Literature summary for 1.14.11.1 extracted from

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 (2014), J. Med. Chem., 57, 2213-2236 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
ascorbate	required	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of His6-tagged enzyme in Saccharomyces cerevisiae strain AH22	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
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	Homo sapiens

Crystallization (Comment)

Organism

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

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(E)-4-(trimethylammonio)but-2-enoate	-	Homo sapiens
1,1,1-trimethyl-2-(2-phosphonoethyl)hydrazin-1-ium Iodide	-	Homo sapiens
1-(3-carboxypropyl)-1-methylpyrrolidin-1-ium	-	Homo sapiens
1-(3-carboxypropyl)pyrrolidin-1-ium	-	Homo sapiens
2-(1,1,1-trimethylhydrazin-1-ium-2-yl)ethanesulfonate	-	Homo sapiens
2-(2-carboxyethyl)-1,1-diethyl-1-methylhydrazin-1-ium chloride	-	Homo sapiens
2-(2-carboxyethyl)-1,1-dimethyl-1-(prop-2-yn-1-yl)-hydrazin-1-ium bromide	-	Homo sapiens
2-(2-carboxyethyl)-1-(2-chloroethyl)-1,1-dimethylhydrazin-1-ium bromide	-	Homo sapiens
3-(1,1,1,2-tetramethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
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	Homo sapiens
3-(1,1,2-trimethyl-1-propylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(1,1-dimethyl-1-vinylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(1-allyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(1-ethyl-1,1,2-trimethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(1-ethyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(1-isopropyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(2-ethyl-1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate	-	Homo sapiens
3-(ethyldimethylammonio)propane-1-sulfonate	-	Homo sapiens
3-(trimethylammonio)cyclohexanecarboxylate	-	Homo sapiens
3-(trimethylammonio)propane-1-sulfonate	-	Homo sapiens
3-carboxy-2-chloro-N,N,N-trimethylpropan-1-aminium	-	Homo sapiens
3-carboxy-N-(2-chloroethyl)-N,N-dimethylpropan-1-aminium	-	Homo sapiens
3-carboxy-N-(2-fluoroethyl)-N,N-dimethylpropan-1-aminium	-	Homo sapiens
3-[1-(2-aminoethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate	-	Homo sapiens
3-[1-(2-hydroxyethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate	-	Homo sapiens
4-(allyldimethylammonio)butanoate	-	Homo sapiens
4-(benzyldimethylammonio)butanoate	-	Homo sapiens
4-(butyldimethylammonio)butanoate	-	Homo sapiens
4-(cyclobutyldimethylammonio)butanoate	-	Homo sapiens
4-(cyclopentyldimethylammonio)butanoate	-	Homo sapiens
4-(cyclopropyldimethylammonio)butanoate	-	Homo sapiens
4-(dimethylsulfonio)butanoate	-	Homo sapiens
4-(ethyldimethylammonio)butanoate	-	Homo sapiens
4-(trimethylammonio)pentanoate	-	Homo sapiens
4-[(2-hydroxyethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(bromomethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(chloromethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(cyclobutylmethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(cyclopropylmethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(iodomethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[(methoxymethyl)dimethylammonio]butanoate	-	Homo sapiens
4-[diethyl(methyl)ammonio]butanoate	-	Homo sapiens
4-[dimethyl(prop-2-yn-1-yl)ammonio]butanoate	-	Homo sapiens
4-[dimethyl(propyl)ammonio]butanoate	-	Homo sapiens
4-[dimethyl(vinyl)ammonio]butanoate	-	Homo sapiens
4-[isopropyl(dimethyl)ammonio]butanoate	-	Homo sapiens
5-(trimethylammonio)pentanoate	-	Homo sapiens
gamma-butyrobetaine	substrate inhibition at high concentrations. Enzyme-inhibitor interactions from structure PDB ID 3MS5	Homo sapiens
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	Homo sapiens
N,N,N-trimethyl-3-(1H-tetrazol-5-yl)propan-1-aminium	-	Homo sapiens
N,N,N-trimethyl-3-phosphonopropan-1-aminium	-	Homo sapiens
N-(2-bromoethyl)-3-carboxy-N,N-dimethylpropan-1-aminium	-	Homo sapiens
[3-(ethyldimethylammonio)propyl]phosphinate	-	Homo sapiens
[3-(trimethylammonio)propyl]phosphinate	-	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Fe2+	dependent on, required for catalysis	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
4-trimethylammoniobutanoate + 2-oxoglutarate + O2	Homo sapiens	-	3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	O75936	-	-

Purification (Commentary)

Purification (Comment)	Organism
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	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
4-trimethylammoniobutanoate + 2-oxoglutarate + O2	-	Homo sapiens	3-hydroxy-4-trimethylammoniobutanoate + succinate + CO2	-	?

Synonyms

Synonyms	Comment	Organism
BBOX	-	Homo sapiens
gamma-butyrobetaine hydroxylase	-	Homo sapiens
GBBH	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7	-	assay at	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.016	-	3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate	pH 7.0, 37°C, recombinant enzyme	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.00009	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1,1,1,2-tetramethylhydrazin-1-ium-2-yl)propanoate
0.0001	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	N,N,N-trimethyl-3-phosphonopropan-1-aminium
0.00026	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-carboxy-N-(2-chloroethyl)-N,N-dimethylpropan-1-aminium
0.00049	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	1-(3-carboxypropyl)-1-methylpyrrolidin-1-ium
0.00052	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	[3-(trimethylammonio)propyl]phosphinate
0.00053	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	[3-(ethyldimethylammonio)propyl]phosphinate
0.00061	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-carboxy-N-(2-fluoroethyl)-N,N-dimethylpropan-1-aminium
0.00081	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(cyclobutyldimethylammonio)butanoate
0.0012	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	N-(2-bromoethyl)-3-carboxy-N,N-dimethylpropan-1-aminium
0.0014	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[dimethyl(prop-2-yn-1-yl)ammonio]butanoate
0.0017	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(trimethylammonio)propane-1-sulfonate
0.0021	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(cyclopropyldimethylammonio)butanoate
0.0027	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(allyldimethylammonio)butanoate
0.0028	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(2-ethyl-1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate
0.0031	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1,1,2-trimethyl-1-propylhydrazin-1-ium-2-yl)propanoate
0.0033	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(ethyldimethylammonio)butanoate
0.0038	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	(E)-4-(trimethylammonio)but-2-enoate
0.0057	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[isopropyl(dimethyl)ammonio]butanoate
0.0067	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(ethyldimethylammonio)propane-1-sulfonate
0.0068	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1,1-dimethyl-1-vinylhydrazin-1-ium-2-yl)propanoate
0.0072	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1-ethyl-1,1,2-trimethylhydrazin-1-ium-2-yl)propanoate
0.0102	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	2-(2-carboxyethyl)-1-(2-chloroethyl)-1,1-dimethylhydrazin-1-ium bromide
0.024	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	2-(2-carboxyethyl)-1,1-dimethyl-1-(prop-2-yn-1-yl)-hydrazin-1-ium bromide
0.087	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	2-(1,1,1-trimethylhydrazin-1-ium-2-yl)ethanesulfonate
0.1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[diethyl(methyl)ammonio]butanoate
0.117	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	1,1,1-trimethyl-2-(2-phosphonoethyl)hydrazin-1-ium Iodide
0.119	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1-allyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
0.127	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[dimethyl(vinyl)ammonio]butanoate
0.14	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1-ethyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
0.268	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(chloromethyl)dimethylammonio]butanoate
0.343	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(trimethylammonio)pentanoate
0.388	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(dimethylsulfonio)butanoate
0.459	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-carboxy-2-chloro-N,N,N-trimethylpropan-1-aminium
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	1-(3-carboxypropyl)pyrrolidin-1-ium
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	2-(2-carboxyethyl)-1,1-diethyl-1-methylhydrazin-1-ium chloride
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(1-isopropyl-1,1-dimethylhydrazin-1-ium-2-yl)propanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-(trimethylammonio)cyclohexanecarboxylate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-[1-(2-aminoethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	3-[1-(2-hydroxyethyl)-1,1-dimethylhydrazin-1-ium-2-yl]-propanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(benzyldimethylammonio)butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(butyldimethylammonio)butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-(cyclopentyldimethylammonio)butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(2-hydroxyethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(bromomethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(cyclobutylmethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(cyclopropylmethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(iodomethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[(methoxymethyl)dimethylammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	4-[dimethyl(propyl)ammonio]butanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	5-(trimethylammonio)pentanoate
1	-	pH 7.0, 37°C, recombinant enzyme	Homo sapiens	N,N,N-trimethyl-3-(1H-tetrazol-5-yl)propan-1-aminium

General Information

General Information	Comment	Organism
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	Homo sapiens