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Information on EC 3.5.4.9 - methenyltetrahydrofolate cyclohydrolase and Organism(s) Homo sapiens and UniProt Accession P13995
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3.5.4.9 methenyltetrahydrofolate cyclohydrolaseIUBMB Comments
In eukaryotes, the enzyme occurs as a trifunctional enzyme that also has methylenetetrahydrofolate dehydrogenase (NADP+) (EC 1.5.1.5) and formate---tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes, it occurs as a bifunctional enzyme that also has dehydrogenase (EC 1.5.1.5) activity or formimidoyltetrahydrofolate cyclodeaminase (EC 4.3.1.4) activity.
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Word Map
- 3.5.4.9
- gtp
- purine
-
one-carbon
- guanosine
- tetrahydrobiopterin
-
trifunctional
- bh4
- 5,10-methylenetetrahydrofolate
- mthfd1
- 10-formyltetrahydrofolate
- aicar
-
c1-tetrahydrofolate
- 5-aminoimidazole-4-carboxamide
-
folate-dependent
-
10-formyl-thf
-
c1-thf
-
transformylase
-
6.3.4.3
- sepiapterin
-
formyltransferase
- dihydroneopterin
-
dopa-responsive
-
5,10-methylene-thf
- gtpch1
- 2,4-diamino-6-hydroxypyrimidine
-
folate-mediated
- biopterins
- drug development
- 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
Synonyms
mthfd2, cyclohydrolase, methenyltetrahydrofolate cyclohydrolase, 5,10-methenyltetrahydrofolate cyclohydrolase, mthfd2l, 5,10-methenyl-thf cyclohydrolase, methylenetetrahydrofolate dehydrogenase/cyclohydrolase, nad-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase, dhch1, methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
5,10-methenyl-H4folate cyclohydrolase
-
-
-
-
Citrovorum factor cyclodehydrase
-
-
-
-
cyclohydrolase
formyl-methenyl-methylenetetrahydrofolate synthetase (combined)
-
-
-
-
methenyl-THF cyclohydrolase
-
-
-
-
methenyltetrahydrofolate cyclohydrolase
methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase
MTHFD1
cyclohydrolase
-
-
-
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase
-
-
methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase
-
trifunctional folate enzyme
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate
catalytic mechanism, Glu100 is responsible for activation of the critical Lys56 for cyclohydrolase catalysis, Asp125 is involved in binding of the 10-formyltetrahydrofolate substrate
5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate
In eukaryotes, the enzyme occurs as a trifunctional enzyme that also has methylenetetrahydrofolate dehydrogenase (NADP+), EC 1.5.1.5, and formate-tetrahydrofolate ligase, EC 6.3.4.3, activity. In some prokaryotes, it occurs as a bifunctional enzyme, that also has methylenetetrahydrofolate dehydrogenase (NADP+), EC 1.5.1.5, activity or formiminotetrahydrofolate cyclodeaminase, EC 4.3.1.4, activity, residue Arg173 is critical for binding of NADP+ with Ser197 playing a supporting role, both residues interact with the 2'-phosphate of NADP+
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
amidine hydrolysis
amidine hydrolysis
-
-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
5,10-methenyltetrahydrofolate 5-hydrolase (decyclizing)
In eukaryotes, the enzyme occurs as a trifunctional enzyme that also has methylenetetrahydrofolate dehydrogenase (NADP+) (EC 1.5.1.5) and formate---tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes, it occurs as a bifunctional enzyme that also has dehydrogenase (EC 1.5.1.5) activity or formimidoyltetrahydrofolate cyclodeaminase (EC 4.3.1.4) activity.
CAS REGISTRY NUMBER
COMMENTARY
9027-97-8
-
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-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate + ?
cyclodehydrolase activity of MTHFD1
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
-
-
-
?
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
5,10-methenyltetrahydrofolate 5-hydrolase (decyclizing), EC 3.5.4.9, activity of the enzyme
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
5,10-methenyltetrahydrofolate 5-hydrolase (decyclizing), EC 3.5.4.9, activity of the enzyme
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
bifunctional enzyme exhibits dihydrogenase and cyclohydrolase activities
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
-
methylenetetrahydrofolate dehydrogenase (NADP+), EC 1.5.1.5, activity of the enzyme
-
-
r
5,10-methylenetetrahydrofolate + NADP+
5,10-methenyltetrahydrofolate + NADPH + H+
methylenetetrahydrofolate dehydrogenase (NADP+), EC 1.5.1.5, activity of the enzyme
-
-
r
additional information
?
-
bifunctional enzyme, channeling efficiency
-
-
?
additional information
?
-
-
the enzyme has a bifunctional DC domain that binds NADP+ and one folate molecule within a single catalytic cleft being part of a trifunctional enzyme, substrate channeling with high efficiency independent of NADP+ substrate binding efficiency
-
-
?
additional information
?
-
-
enzyme deficiency by G1958A polymorphism is involved in spontaneous cervical artery dissections
-
-
?
additional information
?
-
MTHFD1 is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
-
-
?
additional information
?
-
-
the conversion of formyl- to methylenehydrofolate is rate-limited by the slow conversion by the cyclohydrolase of formyl- to methenyltetrahydrofolate
-
-
?
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-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate + ?
cyclodehydrolase activity of MTHFD1
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
-
-
-
?
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
bifunctional enzyme exhibits dihydrogenase and cyclohydrolase activities
-
-
r
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
-
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
-
-
r
additional information
?
-
-
enzyme deficiency by G1958A polymorphism is involved in spontaneous cervical artery dissections
-
-
?
additional information
?
-
MTHFD1 is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis
-
-
?
additional information
?
-
-
the conversion of formyl- to methylenehydrofolate is rate-limited by the slow conversion by the cyclohydrolase of formyl- to methenyltetrahydrofolate
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-[[4-[(6aR)-3-amino-1,9-dioxo-5,6,6a,7-tetrahydro-4H-imidazo[1,5-f]pteridin-8-yl]benzoyl]amino]pentanedioic acid
i.e. LY345899
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2',5'-ADP
-
stimulates the cyclohydrolase reverse reaction, 2'-phosphate is involved
2',5'-ADP
-
analog of NADP+ does not stimulate the reverse cyclohydrolase activity
2',5'-ADP
-
the analog of NADP+ stimulates the reverse cyclohydrolase activity by more than 2fold
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.016
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant S197D, substrate 10-formyltetrahydrofolate
0.018
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant R173K, substrate 10-formyltetrahydrofolate
0.02
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant S197T, substrate 10-formyltetrahydrofolate
0.024
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant R173A, substrate 10-formyltetrahydrofolate
0.026
10-formyltetrahydrofolate
-
reverse reaction, recombinant wild-type enzyme, substrate 10-formyltetrahydrofolate
0.028
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant S197R, substrate 10-formyltetrahydrofolate
0.031
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant R173E, substrate 10-formyltetrahydrofolate
0.043
10-formyltetrahydrofolate
-
reverse reaction, recombinant mutant S197A, substrate 10-formyltetrahydrofolate
0.021
methenyltetrahydrofolate
-
forward reaction, recombinant mutant R173A and R173K
additional information
additional information
-
the His-tag does not alter the activity and kinetics of the enzymes
-
additional information
additional information
-
the overall forward reaction from mythylene- to formyltetrahydrofolate shows a hydride transfer kinetic isotope effect, whereas the the overall reverse reaction does not
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10.8
1173
-
forward reaction, recombinant mutant R173A, substrate 5,10-methenyltetrahydrofolate
12.8
-
reverse reaction, recombinant mutant R173K, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
13.5
-
forward reaction, recombinant mutant S197A, substrate 5,10-methenyltetrahydrofolate
15.9
-
reverse reaction, recombinant mutant S197T, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
22.4
-
reverse reaction, recombinant wild-type enzyme, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
22.8
-
reverse reaction, recombinant mutant S197R, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
3.4
-
forward reaction, recombinant mutant S197R, substrate 5,10-methenyltetrahydrofolate
329
-
forward reaction, recombinant mutant R173K, substrate 5,10-methenyltetrahydrofolate
6.4
-
reverse reaction, recombinant mutant S197A, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
61.6
-
forward reaction, recombinant mutant S197D, substrate 5,10-methenyltetrahydrofolate
7.2
-
forward reaction, recombinant wild-type enzyme, substrate 5,10-methenyltetrahydrofolate
7.3
-
reverse reaction, recombinant mutant S197R, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
7.6
-
reverse reaction, recombinant mutant S197A, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
8
-
reverse reaction, recombinant mutant R173A, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
9
-
reverse reaction, recombinant mutant R173K, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
9.2
9.3
-
reverse reaction, recombinant mutant S197D, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
9.6
-
reverse reaction, recombinant wild-type enzyme, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
additional information
10.8
-
forward reaction, recombinant mutant S197T, substrate 5,10-methenyltetrahydrofolate
10.8
-
reverse reaction, recombinant mutant S197D, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
9.2
-
reverse reaction, recombinant mutant R173E, substrate 10-formyltetrahydrofolate, in presence of 2',5'-ADP
9.2
-
reverse reaction, recombinant mutant S197T, substrate 10-formyltetrahydrofolate, in absence of 2',5'-ADP
additional information
channeling efficiency of wild-type and mutant enzymes
additional information
-
the His-tag does not alter the activity and kinetics of the enzymes, determination of methylenetetrahydrofolate dehydrogenase (NADP+), EC 1.5.1.5, activity, determination of forward channeling in percent
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
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
additional information
additional information
-
the cytoplasmic MTHFD1 is ubiquitously expressed in all mammalian cells
additional information
-
the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
metabolism
the enzyme is involved in folate pathway. It is involved in mitochondrial NADPH production
metabolism
the enzyme is involved in folate pathway. It is involved in mitochondrial NADPH production
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). MTDC_HUMAN
350
0
37895
Swiss-Prot
Mitochondrion (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
34000
-
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of the enzyme (MTHFD2) in complex with a substrate-based inhibitor and the enzyme cofactors NAD+ and inorganic phosphate
crystal structure of DC301, the cytosolic DC domain of the trifunctional enzyme
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D125E
site-directed mutagenesis, 95% reduced activity in the forward reaction compared to the wild-type enzyme
K56Q/Q100K
R173A
-
site-directed mutagenesis, at least 500fold increased Km for NADP+ compared to the wild-type, 163fold increased activity in the forward and reduced activity in the reverse reaction of the cyclohydrolase, unaltered channeling efficiency
R173E
-
site-directed mutagenesis, no dehydrogenase forward reaction activity, no forward channeling
R173K
-
site-directed mutagenesis, at least 500fold increased Km for NADP+ compared to the wild-type, 46fold increased activity in the forward and reduced activity in the reverse reaction of the cyclohydrolase, unaltered channeling efficiency
R250A
site-directed mutagenesis, 29.7% reduced activity in forward and reduced activity in the reverse reaction compared to the wild-type enzyme
R653Q
S197A
-
site-directed mutagenesis, 20fold increased Km for NADP+ compared to the wild-type, reduced activity in the reverse reaction of the cyclohydrolase, no stimulation by 2',5'-ADP, unaltered channeling efficiency
S197D
-
site-directed mutagenesis, 8.5fold increased activity in the forward reaction of the cyclohydrolase, unaltered channeling efficiency
S197R
-
site-directed mutagenesis, 10fold increased Km for methenyltetrahydrofolate, reduced activity in the forward and reverse reaction of the cyclohydrolase, unaltered channeling efficiency
S197T
-
site-directed mutagenesis, slightly increased activity in the forward reaction of the cyclohydrolase, unaltered channeling efficiency
Y240A
site-directed mutagenesis, 52,5% reduced activity in forward and reduced activity in the reverse reaction compared to the wild-type enzyme
additional information
K56Q/Q100K
site-directed mutagenesis, mutant shows no cyclohydrolase activity, but retains more than 2 thirds of wild-type dehydrogenase activity
K56Q/Q100K
-
site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity
R653Q
-
geneotype analysis of 125 women, A1958A polymorphism, leading to amino acid exchange R653Q, in the MTHFD1 gene 1.64fold increases a mothers risk of having an unexplained second trimester pregnancy loss, overview
additional information
construction of loop3G and loop5G deletion mutants which show 68.3% and 58.6% reduced activity, respectively, compared to the wild-type
additional information
-
construction of loop3G and loop5G deletion mutants which show 68.3% and 58.6% reduced activity, respectively, compared to the wild-type
additional information
-
MTHFD1 G1958A polymorphism/genotype occurs in spontaneous cervical artery dissections, methyleneterahydrofolate reductase and plasma homocysteine levels are also important, overview
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, 50 mM potassium phosphate, 30% glycerol buffer, stable for over 1 month
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by Ni2+-chelate affinity chromatography
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by Ni2+-chelate affinity chromatography
-
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by Ni2+-chelate affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
bifunctional dehydrogenase/cyclohydrolase portion of the cytoplasmic trifunctional enzyme cloned and heterologous expressed in the yeast strain YA3-1
-
cDNA encoding bifunctional enzyme cloned and expressed in Escherichia coli K38
-
expression of wild-type and mutant enzymes in Escherichia coli BL21 as C-terminally His-tagged enzymes
expression of wild-type and mutant enzymes in Escherichia coli JM109 as C-terminally His-tagged enzymes
-
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
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
enzyme represents a potential pharmaceutical target for manipulation of cell growth and development and hence cancer prevention or treatment
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tabor, H.; Wyngarden, L.
The enzymatic formation of formiminotetrahydrofolic acid, 5,10-methenyltetrahydrofolic acid, and 10-formyltetrahydrofolic acid in the metabolism of formiminoglutamic acid
J. Biol. Chem.
234
1830-1846
1959
Bos taurus, Cavia porcellus, Clostridium cylindrosporum, Felis sp., Gottschalkia acidurici, Homo sapiens, Mus musculus, Oryctolagus cuniculus, Ovis aries, Pseudomonas fluorescens, Rattus norvegicus, Sus scrofa
D'Ari, L.; Rabinowitz, J.C.
Purification, characterization, cloning, and amino acid sequence of the bifunctional enzyme 5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase from Escherichia coli
J. Biol. Chem.
266
23953-23958
1991
Clostridium cylindrosporum, Columba sp., Escherichia coli, Escherichia coli BE, Gallus gallus, Homo sapiens, Moorella thermoacetica, Mus musculus, Oryctolagus cuniculus, Ovis aries, Rattus norvegicus, Saccharomyces cerevisiae, Sus scrofa
Xiao-Ming, Y.; MacKenzie, R.E.
Expression of human NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase in Escherichia coli: Purification and partial characterization
Protein Expr. Purif.
3
256-262
1992
Homo sapiens
Pelletier, J.N.; MacKenzie, R.E.
Binding to the 2',5'-ADP subsite stimulates cyclohydrolase activity of human NADP+-dependent methylenetetrahydrofolate dehydrogenase/cyclohydrolase
Biochemistry
33
1900-1906
1994
Saccharomyces cerevisiae, Homo sapiens, Sus scrofa
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
Acetobacterium woodii, Clostridium formicaceticum, Drosophila melanogaster, Escherichia coli, Homo sapiens, Mus musculus, Photobacterium phosphoreum, Rattus norvegicus, Saccharomyces cerevisiae, Salmonella enterica subsp. enterica serovar Typhimurium, Spodoptera frugiperda, Spodoptera frugiperda Sf9
Cheung, E.; D'Ari, L.; Rabinowitz, J.C.; Dyer, D.H.; Huang, J.Y.; Stoddard, B.L.
Purification, crystallization, and preliminary X-ray studies of a bifunctional 5,10-methenyl/methylene tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli
Proteins
27
322-324
1997
Saccharomyces cerevisiae, Drosophila melanogaster, Escherichia coli, Homo sapiens, Rattus norvegicus, Escherichia coli BE
Schmidt, A.; Wu, H.; MacKenzie, R.E.; Chen, V.J.; Bewly, J.R.; Ray, J.E.; Toth, J.E; Cygler, M.
Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase
Biochemistry
39
6325-6335
2000
Drosophila melanogaster, Mus musculus, Rattus norvegicus, Homo sapiens (P11586), 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, Mus musculus, Photobacterium phosphoreum, Saccharomyces cerevisiae, Sus scrofa
Pawelek, P.D.; Allaire, M.; Cygler, M.; MacKenzie, R.E.
Channeling efficiency in the bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase domain: the effects of site-directed mutagenesis of NADP binding residues
Biochim. Biophys. Acta
1479
59-68
2000
Homo sapiens
Sundararajan, S.; MacKenzie, R.E.
Residues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: The roles of glutamine 100 and aspartate 125
J. Biol. Chem.
277
18703-18709
2002
Homo sapiens (P11586), Homo sapiens
Konrad, C.; Mueller, G.A.; Langer, C.; Kuhlenbaeumer, G.; Berger, K.; Nabavi, D.G.; Dziewas, R.; Stoegbauer, F.; Ringelstein, E.B.; Junker, R.
Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections
J. Neurol.
251
1242-1248
2004
Homo sapiens
Parle-McDermott, A.; Pangilinan, F.; Mills, J.L.; Signore, C.C.; Molloy, A.M.; Cotter, A.; Conley, M.; Cox, C.; Kirke, P.N.; Scott, J.M.; Brody, L.C.
A polymorphism in the MTHFD1 gene increases a mothers risk of having an unexplained second trimester pregnancy loss
Mol. Hum. Reprod.
11
477-480
2005
Homo sapiens
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
Homo sapiens, Saccharomyces cerevisiae (P07245), Saccharomyces cerevisiae (P09440)
Kruszyna, L.; Lianeri, M.; Rydzanicz, M.; Gajecka, M.; Szyfter, K.; Jagodzinski, P.P.
Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer
Mol. Biol. Rep.
37
241-247
2010
Homo sapiens
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), Homo sapiens
Gustafsson, R.; Jemth, A.S.; Gustafsson, N.M.; Faernegardh, K.; Loseva, O.; Wiita, E.; Bonagas, N.; Dahllund, L.; Llona-Minguez, S.; Haeggblad, M.; Henriksson, M.; Andersson, Y.; Homan, E.; Helleday, T.; Stenmark, P.
Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitor
Cancer Res.
77
937-948
2017
Homo sapiens (P13995), Homo sapiens
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), Homo sapiens
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