1.14.11.1: gamma-butyrobetaine dioxygenase
This is an abbreviated version!
For detailed information about gamma-butyrobetaine dioxygenase, go to the full flat file.
Word Map on EC 1.14.11.1
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1.14.11.1
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cardioprotective
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carnitine-dependent
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3-2,2,2-trimethylhydrazinium
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mildronate
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trimethyllysine
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mid1
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alpha4
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medicine
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d-carnitine
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dihydrate
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drug development
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molecular biology
- 1.14.11.1
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cardioprotective
-
carnitine-dependent
-
3-2,2,2-trimethylhydrazinium
- mildronate
- trimethyllysine
- mid1
-
alpha4
- medicine
- d-carnitine
- dihydrate
- drug development
- molecular biology
Reaction
Synonyms
4-trimethylaminobutyric acid dioxygenase, alpha-butyrobetaine hydroxylase, BBD, BBH, BBOX, BBOX1, Bu hydroxylase, butyrobetaine hydroxylase, gamma butyrobetaine hydroxylase, gamma-BBD, gamma-BBH, gamma-buryrobetaine dioxygenase, gamma-butyrobetaine dioxygenase, gamma-butyrobetaine hydroxylase, gamma-butyrobetaine hydroxylase 1, GBB hydroxylase, GBBH, hBBOX, oxygenase, gamma-butyrobetaine di-, psBBOX
ECTree
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Inhibitors
Inhibitors on EC 1.14.11.1 - gamma-butyrobetaine dioxygenase
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2-(2-carboxyethyl)-1,1-dimethyl-1-(prop-2-yn-1-yl)-hydrazin-1-ium bromide
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2-(2-carboxyethyl)-1-(2-chloroethyl)-1,1-dimethylhydrazin-1-ium bromide
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3-(2,2,2-trimethylhydrazinium propionate dihydrate)
i.e. mildronate, a synthetic inhibitor of GBBH, is a non-hydroxylatable analog of gamma-butyrobetaine
3-Bromo-2-oxoglutarate
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noncompetitive inhibition, 2-oxoglutarate as variable substrate
4-([(2E)-3-carboxyprop-2-enoyl](hydroxy)amino)-N,N,N-trimethylbutan-1-aminium
i.e. RL190B
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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
Clofibrate
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activity of gamma-butyrobetaine dioxygenase in the liver is lower in pigs treated with clofibrate than in control pigs
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
p-aminomethylbenzoic acid
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1.2 mmol/kg reduces the conversion of 4-dimethylaminobutyric acid to 4-dimethylamino-3-hydroxybutyric acid from 62.6% to 46.8%
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
substrate inhibition at concentrations above 0.2 mM
4-Trimethylammoniobutanoate
substrate inhibition at high concentrations
4-Trimethylammoniobutanoate
substrate inhibition associated with age is observed at concentrations above 0.6 mM
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uncouples the decarboxylation from the hydroxylation, mammalian enzyme
gamma-butyrobetaine
substrate inhibition at high concentrations. Enzyme-inhibitor interactions from structure PDB ID 3MS5
both a relatively weak BBOX inhibitor in vitro and a competitive substrate producing multiple products. The mode of action of mildronate may be nonselective
i.e AR692B
N-(3-hydroxypyridine-2-carbonyl)-S-[(pyridin-2-yl)methyl]-L-cysteine
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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
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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
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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
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additional information
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inhibition by cyclopropyl-substituted gamma-butyrobetains
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