Information on EC 1.14.11.1 - gamma-butyrobetaine dioxygenase

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

EC NUMBER
COMMENTARY hide
1.14.11.1
-
RECOMMENDED NAME
GeneOntology No.
gamma-butyrobetaine dioxygenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
4-trimethylammoniobutanoate + 2-oxoglutarate + O2 = 3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
oxidative decarboxylation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
gamma-butyrobetaine degradation
-
-
L-carnitine biosynthesis
-
-
carnitine metabolism
-
-
Lysine degradation
-
-
SYSTEMATIC NAME
IUBMB Comments
4-trimethylammoniobutanoate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)
Requires Fe2+ and ascorbate.
CAS REGISTRY NUMBER
COMMENTARY hide
9045-31-2
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
the GBBH residues involved in zinc binding are evolutionary conserved in all sequenced eukaryotes more complex than Caenorhabditis elegans
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(3R)-3-fluoro-4-(trimethylammonio)butanoate + 2-oxoglutarate + O2
?
show the reaction diagram
-
weak substrate, below 5% turnover after 3 h
-
-
?
(3S)-3-fluoro-4-(trimethylammonio)butanoate + 2-oxoglutarate + O2
?
show the reaction diagram
-
S-stereoisomer preferred substrate
-
-
?
3-trimethylaminopropionic acid + 2-oxoglutarate + O2
?
show the reaction diagram
-
20% of the hydroxylation rate of gamma-butyrobetaine
-
-
?
4-(trimethylammonio)butanoic acid + 2-oxoglutarate + O2
?
show the reaction diagram
-
-
-
-
?
4-dimethylaminobutyric acid + 2-oxoglutarate + O2
4-dimethylamino-3-hydroxybutyric acid + succinate + CO2
show the reaction diagram
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
show the reaction diagram
5,5-dimethylhexanoate + 2-oxoglutarate + O2
?
show the reaction diagram
6-N-trimethyl-L-lysine + 2-oxoglutarate + O2
?
show the reaction diagram
-
-
-
-
?
gamma-butyrobetaine + 2-oxoglutarate + O2
carnitine + succinate + CO2
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
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,6-dichlorophenolindophenol
-
-
ascorbate
additional information
-
KCl, nicotinamide, MgCl2 or catalase not required for full activity
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zn2+
quantitative determination of Zn2+ by atomic absorption spectrometry, zinc-binding site structure in the N-terminal domain of GBBH, overview
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-oxoglutarate
-
at concentrations above 1 mM
3,4-dihydroxybenzoate
-
-
3-(2,2,2-trimethylhydrazinium propionate dihydrate)
i.e. mildronate, a synthetic inhibitor of GBBH, is a non-hydroxylatable analog of gamma-butyrobetaine
3-(2,2,2-trimethylhydrazinium)propionate
-
complete inhibition at 0.05 mM
3-(2,2,2-trimethylhydrazinium)propionate dihydrate
-
-
3-(2,2-Dimethylcyclopropyl)propionic acid
-
mechanism-based inhibitor
3-Bromo-2-oxoglutarate
-
noncompetitive inhibition, 2-oxoglutarate as variable substrate
3-glutathione-2-oxoglutarate
-
noncompetitive to 2-oxoglutarate
3-trimethylaminopropyl-1-sulfonate
-
-
4-Trimethylammoniobutanoate
substrate inhibition at concentrations above 0.2 mM
alpha,alpha'-bipyridyl
-
no activity at 2 mM
arsenite
-
-
ascorbate
Ba2+
-
-
bicyclic isoquinolinyl
-
-
-
Ca2+
-
-
Cd2+
-
-
Clofibrate
-
activity of gamma-butyrobetaine dioxygenase in the liver is lower in pigs treated with clofibrate than in control pigs
Co2+
-
-
Cu2+
-
-
Cyclopropyl-substituted gamma-butyrobetaines
-
-
-
D-carnitine
-
uncoupling agent
dioxane
-
-
DL-carnitine
FMN
-
in high concentrations
gamma-butyrobetaine
-
at concentrations above 0.2 mM
Hg2+
-
-
iodoacetate
-
less effective than p-chloromercuriphenylsulfonate
Iodosobenzoate
-
less effective than p-chloromercuriphenylsulfonate
Mg2+
-
-
Mn2+
-
-
N-ethylmaleimide
-
less effective than p-chloromercuriphenylsulfonate
Ni2+
-
-
O2
-
irreversible
p-aminomethylbenzoic acid
-
1.2 mmol/kg reduces the conversion of 4-dimethylaminobutyric acid to 4-dimethylamino-3-hydroxybutyric acid from 62.6% to 46.8%
p-chloromercuribenzoate
-
inactivates enzyme completely at 0.1 mM
p-Chloromercuriphenylsulfonate
-
inactivates enzyme completely at 0.1 mM
Pb2+
-
-
phosphate
-
-
Pyridine 2,4-dicarboxylate
-
-
Pyridine-2,4-dicarboxylate
-
-
Quinacrine
-
-
Sn2+
-
-
Structure analogues of gamma-butyrobetaine and 2-oxoglutarate
-
Succinic semialdehyde
-
-
Zn2+
-
-
ZnCl2
-
1 mM, complete inhibition
additional information
-
inhibition by cyclopropyl-substituted gamma-butyrobetains
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-amino-6,7-dimethyl-4-hydroxy-5,6,7,8-tetrahydropteridine
-
-
catalase
-
Cs+
-
increase of activity
GSH/GSH-peroxidase
-
increase of activity, more efficient in assay and during preincubation than catalase, protects the enzyme from increasing phosphate concentrations
-
isoascorbate
-
increase of activity
K+
-
efficient coupling of decarboxylation and hydroxylation, stimulation
L-histidine
-
-
Microsomal preparation
-
increase of activity
-
NADPH
-
NADPH-regenerating system, increase of activity, no absolute requirement
NH4+
-
,increase of activity
nicotinamide
-
increase of activity
Rb+
-
increase of activity
additional information
-
various proteins such as lactoperoxidase, horseradish peroxidase, hemoglobin, myoglobin, cytochrome c, bovine serum albumin activate
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.012 - 0.083
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
0.125
2-oxo-glutarate
-
-
0.018 - 0.82
2-oxoglutarate
0.16
4-(trimethylammonio)butanoic acid
-
co-substrate: 2-oxoglutarate, pH 7.5, 25C, NMR assay
-
0.04
4-Dimethylaminobutyric acid
-
in 20mM potassium phosphate buffer (pH 7.4) containing 50 mM KCl, 3mM 2-oxoglutarate, 10 mM sodium ascorbate, 0.5 mM DTT, 0.5 mM ammonium iron sulfate, 2.5 mg/ml bovine serum albumin, 0.01% (w/v) Triton X-100 and 2 mM 6-N-trimethyllysine
0.0275
4-Trimethylammoniobutanoate
pH 7.0, 37C, recombinant enzyme
0.47
D-carnitine
-
-
0.012
Fe2+
-
-
0.029 - 2.4
gamma-butyrobetaine
0.052
L-carnitine
-
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1 - 0.62
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
0.39 - 5.1
2-oxoglutarate
5.3
4-(trimethylammonio)butanoic acid
Homo sapiens
-
co-substrate: 2-oxoglutarate, pH 7.5, 25C, NMR assay
-
34
gamma-butyrobetaine
Pseudomonas sp.
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0006
3,4-dihydroxybenzoate
-
-
0.0002
Pyridine-2,4-dicarboxylate
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.062
3-(2,2,2-trimethylhydrazinium propionate dihydrate)
Homo sapiens
O75936
pH 7.0, 37C, recombinant enzyme
0.018
bicyclic isoquinolinyl
Homo sapiens
-
pH 7.5, 25C
-
0.082
Pyridine 2,4-dicarboxylate
Homo sapiens
-
pH 7.5, 25C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.00000125
-
value below, activity in heart; value below, activity in skeletal muscle
0.000008
-
activity in spleen
0.000018
-
activity in brain
0.00007
-
activity in ileum
0.000393
-
activity in liver
0.0004
-
activity of gamma-butyrobetaine dioxygenase in liver
0.002367
-
activity in kidney
0.0024
-
activity of gamma-butyrobetaine dioxygenase in kidney
0.053
-
-
0.162
-
human kidney
1.02 - 1.74
-
three isozymes of mammalian enzyme
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 7.5
-
half-maximal activity at pH 6.0 and 7.5
6 - 8.4
-
half-maximal activity at pH 6.0 and 8.4, partially purified preparation
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
-
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
additional information
-
no activity found: muscle, kidney
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
64000
-
gel filtration, 3 isozymes, detection by chromatofocusing and anion exchange chromatography
68000
-
gel filtration
80000
-
gel filtration
86000 - 95000
-
gel filtration, sedimentation equilibrium centrifugation
86000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
purified recombinant His-tagged GBBH, and SeMet-labeled variant, by sitting drop vapor diffusion technique, mixing 0.001 ml of 7 mg/ml protein in 20 mM Tris-HCl, pH 8.0, with 0.001 ml of reservoir solution containing 1.2 M ammonium sulfate and 100 mM sodium acetate, pH 4.5. In co-crystallization trials with ligands, each ligand is added to the reservoir solution to a final concentration of 5 mM, X-ray diffraction structure determination and analysis at 2.0 A and 3.5 A resolution, respectively
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
-
12 min half-life
60
-
complete inactivation after 15 min
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
dialysis, 4C, 50% loss of activity overnight
-
DTT, prevents inactivation by O2, ascorbate or H2O2
-
His, stabilizes
-
ultra-filtration, 4C, 50% loss of activity overnight
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acetone
-
powder, retains full activity of fresh liver homogenate
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
O2, irreversible inactivation during preincubation
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20C to 4C, 50% loss of activity in a week
-
-60 to -170C, stable for 6 months in potassium phosphate buffer, pH 6.5
-
-90C, stable for a year or more as acetone powder, stable for 3 months as purified and lyophilized enzyme
-
4C, 50 mM sodium phosphate pH 7.4, 20 mM KCl, 10 mM DTT, 200g/l glycerol are best conservation conditions
-
addition of EDTA causes total loss of activity
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged GBBH from Escherichia coli strain WK6 by nickel affinity chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in HEK293 cells
-
expression of His-tagged GBBH in Escherichia coli strain WK6
recombinant protein is used
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
activity of gamma-butyrobetaine dioxygenase lowest at birth in liver and kidney, but increase until age of 2 weeks
-
detection of mRNA levels during suckling period onwards, expression is ontogenically regulated
highest mRNA concentrations in epididymis and in kidney. In heart, colon, small intestine, lung, spleen, testes and brain lower mRNA levels compared to liver. In skeletal muscle almost absent mRNA amount
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
molecular biology
-
a fluorescence assay based on the detection of fluoride released from reactions of fluorinated substrates with BBOX by the use of tert-butyldimethylsilyl-protected fluorescein is developed. (3S)-3-fluoro-4-(trimethylammonio)butanoate is a good substrate for BBOX, releasing fluoride when subjected to the enzyme
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