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Information on EC 1.14.11.1 - gamma-butyrobetaine dioxygenase and Organism(s) Homo sapiens and UniProt Accession O75936
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1.14.11.1 gamma-butyrobetaine dioxygenaseIUBMB Comments
Requires Fe2+ and ascorbate.
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Word Map
- 1.14.11.1
-
cardioprotective
-
carnitine-dependent
-
3-2,2,2-trimethylhydrazinium
- mildronate
- trimethyllysine
- mid1
-
alpha4
- medicine
- d-carnitine
- dihydrate
- drug development
- molecular biology
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
gamma-butyrobetaine hydroxylase, bbox1, butyrobetaine hydroxylase, gamma-butyrobetaine dioxygenase, gamma-butyrobetaine hydroxylase 1, bu hydroxylase, gbb hydroxylase, alpha-butyrobetaine hydroxylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
gamma-butyrobetaine hydroxylase
-
alpha-butyrobetaine hydroxylase
-
-
-
-
butyrobetaine hydroxylase
-
-
-
-
gamma-butyrobetaine hydroxylase
oxygenase, gamma-butyrobetaine di-
-
-
-
-
gamma-butyrobetaine hydroxylase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
oxidative decarboxylation
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
4-trimethylammoniobutanoate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)
Requires Fe2+ and ascorbate.
CAS REGISTRY NUMBER
COMMENTARY
9045-31-2
-
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
(3R)-3-fluoro-4-(trimethylammonio)butanoate + 2-oxoglutarate + O2
3-carboxy-N,N,N-trimethyl-2-oxopropan-1-aminium + succinate + formylfluoride
-
-
-
?
2-carboxy-N,N,N-trimethylethan-1-aminium + 2-oxoglutarate + O2
4-carboxy-3-hydroxy-N,N,N-trimethylbutan-1-aminium + succinate + CO2
-
-
-
?
3-carboxy-N-(fluoromethyl)-N,N-dimethylpropan-1-aminium + 2-oxoglutarate + O2
(2S)-3-carboxy-N-(fluoromethyl)-2-hydroxy-N,N-dimethylpropan-1-aminium + succinate + CO2
-
-
-
?
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
4-trimethylammoniopropanoate + 2-oxoglutarate + O2
2-carboxy-2-hydroxy-N,N,N-trimethylethan-1-aminium + succinate + CO2
-
-
-
?
D-carnitine + 2-oxoglutarate + O2
3-carboxy-N,N,N-trimethyl-2-oxopropan-1-aminium + succinate + CO2
-
-
-
?
L-carnitine + 2-oxoglutarate + O2
3-carboxy-N,N,N-trimethyl-2-oxopropan-1-aminium + succinate + CO2
-
-
-
?
mildronate + O2
?
both a relatively weak BBOX inhibitor in vitro and a competitive substrate producing multiple products
-
-
?
(3R)-3-fluoro-4-(trimethylammonio)butanoate + 2-oxoglutarate + O2
?
-
weak substrate, below 5% turnover after 3 h
-
-
?
(3S)-3-fluoro-4-(trimethylammonio)butanoate + 2-oxoglutarate + O2
?
-
S-stereoisomer preferred substrate
-
-
?
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
-
-
-
?
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
catalytic domain and active site structure, overview
-
-
?
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
-
-
-
?
4-trimethylammoniobutanoate + 2-oxoglutarate + O2
3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2
-
-
-
?
additional information
?
-
no activity with trimethyllysine, acetylcholine, phosphocholine, thioacetylcholine, carbachol, and gamma-butyrobetaine analogues carboxy-N,N,N-trimethylmethanaminium, 5-carboxy-N,N,N-trimethylpentan-1-aminium, N,N,N-trimethyl-4-oxopentan-1-aminium, and 4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium, substrate specificity, overview
-
-
?
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
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Zn2+
Fe2+
dependent on, required for catalysis, bound to the active site
Fe2+
nonheme Fe2+-dependent oxygenase, dependent on, required for catalysis
Zn2+
quantitative determination of Zn2+ by atomic absorption spectrometry, zinc-binding site structure in the N-terminal domain of GBBH, overview
Zn2+
dependent on, ejection of structural zinc, e.g. by Selenium and sulfur based compounds, leads to inhibition of the enzyme, an undisrupted N-terminal zinc binding domain of BBOX is required for catalysis
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(2-carboxyethyl)-1,1-dimethyl-1-(prop-2-yn-1-yl)-hydrazin-1-ium bromide
-
2-(2-carboxyethyl)-1-(2-chloroethyl)-1,1-dimethylhydrazin-1-ium bromide
-
3-(2,2,2-trimethylhydrazinium propionate dihydrate)
i.e. mildronate, a synthetic inhibitor of GBBH, is a non-hydroxylatable analog of gamma-butyrobetaine
4-([(2E)-3-carboxyprop-2-enoyl](hydroxy)amino)-N,N,N-trimethylbutan-1-aminium
i.e. RL190B
-
N-(3-hydroxypyridine-2-carbonyl)-S-[(pyridin-2-yl)methyl]-L-cysteine
i.e AR692B
3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate
i.e. mildronate, a clinically used and approved drug, but weak inhibitor. Enzyme-inhibitor interactions from structure PDB ID 3O2G
4-Trimethylammoniobutanoate
substrate inhibition at concentrations above 0.2 mM
AR692B
a potent and selective inhibitor for human enzyme BBOX, binds in two modes, one of which adopts an unusual U-shape conformation stabilised by inter- and intra-molecular Pi-stacking interactions. Conformational changes observed on binding of the inhibitor to BBOX likely reflect those occurring in catalysis. The BBOX-AR692B with and without substrate/ inhibitor crystal structures (PDB ID 3O2G/3N6W) reveal substantial conformational differences
gamma-butyrobetaine
substrate inhibition at high concentrations. Enzyme-inhibitor interactions from structure PDB ID 3MS5
mildronate
both a relatively weak BBOX inhibitor in vitro and a competitive substrate producing multiple products. The mode of action of mildronate may be nonselective
N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine
i.e. FG-2216, BIQ, or IOX3, an isoquinoline derivative, that inhibits BBOX and other 2-oxoglutarate dependent oxygenases through chelating active site Fe(II) and interacting with specific active site residues. Time course of Zn(II) ejection from BBOX by the inhibitors
DL-carnitine
-
uncouples the decarboxylation from the hydroxylation, mammalian enzyme
additional information
development and application of 1H NMR GBB/2OG reporter based assays employing paramagnetic relaxation enhancement to monitor inhibitor binding to the BBOX active site, method development and evaluation, overview. The method assesses inhibitors for competitive binding with 2-oxoglutarate or gamma-butyrobetaine, or both, and is exemplified with a set of isoquinoline-based inhibitors, structure-activity relationships. Docking simulation showing possible conformational changes as a result of binding inhibitors N-(1-chloro-4-hydroxyisoquinoline-3-carbonyl)glycine or N-(1-chloro-4-hydroxyisoquinoline-3-carbonyl)-L-tryptophan. NMR spectroscopic structures
-
additional information
discovery of inhibitors of gamma-butyrobetaine hydroxylase, design, synthesis, and properties of 51 compounds, which include both gamma-butyrobetaine and mildronate analogues, structure-activity relationships, overview
-
additional information
identification of selective BBOX inhibitors, active against both isolated enzyme and in cells, docking study, overview. The identified template BBOX inhibitor binds to the active site iron via its carbonyl group and either its pyridine-nitrogen or C-3 hydroxyl group, the pyridine-nitrogen, C-3 hydroxyl group and side chain carboxylate are essential for binding. Examination of scaffolds with bicyclic aromatic rings, i.e. with quinoline and isoquinoline derivatives substituting for the (hydroxyl)pyridine ring reveal that quinolines have rather weak potency, while isoquinolines are relatively good inhibitors with the IC50 values in the low micromolar range. In the isoquinoline series, C-alpha side chains with the (S)-stereochemistry are preferred over those with the (R)-stereochemistry. In contrast to the pyridine series small side chains are preferred with the hydroxy-isoquinolines, with the methyl group having the best inhibitory properties
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.02
(2S)-3-carboxy-N-(fluoromethyl)-2-hydroxy-N,N-dimethylpropan-1-aminium
pH 7.5, temperature not specified in the publication
0.02
(3R)-3-fluoro-4-(trimethylammonio)butanoate
pH 7.5, temperature not specified in the publication
0.153
2-oxoglutarate
pH 7.5, temperature not specified in the publication
0.16
4-(trimethylammonio)butanoic acid
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, NMR assay
additional information
additional information
Michaelis-Menten kinetics
-
0.0042
4-Trimethylammoniobutanoate
pH 7.5, temperature not specified in the publication
0.012
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, NMR assay
0.083
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, fluoride assay
0.026
2-oxoglutarate
-
co-substrate: 4-(trimethylammonio)butanoic acid, pH 7.5, 25°C, NMR assay
0.1 - 0.13
2-oxoglutarate
-
gamma-butyrobetaine, values about the same for all three isozymes
0.15
2-oxoglutarate
-
co-substrate: (3S)-3-fluoro-4-(trimethylammonio)butanoate, pH 7.5, 25°C, NMR assay
0.47
2-oxoglutarate
-
co-substrate: (3S)-3-fluoro-4-(trimethylammonio)butanoate, pH 7.5, 25°C, fluoride assay
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.3
(2S)-3-carboxy-N-(fluoromethyl)-2-hydroxy-N,N-dimethylpropan-1-aminium
pH 7.5, temperature not specified in the publication
0.14
(3R)-3-fluoro-4-(trimethylammonio)butanoate
pH 7.5, temperature not specified in the publication
0.83
4-Trimethylammoniobutanoate
pH 7.5, temperature not specified in the publication
5.3
4-(trimethylammonio)butanoic acid
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, NMR assay
0.1
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, NMR assay
0.62
(3S)-3-fluoro-4-(trimethylammonio)butanoate
-
co-substrate: 2-oxoglutarate, pH 7.5, 25°C, fluoride assay
0.39
2-oxoglutarate
-
co-substrate: (3S)-3-fluoro-4-(trimethylammonio)butanoate, pH 7.5, 25°C, NMR assay
0.55
2-oxoglutarate
-
co-substrate: (3S)-3-fluoro-4-(trimethylammonio)butanoate, pH 7.5, 25°C, fluoride assay
5.1
2-oxoglutarate
-
co-substrate: 4-(trimethylammonio)butanoic acid, pH 7.5, 25°C, NMR assay
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.136
(3R)-3-fluoro-4-(trimethylammonio)butanoate
pH 7.5, temperature not specified in the publication
0.016
3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate
pH 7.0, 37°C, recombinant enzyme
0.226
3-carboxy-N-(fluoromethyl)-N,N-dimethylpropan-1-aminium
pH 7.5, temperature not specified in the publication
0.024
4-Trimethylammoniobutanoate
pH 7.5, temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0038
(E)-4-(trimethylammonio)but-2-enoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.117
1,1,1-trimethyl-2-(2-phosphonoethyl)hydrazin-1-ium Iodide
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00049
1-(3-carboxypropyl)-1-methylpyrrolidin-1-ium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.087
2-(1,1,1-trimethylhydrazin-1-ium-2-yl)ethanesulfonate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
2-(2-carboxyethyl)-1,1-diethyl-1-methylhydrazin-1-ium chloride
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.024
2-(2-carboxyethyl)-1,1-dimethyl-1-(prop-2-yn-1-yl)-hydrazin-1-ium bromide
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0102
2-(2-carboxyethyl)-1-(2-chloroethyl)-1,1-dimethylhydrazin-1-ium bromide
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00009
3-(1,1,1,2-tetramethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0031
3-(1,1,2-trimethyl-1-propylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0068
3-(1,1-dimethyl-1-vinylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
-
0.119
3-(1-allyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0072
3-(1-ethyl-1,1,2-trimethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.14
3-(1-ethyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
3-(1-isopropyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.062
3-(2,2,2-trimethylhydrazinium propionate dihydrate)
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0028
3-(2-ethyl-1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0067
3-(ethyldimethylammonio)propane-1-sulfonate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
3-(trimethylammonio)cyclohexanecarboxylate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0017
3-(trimethylammonio)propane-1-sulfonate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.459
3-carboxy-2-chloro-N,N,N-trimethylpropan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00026
3-carboxy-N-(2-chloroethyl)-N,N-dimethylpropan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00061
3-carboxy-N-(2-fluoroethyl)-N,N-dimethylpropan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
3-hydroxy-N-(2-phenylethyl)pyridine-2-carboxamide
Homo sapiens
above, pH and temperature not specified in the publication
1
3-[1-(2-aminoethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
3-[1-(2-hydroxyethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
-
0.0027
4-(allyldimethylammonio)butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00081
4-(cyclobutyldimethylammonio)butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-(cyclopentyldimethylammonio)butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0021
4-(cyclopropyldimethylammonio)butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0033
4-(ethyldimethylammonio)butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.015
4-([(2E)-3-carboxyprop-2-enoyl](hydroxy)amino)-N,N,N-trimethylbutan-1-aminium
Homo sapiens
pH and temperature not specified in the publication
-
1
4-[(2-hydroxyethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-[(bromomethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.268
4-[(chloromethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-[(cyclobutylmethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-[(cyclopropylmethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-[(iodomethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
4-[(methoxymethyl)dimethylammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0014
4-[dimethyl(prop-2-yn-1-yl)ammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.127
4-[dimethyl(vinyl)ammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0057
4-[isopropyl(dimethyl)ammonio]butanoate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
1
N,N,N-trimethyl-3-(1H-tetrazol-5-yl)propan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0001
N,N,N-trimethyl-3-phosphonopropan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.026
N-(1-chloro-4-hydroxyisoquinoline-3-carbonyl)-L-tryptophan
Homo sapiens
pH 7.5, temperature not specified in the publication, recombinant enzyme
0.0012
N-(1-chloro-4-hydroxyisoquinoline-3-carbonyl)glycine
Homo sapiens
pH 7.5, temperature not specified in the publication, recombinant enzyme
0.0012
N-(2-bromoethyl)-3-carboxy-N,N-dimethylpropan-1-aminium
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.088
N-(2-hydroxybenzoyl)-L-phenylalanine
Homo sapiens
pH and temperature not specified in the publication
0.537
N-(2-hydroxybenzoyl)glycine
Homo sapiens
pH and temperature not specified in the publication
0.522
N-(3-hydroxypyridine-2-carbonyl)-beta-alanine
Homo sapiens
pH and temperature not specified in the publication
0.15
N-(3-hydroxypyridine-2-carbonyl)-D-phenylalanine
Homo sapiens
pH and temperature not specified in the publication
0.0018
N-(3-hydroxypyridine-2-carbonyl)-L-glutamic acid
Homo sapiens
pH and temperature not specified in the publication
0.0002
N-(3-hydroxypyridine-2-carbonyl)-S-[(pyridin-2-yl)methyl]-L-cysteine
Homo sapiens
pH and temperature not specified in the publication
0.0125
N-(pyridine-2-carbonyl)-L-phenylalanine
Homo sapiens
pH and temperature not specified in the publication
0.032
N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine
Homo sapiens
pH 7.0, 22°C, 20 min
0.00053
[3-(ethyldimethylammonio)propyl]phosphinate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.00052
[3-(trimethylammonio)propyl]phosphinate
Homo sapiens
pH 7.0, 37°C, recombinant enzyme
0.0005
N-(3-hydroxypyridine-2-carbonyl)-L-phenylalanine
Homo sapiens
pH and temperature not specified in the publication
0.002
N-(3-hydroxypyridine-2-carbonyl)-L-phenylalanine
Homo sapiens
pH and temperature not specified in the publication
0.006
N-(3-hydroxypyridine-2-carbonyl)glycine
Homo sapiens
pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
inhibitors of gamma-butyrobetaine hydroxylase 1 (BBOX1) could be a potential therapeutic option for Triple-negative breast cancer
evolution
metabolism
physiological function
evolution
the GBBH residues involved in zinc binding are evolutionary conserved in all sequenced eukaryotes more complex than Caenorhabditis elegans
evolution
comparison of properties, substrate specificities, and structures of the human enzyme (PDB ID 3O2G) and the enzyme from Pseudomonas sp. AK1, detailed overview
evolution
the enzyme belongs to the 2-oxoglutarate/Fe(II) dependent oxygenase family
evolution
the enzyme belongs to the superfamily of Fe(II) and 2OG dependent dioxygenases
metabolism
gamma-butyrobetaine hydroxylase (BBOX) catalyses the final step in the biosynthesis of carnitine i.e. the stereoselective hydroxylation of gamma-butyrobetaine (GBB)
metabolism
gamma-butyrobetaine hydroxylase (BBOX) catalyses the final step of carnitine biosynthesis
metabolism
the enzyme catalyses the second, essential step of carnitine biosynthesis
metabolism
the enzyme catalyzes the final step in the biosynthesis of L-carnitine in humans
physiological function
GBBH is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of L-carnitine by hydroxylation of gamma-butyrobetaine. L-Carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy
physiological function
enzyme BBOX catalyses the stereospecific C-3 hydroxylation of gamma-butyrobetaine (GBB) to give L-carnitine
physiological function
gamma-butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to L-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids
physiological function
gamma-butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate-dependent oxygenase that catalyses the stereoselective C-3 hydroxylation of gamma-butyrobetaine to give L-carnitine. L-Carnitine is involved in fatty acid metabolism
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). BODG_HUMAN
387
0
44715
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
64000
-
gel filtration, 3 isozymes, detection by chromatofocusing and anion exchange chromatography
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
homodimer
dimer
dimer
the GBBH monomer consists of a catalytic double-stranded beta-helix domain, and a smaller N-terminal domain, the N-terminal domain of GBBH has a similar fold to the DUF971 superfamily. GBBH is dimeric in its biological state. the dimerization interface of GBBH is very different from that of related enzymes, three-dimensional structure, overview
homodimer
BBOX is a homodimer comprising of catalytic domain where Fe(II) and substrates bind and zinc binding domain
dimer
-
SDS-PAGE, same value for all three isozymes, dimeric combinations of two subunits
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of a crystal structure of human BBOX in complex with inhibitor AR692B and Ni2+ (an Fe2+ surrogate), P212121 space group, 2.8 A resolution
purified recombinant enzyme in complex with inhibitors 4-(ethyldimethylammonio)butanoate, 3-carboxy-N-(2-fluoroethyl)-N,N-dimethylpropan-1-aminium, 1-(3-carboxypropyl)-1-methylpyrrolidin-1-ium, 4-(trimethylammonio)pentanoate, [3-(trimethylammonio)propyl]phosphinate, and 3-(1,1,1,2-tetramethylhydrazin-1-ium-2-yl)propanoate, sitting drop vapor technique, mixing of 0.001 ml of 7 mg/ml protein, 8 mM N-oxalylglycine and 4 mM inhibitor, with 0.001 ml of well solution containing 0.2 M ammonium citrate, 20% PEG 3350, 3% hexanediamine, and 10 mM ZnSO4, pH 7.0, X-ray diffraction structure determination and analysis at 1.70-2.40 A resolution
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
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, gel filtration, and anion exchange chromatography
recombinant His-tagged GBBH from Escherichia coli strain WK6 by nickel affinity chromatography
recombinant His6-tagged enzyme from Saccharomyces cerevisiae strain AH22 by nickel affinity chromatography, desalting gel filtration, anion exchange chromatography, tag cleavage by recombinant TEV protease, desalting gel filtration, and another step of nickel affinity chromatography to remove the His-tag
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene BBOX1, recombinant expression of His-tagged codon-optimized enzyme in Escherichia coli strain BL21(DE3)
recombinant expression of His6-tagged enzyme in Saccharomyces cerevisiae strain AH22
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
enzyme BBOX is a drug target for the treatment of myocardial infarction
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
medicine
BBOX is a therapeutic target in humans, the BBOX inhibitor mildronate is used to decrease fatty acid oxidation in patients after myocardial infarction
medicine
inhibition of BBOX is reported to aid in recovery after acute stroke
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Holme, E.; Lindstedt, S.; Nordin, I.
Uncoupling in the gamma-butyrobetaine hydroxylase reaction by D- and L-carnitine
Biochem. Biophys. Res. Commun.
107
518-524
1982
Homo sapiens, Pseudomonas sp., Pseudomonas sp. AK1
Lindstedt, S.; Nordin, I.
Multiple forms of gamma-butyrobetaine hydroxylase (EC 1.14.11.1)
Biochem. J.
223
119-127
1984
Homo sapiens
Ruetschi, U.; Nordin, I.; Odelhog, B.; Jornvall, H.; Lindstedt, S.
gamma-Butyrobetaine hydroxylase. Structural characterization of the Pseudomonas enzyme
Eur. J. Biochem.
213
1075-1080
1993
Homo sapiens, Pseudomonas sp., Pseudomonas sp. AK1
Rigault, C.; Le Borgne, F.; Demarquoy, J.
Genomic structure, alternative maturation and tissue expression of the human BBOX1 gene
Biochim. Biophys. Acta
1761
1469-1481
2006
Homo sapiens
Tars, K.; Rumnieks, J.; Zeltins, A.; Kazaks, A.; Kotelovica, S.; Leonciks, A.; Sharipo, J.; Viksna, A.; Kuka, J.; Liepinsh, E.; Dambrova, M.
Crystal structure of human gamma-butyrobetaine hydroxylase
Biochem. Biophys. Res. Commun.
398
634-639
2010
Homo sapiens (O75936), Homo sapiens
Rydzik, A.M.; Leung, I.K.; Kochan, G.T.; Thalhammer, A.; Oppermann, U.; Claridge, T.D.; Schofield, C.J.
Development and application of a fluoride-detection-based fluorescence assay for gamma-butyrobetaine hydroxylase
ChemBioChem
13
1559-1563
2012
Homo sapiens
Rydzik, A.M.; Brem, J.; Struwe, W.B.; Kochan, G.T.; Benesch, J.L.; Schofield, C.J.
Ejection of structural zinc leads to inhibition of gamma-butyrobetaine hydroxylase
Bioorg. Med. Chem. Lett.
24
4954-4957
2014
Homo sapiens (O75936)
Rydzik, A.M.; Chowdhury, R.; Kochan, G.T.; Williams, S.T.; McDonough, M.A.; Kawamura, A.; Schofield, C.J.
Modulating carnitine levels by targeting its biosynthesis pathway - selective inhibition of gamma-butyrobetaine hydroxylase
Chem. Sci.
5
1765-1771
2014
Homo sapiens (O75936)
Tars, K.; Leitans, J.; Kazaks, A.; Zelencova, D.; Liepinsh, E.; Kuka, J.; Makrecka, M.; Lola, D.; Andrianovs, V.; Gustina, D.; Grinberga, S.; Liepinsh, E.; Kalvinsh, I.; Dambrova, M.; Loza, E.; Pugovics, O.
Targeting carnitine biosynthesis discovery of new inhibitors against gamma-butyrobetaine hydroxylase
J. Med. Chem.
57
2213-2236
2014
Homo sapiens (O75936)
Khan, A.; Lesniak, R.; Brem, J.; Rydzik, A.; Choi, H.; Leung, I.; McDonough, M.; Schofield, C.; Claridge, T.
Development and application of ligand-based NMR screening assays for gamma-butyrobetaine hydroxylase
MedChemComm
7
873-880
2016
Homo sapiens (O75936)
-
Rydzik, A.M.; Leung, I.K.; Kochan, G.T.; Loik, N.D.; Henry, L.; McDonough, M.A.; Claridge, T.D.; Schofield, C.J.
Comparison of the substrate selectivity and biochemical properties of human and bacterial gamma-butyrobetaine hydroxylase
Org. Biomol. Chem.
12
6354-6358
2014
Homo sapiens (O75936), Pseudomonas sp. (P80193), Pseudomonas sp. AK-1 (P80193)
Lesniak, R.K.; Rydzik, A.M.; Kamps, J.J.A.G.; Kahn, A.; Claridge, T.D.W.; Schofield, C.J.
19F NMR studies on gamma-butyrobetaine hydroxylase provide mechanistic insights and suggest a dual inhibition mode
Chem. Commun. (Camb.)
55
14717-14720
2019
Homo sapiens (O75936)
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