Information on EC 1.5.1.6 - formyltetrahydrofolate dehydrogenase

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The expected taxonomic range for this enzyme is: Euteleostomi

EC NUMBER
COMMENTARY hide
1.5.1.6
-
RECOMMENDED NAME
GeneOntology No.
formyltetrahydrofolate dehydrogenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
10-formyltetrahydrofolate + NADP+ + H2O = tetrahydrofolate + CO2 + NADPH + H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
redox reaction
reduction
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-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
One carbon pool by folate
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-
SYSTEMATIC NAME
IUBMB Comments
10-formyltetrahydrofolate:NADP+ oxidoreductase
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CAS REGISTRY NUMBER
COMMENTARY hide
37256-25-0
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
male mice, maintained on Teklad rodent diet no. 8604
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-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
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FDH induces apoptosis in PC-3 prostate cells through simultaneous activation of the c-Jun-NH2-kinase JNK and extracellular signal-regulated kinase ERK pathways with JNK phosphorylating c-Jun and ERK1/2 phosphorylating Elk-1. The JNK1/2 inhibitor SP600125 or ERK1/2 inhibitor PD98059 prevents phosphorylation of c-Jun and Elk-1, correspondingly and partially protects PC-3 cells from FDH-induced cytotoxicity. Combination of the two inhibitors produces an additive effect. The FDH-induced apoptosis in p53-proficient A-549 cells also proceeds through activation of JNK1/2, but the down-stream target for JNK2 is p53 instead of c-Jun. In A-549 cells, FDH activates caspase 9, whereas in PC-3 cells, it activates caspase 8
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
show the reaction diagram
10-formyl-5,8-dideazafolate tetraglutamate + NADP+ + H2O
5,8-dideazafolate tetraglutamate + CO2 + NADPH + H+
show the reaction diagram
-
-
tightly bound product
ir
10-formyltetrahydrofolate + NADP+ + H2O
?
show the reaction diagram
-
the enzyme is composed of three domains and possesses three catalytic activities but has only two catalytic centers. The amino-terminal domain (residues 1-310) bears 10-formyltetrahydrofolate hydrolase activity, the carboxyl-terminal domain (residues 420-902) bears an aldehyde dehydrogenase activity, and the full-length FDH produces 10-formyltetrahydrofolate dehydrogenase activity
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
show the reaction diagram
10-formyltetrahydropteroylhexaglutamate + NADP+ + H2O
tetrahydropteroylhexaglutamate + CO2 + NADPH
show the reaction diagram
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
show the reaction diagram
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
show the reaction diagram
ATP + formate + tetrahydrofolate
ADP + phosphate + 10-formyltetrahydrofolate
show the reaction diagram
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-
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
show the reaction diagram
10-formyltetrahydropteroylhexaglutamate + NADP+ + H2O
tetrahydropteroylhexaglutamate + CO2 + NADPH
show the reaction diagram
-
-
-
?
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
10-formyltetrahydrofolate
5-formyltetrahydrofolate
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covalent linkage of 5-formyltetrahydrofolate to enzyme, 2 mol bound per mol of enzyme monomer, it is a minor form of the folate coenzymes and arises from 10-formyltetrahydrofolate
folate
NAD+
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less than 5% of the activity with NADP+
tetrahydrofolate
additional information
-
no effect: NADPH
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5,10-dideazatetrahydrofolate
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0.4 mM, 98% inhibition, folate analog
5-formyltetrahydrofolate
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covalent attachment completely inhibits
Chymotrypsin
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cleavage between the two domains, inactivates 10-formyltetrahydrofolate dehydrogenase but not hydrolase and aldehyde dehydrogenase activity
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hydroxylamine
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0.1 M, strong inhibition
iodoacetamide
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inhibition reversed by 2-mercaptoethanol
N-ethylmaleimide
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1 mM or 10 mM, complete inhibition
p-chloromercuribenzoate
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inhibition reversed by 2-mercaptoethanol
propanal
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FDH activity decreases with increasing concentrations, competes with 10-formyltetrahydrofolate for NADP+-dependent oxidation
Subtilisin
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cleavage between the two domains, inactivates 10-formyltetrahydrofolate dehydrogenase but not hydrolase and aldehyde dehydrogenase activity
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tetrahydrofolate
tetrahydropteroylhexaglutamate
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1 mol per mol of tetrameric protein, potent product inhibitor: 0.0003 mM, 90% inhibition
Tetrahydropteroylpentaglutamate
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strong product inhibition
tetrahydropteroylpolyglutamate
Trypsin
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-mercaptoethanol
4'-phosphopantetheinyl transferase
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4'-phosphopantetheinyl transferase activates dehydrogenase catalysis of ALDH1L2 by modifying Ser375
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C1-tetrahydrofolate synthase
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10-formyltetrahydrofolate synthetase activity of trifunctional enzyme causes together with its substrates MgATP, formate, and tetrahydrofolate an 3fold increase of initial velocity
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serine hydroxymethyltransferase
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addition of SHMT and of its substrate L-serine increases the initial reaction rate by 1.8fold with 10-formyltetrahydropteroylpentaglutamate as substrate, SHMT increases the release of product
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additional information
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not activated by methionine or ethionine
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0032
10-formyl-5,8-dideazafolate
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-
0.0044 - 0.05
10-formyltetrahydrofolate
0.0004 - 0.0035
NADP+
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.967 - 97
10-formyltetrahydrofolate
0.867 - 0.9
10-formyltetrahydropteroylpentaglutamate
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.048
5,10-dideazatetrahydrofolate
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0.001 - 0.01
tetrahydrofolate
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.00278
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liver samples enriched for cytosolic proteins, heterozygous mice with deletion mutation in the FDH structural gene
0.00478
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liver samples enriched for cytosolic proteins, normal mice
0.094
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recombinant FDH, 10-formyltetrahydrofolate as substrate
0.144
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with 10-formyl-5,8-dideazafolate as substrate
0.26
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with 10-formyltetrahydrofolate as substrate
0.305
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0.51
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0.64
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0.7 - 0.8
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at 25C
0.98
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1.04
30C, pH not specified in the publication, recombinant enzyme expressed in Pichia pastoris
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 8.5
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in Tris buffer 30% faster reaction than in phosphate buffer
8
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broad pH-maximum at pH 8.0
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 8.5
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more than 60% of maximal activity at pH 6.5 and 8.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
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assay at
25
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assay at
37
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maximal catalytic capacity at
additional information
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.6
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predicted
7
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two-dimensional gel electrophoresis
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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transformed embryonic kidney cell line HEK-293A
Manually annotated by BRENDA team
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moderate FDH mRNA level
Manually annotated by BRENDA team
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moderate FDH mRNA level
Manually annotated by BRENDA team
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moderate FDH mRNA level
Manually annotated by BRENDA team
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less activity
Manually annotated by BRENDA team
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moderate FDH mRNA level
Manually annotated by BRENDA team
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moderate FDH mRNA level
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
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Manually annotated by BRENDA team
additional information
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not detected in nucleus, lysosomes or peroxisomes
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Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
58000
-
C-terminal domain, gel filtration
90000
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SDS-PAGE
100000
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full-length enzyme, gel filtration
320000
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gel filtration
390000
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gel filtration
393200
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C707A mutant FDH, molecular size detector employing laser-light scattering methodology
398800
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wild-type FDH, molecular size detector employing laser-light scattering methodology
400000
gel fitlration
413000
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gel filtration, sedimentation analysis
440000
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gel filtration
450000
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nondenaturing PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homotetramer
tetramer
4 * 100000, calculated
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospholipoprotein
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the broad specificity human 4-phosphopantetheinyl transferase phosphopantetheinylates apo-FDH to holoenzyme and thus activates FDH catalysis. Silencing 4-phosphopantetheinyl transferase by small interfering RNA in A-549 cells prevents FDH modification
proteolytic modification
sequence contains a 22 amino acid N-terminal mitochondrial translocation signal
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
C-terminal domain of FDH and its complexes with oxidized and reduced forms of NADP+ are crystallized using the hanging drop vapour diffusion method with 1.4-1.5 M ammonium sulfate and 0.1 M Tris-HCl, pH 7.0-7.5
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crystal structure of the hydrolase domain of FDH, solved to 2.3 A resolution
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
in general activity is labile
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
prone to oxidative inactivation, but may be partially reactivated by incubation with 100 mM 2-mercaptoethanol or 100 mM dithiothreitol
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392342
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-15C, presence of 0.01 mM 2-mercaptoethanol, several weeks, stable
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-20C, 20% glycerol, over 12 months, no loss of activity
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-20C, 20% glycerol, several months, stable
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-20C, dialyzed against 0.01 M potassium phosphate buffer, pH 7.3, 40% glycerol, 0.1 M KCl, several weeks, stable
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-20C, stable for several months
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-70C, 0.05 M phosphate buffer, pH 7.2, 50%-saturated (NH4)2SO4, 20% glycerol, 1 mM EDTA, 0.1 mM dithioerythritol, 0.01 mM phenylmethanesulfonyl fluoride, several months, stable
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4C, stable for 2 weeks
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
200fold partial purification
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250fold purification
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5-fTHFSepharose column chromatography, Sephacryl S-300 gel filtration, and MonoQ column chromatography
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co-purification with carbamoyl-phosphate synthetase 1 and betaine homocysteine S-methyltransferase using Kunitz-type soybean trypsin inhibitor-coupled Sepharose CL-4B column chromatography, Sephacryl S-200 gel filtration, and Superdex 200 gel filtration; Kunitz-type soybean trypsin inhibitor-coupled Sepharose CL-4B column chromatography
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free of 10-formyltetrahydrofolate hydrolase activity
intermediate domain and its mutants
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Ni-NTA column chromatography
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partial purification of MSN13/94, identified as forms of 10-formyltetrahydrofolate dehydrogenase
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purification of a C707A mutant of FDH; purification of recombinant liver FDH
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purification of N-terminal domain mutants and of a D124A mutant of FDH
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purification of N-terminal domain mutants and of a H106K mutant of FDH
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purification of recombinant 310 amino acid residue N-terminal domain
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purification of recombinant liver FDH
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recombinant protein
separated from 10-formyltetrahydrofolate hydrolase, dehydrogenase and hydrolase are closely related and separately compartmentalized enzymes
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; transfection of COS-7 and A-549 cells, and expression with green fluorescent protein fusion construct
clone expressed in insect cells has both dehydrogenase and hydrolase activity and exhibits almost identical kinetic parameters to the native rat liver enzyme; FDH is cloned
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cloning and sequencing of the cDNA encoding FDH from fetal liver
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cloning of the cDNA encoding FDH
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cloning of the cDNA encoding FDH, cells from several tumor cell lines are transfected with FDH cDNA cloned into pcDNA 3.1+ vector using LipofectAMINE, expression of FDH inhibits the proliferation of the cell lines as a result of its enzymatic activity
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cloning of the cDNA encoding FDH; expression of FDH cDNA, subcloned in the pVL 1393 baculovirus vector, in Sf9 insect cells, using the MaxBac expression system
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expressed in Escherichia coli
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expressed in Escherichia coli and Sf9 insect cells
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expressed in Escherichia coli BL21(DE3) Codon Plus cells
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expression in Escherichia coli
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expression in Escherichia coli and Pichia pastoris
expression of D124A mutant of FDH and N-terminal domain mutants in Sf9 insect cells, using a baculovirus expression system
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expression of FDH and its N-terminal and C-terminal domains in insect cells, using a baculovirus expression system, expression of FDH and of its 310 amino acid residue N-terminal domain in Escherichia coli BL21 using the pRSET vector, full-length enzyme expressed in Escherichia coli is nonsoluble, because of the large size of its monomer and uncorrect folding in prokaryotic cells
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expression of FDH cDNA, subcloned in the pVL 1393 baculovirus vector, in Sf9 insect cells, using the MaxBac expression system
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expression of FDH in insect cells using the pVL 1393 baculovirus expression vector
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expression of H106K mutant of FDH in insect cells SF9, using a baculovirus expression system, and of N-terminal domain mutants in Escherichia coli BL 21
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FDH is cloned
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C707A
-
catalytically inactive mutant
S374A
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the mutant is activated by 4'-phosphopantetheinyl transferase
S374A/S375A
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the mutant is not activated by 4'-phosphopantetheinyl transferase
S375A
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the mutant is not activated by 4'-phosphopantetheinyl transferase
C152A
-
95% of the activity with wild-type enzyme
C17A
-
94% of the activity with wild-type enzyme
C191A
-
96% of the activity with wild-type enzyme
C238A
-
102% of the activity with wild-type enzyme
C86A
-
110% of the activity with wild-type enzyme
D142A
-
mutant with a complete loss of 10-formyltetrahydrofolate dehydrogenase and hydrolase activity, aldehyde dehydrogenase activity is similar to wild-type FDH
D399A
-
90% of the dehydrogenase activity of the wild-type enzyme
E398A
-
90% of the dehydrogenase activity of the wild-type enzyme
F384_V405del
-
no dehydrogenase activity
G397A
-
as active as wild-type enzyme
H106A
-
insoluble recombinant protein
H106K
-
mutant with a complete loss of 10-formyltetrahydrofolate dehydrogenase and hydrolase activity, aldehyde dehydrogenase activity is similar to wild-type FDH
K394A
-
75% of the dehydrogenase activity of the wild-type enzyme
K394A/L395A/R396A/G397A/E398A/D399A
-
no dehydrogenase activity
K394_D399del
-
no dehydrogenase activity
L395A
-
80% of the dehydrogenase activity of the wild-type enzyme
R396A
-
as active as wild-type enzyme
S354A
-
no dehydrogenase activity
additional information
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deletion mutation in the 10-formyltetrahydrofolate structural gene in homozygous mice with absence of FDH mRNA and enzyme activity, total folate pool is decreased and the level of tetrahydrofolate is markedly depleted, pairs of homozygotes have a dramatically decreased reproductive efficiency, may be attributable to fetal lethality
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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