Information on EC 1.3.1.6 - fumarate reductase (NADH)

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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota

EC NUMBER
COMMENTARY hide
1.3.1.6
-
RECOMMENDED NAME
GeneOntology No.
fumarate reductase (NADH)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
succinate + NAD+ = fumarate + NADH + H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Carbon fixation pathways in prokaryotes
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-
Microbial metabolism in diverse environments
-
-
SYSTEMATIC NAME
IUBMB Comments
succinate:NAD+ oxidoreductase
-
CAS REGISTRY NUMBER
COMMENTARY hide
9076-99-7
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain Nemuro
-
-
Manually annotated by BRENDA team
strain Nemuro
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
strain S-2
-
-
Manually annotated by BRENDA team
serovar typhimurium SR-11
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
-
the enzyme is part of the NADH-fumarate reductase system in cancer cell microenvironments, with deficiencies of critical nutrients and hypoxia, where it is important for maintaining mitochondrial energy metabolism, overview. The NADH-fumarate reductase system is the function of complex II
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acrylic acid + NADH
propanoic acid + NAD+
show the reaction diagram
-
poor substrate
-
-
?
cinnamic acid + NADH
3-phenylpropanoic acid + NAD+
show the reaction diagram
-
poor substrate
-
-
?
citraconic acid + NADH
2-methylbutanedioic acid + NAD+
show the reaction diagram
-
very poor substrate
-
-
?
fumarate + NADH + H+
succinate + NAD+
show the reaction diagram
fumarate + reduced benzylviologen
succinate + benzylviologen
show the reaction diagram
-
-
-
-
?
maleate + NADH
succinate + NAD+
show the reaction diagram
mesaconate + NADH
methylsuccinate + NAD+
show the reaction diagram
succinate + NAD+
fumarate + NADH + H+
show the reaction diagram
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
fumarate + NADH + H+
succinate + NAD+
show the reaction diagram
succinate + NAD+
fumarate + NADH + H+
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
FADH2
flavocytochrome c3
-
-
-
FMNH2
NADPH
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about 20% of activity with NADH
tetraheme flavocytochrome c3
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Fe-S cluster
-
three Fe-S clusters relay electrons over more than 30 A, varying the medial [4Fe-4S] cluster potential over a 100 mV range does not have a significant effect on the inherent kinetics of electron transfer to and from the active-site flavin
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1-[[2-(4-tert-butylphenyl)ethyl]amino]phthalazin-5-ol
-
-
2',6-dihydroxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
-
-
2,4-dimethoxy-4'-allyloxychalcone
2,4-dimethoxy-4'-butoxychalcone
2-n-heptyl-4-hydroxyquinoline-N-oxide
3',4',6-trihydroxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
-
-
3',6-dihydroxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
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-
4',6-dihydroxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
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-
4,6,3'-hydroxy-4'-methoxy-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-one
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-
4,6,4'-hydroxy-3'-methoxy-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-one
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-
4,6,4'-triacetyl-3',5'-dimethoxy-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-one
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i.e. bracteintriacetate
4,6-dihydroxy-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-ol
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-
6-benzoyl-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-ol
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-
6-hydroxy-2-[(2,3,4-trihydroxyphenyl)-methylene]-3(2H)-benzofuran-3-one-5-beta-D-glucopyranoside
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i.e. bractein
6-hydroxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
-
-
6-hydroxy-3',4'-dimethoxy-2-[phenylhydroxymethylene]-3(2H)-benzofuran-3-one
-
-
6-hydroxy-benzofuran-3-one
-
-
6-methoxy-2-[phenylmethylene]-3(2H)-benzofuran-3-one
-
-
Acriflavin
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specific inhibition of NADH dependent activity
Cinnamic acid
-
preincubation
citraconate
ClHgSO3H
-
inhibition with all cofactors except the methyl viologen dependent activity
decursin
-
-
decursinol
-
-
decursinol angelate
-
-
flutolanil
-
fungizide
iodoacetate
-
slight inhibition
KCN
-
inhibition with all cofactors except the methyl viologen dependent activity
lipochalcone A
malonate
mesaconic acid
-
strong inhibition with and without preincubation
N-(4-[[2-(4-tert-butylphenyl)ethyl]amino]phthalazin-6-yl)prop-2-enamide
-
-
N-[2-(4-tert-butylphenyl)ethyl]-5-(1-methylethoxy)phthalazin-1-amine
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-
N-[2-(4-tert-butylphenyl)ethyl]-5-methoxyphthalazin-1-amine
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-
N-[2-(4-tert-butylphenyl)ethyl]phthalazin-1-amine
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quinazoline
N1-[2-(4-tert-butylphenyl)ethyl]phthalazine-1,6-diamine
-
-
N1-[2-(4-tert-butylphenyl)ethyl]phthalazine-1,7-diamine
-
-
p-chloromercuribenzoate
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slight inhibition
Pd-(pyridine-2-thiol N-oxide)2
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inhibitory effect of metal-pyridine-2-thiol N-oxide complexes, marked increase is obeserved in the inhibitory effect with respect to that of the free ligand, inhibition in a dose-dependent manner, a clear relief of the growth inhibition produced by the metal-mpo complex is observed in the presence of 5 mM succinate
Pt-(pyridine-2-thiol N-oxide)2
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inhibitory effect of metal-pyridine-2-thiol N-oxide complexes, inhibition observed 2 is similar to that obtained with the ligand alone, a clear relief of the growth inhibition produced by the metal-mpo complex is observed in the presence of 5 mM succinate
pyridine-2-thiol N-oxide
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2-mercaptopyridine N-oxide (mpo) is a bioactive ligand with a potential as antitrypanosomal agent
pyrvinium pamoate
sodium pyridine-2-thiol N-oxide
-
inhibitory effect of the sodium salt
succinate
trans-, trans muconate
-
slight inhibition
Triton X-100
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complete loss of NADH dependent activity at concentration of 0.05%, up to 17fold increase in methyl viologen dependent activity
ukulactone A
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polyketide isolated from a culture broth of Penicillium sp. FKI-3389, shows potent inhibitory activity
ukulactone B
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polyketide isolated from a culture broth of Penicillium sp. FKI-3389. Inhibitory activity is 200 times weaker than that of epimer ukulactone A
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
KCl
-
can repace for NaCl
NaCl
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required for full activity, about 10fold activation at 150 mM
Triton X-100
-
up to 17fold increase in methyl viologen dependent activity, loss of NADH dependent activity
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.086 - 0.2
FMNH2
0.005 - 0.129
fumarate
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
15 - 658
fumarate
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0006
2-n-heptyl-4-hydroxyquinoline-N-oxide
-
-
0.001
rotenone
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-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.071
1-[[2-(4-tert-butylphenyl)ethyl]amino]phthalazin-5-ol
Echinococcus multilocularis
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in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.0011
decursin
Ascaris suum
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-
0.0048
decursinol
Ascaris suum
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-
0.0027
decursinol angelate
Ascaris suum
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-
0.000081
flutolanil
Ascaris suum
-
promising lead compound for anthelminthics
0.016
N-(4-[[2-(4-tert-butylphenyl)ethyl]amino]phthalazin-6-yl)prop-2-enamide
Echinococcus multilocularis
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in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.91
N-[2-(4-tert-butylphenyl)ethyl]-5-(1-methylethoxy)phthalazin-1-amine
Echinococcus multilocularis
-
in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.048 - 4.1
N-[2-(4-tert-butylphenyl)ethyl]-5-methoxyphthalazin-1-amine
0.0023
N-[2-(4-tert-butylphenyl)ethyl]phthalazin-1-amine
Echinococcus multilocularis
-
in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.062
N1-[2-(4-tert-butylphenyl)ethyl]phthalazine-1,6-diamine
Echinococcus multilocularis
-
in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.0021
N1-[2-(4-tert-butylphenyl)ethyl]phthalazine-1,7-diamine
Echinococcus multilocularis
-
in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl2, at 25°C
0.0005
pyrvinium pamoate
Homo sapiens
-
pH 7.5, 30°C
0.0000024
ukulactone A
Ascaris suum
-
pH 7.0, 37°C
0.00047
ukulactone B
Ascaris suum
-
pH 7.0, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.015
-
epimastigote homogenate, strain Y
0.045
-
in 30 mM potassium phosphate (pH 7.4) and 1 mM MgCl, at 25°C
0.082
-
procyclic trypomastigote homogenate, strain S-2
0.14 - 0.25
-
with NADH, FMNH2 and FADH2
0.142
glyoxysomal fraction
0.23
-
in presence of 10 mM thioglycolate
0.84
-
with benzyl- or mehtyl viologen
2.7
-
partially purified enzyme
12.3
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in mitochondria of L3 larvae, at 25°C, using 50 mM potassium phosphate (pH 7.5)
20.6
-
in supernatant of spheroplasts
26
wild-type strain, assay under anaerobic conditions
34.4
-
in mitochondria of adult worms, at 25°C, using 50 mM potassium phosphate (pH 7.5)
43
-
in mitochondria of L3 larvae, at 25°C, using 50 mM potassium phosphate (pH 7.5)
2189
-
purified enzyme from promastigotes
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6
-
in presence of NaCl, without NaCl maximum activity below pH 5
7
-
assay at
7.5
-
assay at
additional information
-
-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 7
-
in presence of NaCl
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
pancreatic cancer cells
Manually annotated by BRENDA team
-
colorectal cancer cells
Manually annotated by BRENDA team
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third stage L3 larvae and lung stage LL3 larvae
Manually annotated by BRENDA team
-
from adult Ascaris suum
Manually annotated by BRENDA team
-
pancreatic cancer cells
Manually annotated by BRENDA team
additional information
-
cancer cells have higher FRD activity levels than the normal fibroblast cells
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
soluble at high ionic strength
Manually annotated by BRENDA team
additional information
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
63033
-
x * 63033, wild-type enzyme, mass spectrometry
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
-
x * 63033, wild-type enzyme, mass spectrometry
monomer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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phosphorylation of the flavoprotein subunit is required for enzyme activity. Treatment with phosphatase causes the dephosphorylation of flavoprotein subunit, with a concomitant increase in succinate-ubiquinone reductase activity, whereas FRD activity decreases
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystallized in the presence of octaethyleneglycol monododecyl ether and n-dodecyl-beta-D-maltopyranoside in a 3:2 weight ratio, crystals belongs to a orthorhombic space group with unit-cell parameters a=123.75 A, b= 29.08 A and c=221.12 A, diffracted to 2.8 A resolution using synchrotron radiation
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mutant enzyme H505A and H505Y, hanging drop vapour diffusion method, protein solution: 6 mg/ml, 10 mM Tris-HCl, pH 8.5, well solution: 100 mM Tris-HCl, pH 7.4-8.2, 25°C, 80 mM NaCl, 16-19% PEG 8000, 10 mM fumarate, equal volume of 0.002 ml of protein solution and well solution, 10 days, cryoprotectant solution: 100 mM sodium acetate, pH 6.5, 20% PEG 8000, 10 mM fumarate, 80 mM NaCl, and 23% glycerol, X-ray diffraction structure determination and analysis at 1.8 A and 2.0 A resolution, respectively, molecular replacement
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mutant enzyme H61A and H61M, hanging drop vapour diffusion method, protein solution: 6 mg/ml, 10 mM Tris-HCl, pH 8.5, well solution: 100 mM Tris-HCl, pH 7.4-8.5, 4°C, 80 mM NaCl, 16-19% PEG 8000, 10 mM fumarate, equal volume of 0.002 ml of protein solution and well solution, 10 days, cryoprotectant solution: 100 mM sodium acetate, pH 6.5, 20% PEG 8000, 10 mM fumarate, 80 mM NaCl, and 23% glycerol, X-ray diffraction structure determination and analysis at 2.1 A and 2.2 A resolution, respectively, molecular replacement
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
inactivation by irradiation at 254 nm
-
stabilized against air oxidation with 10 mM thioglycollate
-
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
sensitive to air oxidation, loss of activity
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 20 mM HEPES, pH 8, 0.6 M sucrose, 1 mM DTE, 15% loss of activity within 1 month, 38% loss of activity within 1 year
-
stable in lyophylized whole cells
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
mitochondria prepared from the muscle are used for purification on a DEAE Sepharose FF column
-
native enzyme from cancer cell mitochondria
-
partial, release from subcellular compartment by treatment with digitonin
partially, preparation of the mitochondrial fraction
-
recombinant wild-type and mutant flavocytochrome enzymes from enzyme-deficient strain DELTAfccA EG301
-
recombinant wild-type and mutant flavocytochrome enzymes from the enzyme-deficient strain DELTAfccA
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
delta FDRg2, fumarate reductase deficiency mutant
gene fccA, expression of wild-type and mutant flavocytochrome enzymes in the enzyme-deficient strain DELTAfccA
-
gene fccA, subcloning in Escherichia coli, expression of wild-type and mutant flavocytochrome enzymes in the enzyme-deficient strain DELTAfccA EG301
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gene FRDg, DNA sequence determination and analysis, gene expression inhibition wby RNAi, stem-loop sense/antisense molecules, expresssion of EGFP-tagged enzyme in trypanosomes, cell line EATRO1125.T7T; gene FRDm1, DNA sequence determination and analysis, gene expression inhibition wby RNAi, stem-loop sense/antisense molecules, expresssion of EGFP-tagged enzyme in trypanosomes, cell line EATRO1125.T7T; gene FRDm2, DNA sequence determination and analysis, gene expression inhibition wby RNAi, stem-loop sense/antisense molecules, expresssion of EGFP-tagged enzyme in trypanosomes, cell line EATRO1125.T7T
genes frdA, frdB, and frdC, organized in an operon, DNA sequence determination and analysis, subcloning in Escherichia coli, expression of mutant enzymes
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
H505A
-
site-directed mutagenesis, altered binding structure of the sodium ion, crystal structure analysis, at pH 8.5 the activity of the mutant enzyme is similar to the wild-type enzyme, at pH 6.0 the ctivity is 20fold reduced
H505Y
-
site-directed mutagenesis, altered binding structure of the sodium ion, crystal structure analysis, at pH 8.5 the activity of the mutant enzyme is similar to the wild-type enzyme
H61A
-
site-directed mutagenesis, 5-10fold reduced kcat compared to the wild-type enzyme, elevated pH optimum, electrochemical analysis, crystal structure analysis, altered ligand binding of hemes and heme iron, 80% of wild-type activity can be recovered by addition of exogenous imidazole, overview
H61M
-
site-directed mutagenesis, 5-10fold reduced kcat compared to the wild-type enzyme, elevated pH optimum, electrochemical analysis, crystal structure analysis, altered ligand binding of hemes and heme iron, 80% of wild-type activity can be recovered by addition of exogenous imidazole, overview
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
-
lack of NADH-fumarate reductase in mammalian cells provides an interesting target against Chagas disease
medicine
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