; Varada, R.; Rex, K.; Varshney, U.
Utilisation of 10-formyldihydrofolate as substrate by dihydrofolate reductase (DHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) tranformylase/IMP cyclohydrolase (PurH) in Escherichia coli
Microbiology
164
982-991
2018
Escherichia coli (P24186), Escherichia coli K12 (P24186)
brenda
Hitzel, J.; Lee, E.; Zhang, Y.; Bibli, S.I.; Li, X.; Zukunft, S.; Pflueger, B.; Hu, J.; Schuermann, C.; Vasconez, A.E.; Oo, J.A.; Kratzer, A.; Kumar, S.; Rezende, F.; Josipovic, I.; Thomas, D.; Giral, H.; Schreiber, Y.; Geisslinger, G.; Fork, C.; Yang, X.; Sigala, F.; Romanoski, C.E.; Kroll, J.; Jo, H.; Lan, L.a.n.d.
Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
Nat. Commun.
9
2292
2018
Homo sapiens (P13995)
brenda
Cui, L.; Chen, H.; Zhao, X.
The prognostic significance of immune-related metabolic enzyme MTHFD2 in head and neck squamous cell carcinoma
Diagnostics (Basel)
10
689
2020
Homo sapiens (P11586)
brenda
Haque, M.R.; Higashiura, A.; Nakagawa, A.; Hirowatari, A.; Furuya, S.; Yamamoto, K.
Molecular structure of a 5,10-methylenetetrahydrofolate dehydrogenase from the silkworm Bombyx mori
FEBS open bio
9
618-628
2019
Bombyx mori
brenda
Bidla, G.; Watkins, D.; Chery, C.; Froese, D.S.; Ells, C.; Kerachian, M.; Saskin, A.; Christensen, K.E.; Gilfix, B.M.; Gueant, J.L.; Rosenblatt, D.S.
Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency
Mol. Genet. Metab.
130
179-182
2020
Homo sapiens (P11586)
brenda
Meng, Q.; Lu, Y.X.; Wei, C.; Wang, Z.X.; Lin, J.F.; Liao, K.; Luo, X.J.; Yu, K.; Han, Y.; Li, J.J.; Tan, Y.T.; Li, H.; Zeng, Z.L.; Li, B.; Xu, R.H.; Ju, H.Q.
Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis
Oncogene
41
3912-3924
2022
Homo sapiens (P11586)
brenda
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