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Information on EC 1.5.1.5 - methylenetetrahydrofolate dehydrogenase (NADP+) and Organism(s) Homo sapiens and UniProt Accession Q9H903
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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).
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Word Map
- 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
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
5,10-methylenetetrahydrofolate dehydrogenase
-
-
-
-
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
N5,N10-methylenetetrahydrofolate dehydrogenase
-
-
-
-
methylenetetrahydrofolate dehydrogenase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
reduction
-
-
-
-
oxidation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -, -, -, -, -, -, -
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).
CAS REGISTRY NUMBER
COMMENTARY
9029-14-5
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
-
-
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2L is 3.4fold higher than its NADP+-dependent activity under saturating substrate conditions
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
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
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
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
-
-
?
5,10-methylene tetrahydrofolate + NAD+
5,10-methenyl tetrahydrofolate + NADH + H+
-
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
-
-
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
-
-
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH
dehydrogenase activity of MTHFD1
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
-
the cyclohydrolase forms formyltetrahydrofolate
-
r
5,10-methylenetetrahydropteroylglutamate + NAD+
5,10-methenyltetrahydropteroylglutamate + NADH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
-
-
?
5,10-methylenetetrahydropteroylglutamate + NADP+
5,10-methenyltetrahydropteroylglutamate + NADPH + H+
NAD+-dependent dehydrogenase activity of MTHFD2 is 8.5fold higher than its NADP+-dependent activity
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NAD+
5,10-methenyltetrahydropteroylpentaglutamate + NADH + H+
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
-
-
?
5,10-methylenetetrahydropteroylpentaglutamate + NADP+
5,10-methenyltetrahydropteroylpentaglutamate + NADPH + H+
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
-
-
?
additional information
?
-
(MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
deuterated folate substrate also
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylene tetrahydrofolate + NAD+
5,10-methenyl tetrahydrofolate + NADH + H+
-
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
-
-
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyl tetrahydrofolate + NADPH + H+
-
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
-
-
r
5,10-methylene tetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH
dehydrogenase activity of MTHFD1
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
5,10-methenyl-tetrahydrofolate + NADH
-
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
r
5,10-methylene-tetrahydrofolate + NADP+
5,10-methenyl-tetrahydrofolate + NADPH + H+
-
-
the cyclohydrolase forms formyltetrahydrofolate
-
r
additional information
?
-
(MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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+
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
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
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
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
additional information
NADP+
-
mutation of Arg173 causes a 500fold increase in the Km value for NADP+, while mutation of Ser197 causes a 20fold increase
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
0.012
5,10-methylenetetrahydrofolate
-
NAD+-M2+-phopsphate-dependent mitochondrial dehydrogenase-cyclohydrolase enzyme
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)
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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)
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
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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)
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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
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
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
additional information
additional information
-
the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells
additional information
-
the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues
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
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme behaves as a tightly associated peripheral membrane protein of the mitochondrial inner membrane
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
metabolism
-
cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells
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
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 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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MTD2L_HUMAN
347
0
37315
Swiss-Prot
Mitochondrion (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
101000
-
trifunctional enzyme: 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase, transcription-translation of a cDNA clone
34000
-
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
three ternary complex structures of human methylenetetrahydrofolate dehydrogenase/cyclohydrolase, models are deposited in PDB following further refinement and with interpretation of the data
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D133E
K56Q/Q100K
R653Q
mutant enzyme has normal substrate affinity but a 36% reduction in half-life at 42°C
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
-
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
-
knockout mutant of MTHFD2 is embryonic lethal in mice at about 12 days gestation, no normal development of hematogenesis in the liver
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in vitro transcription-translation of cDNA clone, trifunctional enzyme: 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrase and 10-formyltetrahydrofolate synthetase
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis
-
the wild type and R653Q mutant pBKeDCS constructs are transformed into Escherichia coli BL21 DE3 to express the full-length protein
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
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
-
MTHFD1 G1958A polymorphism might be a weak risk factor for early onset Alzheimers disease in the age group below 65 years
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
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
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
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
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)
Christensen, K.E.; Mackenzie, R.E.
Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases
Vitam. Horm.
79
393-410
2008
Saccharomyces cerevisiae, Homo sapiens
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
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
Bueno, R.; Dawson, A.; Hunter, W.N.
An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement
Acta Crystallogr. Sect. F
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148-152
2019
Homo sapiens (P11586)
Shin, M.; Momb, J.; Appling, D.R.
Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
Cancer Metab.
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11
2017
Homo sapiens (P13995), Homo sapiens (Q9H903)
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)
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