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N5,N5,N5-trimethyl-L-ornithine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N5,N5,N5-trimethyl-L-ornithine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
N6,N6-dimethyl-N6-ethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6-dimethyl-N6-ethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6-dimethyl-N6-isopropyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6-dimethyl-N6-isopropyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6-dimethyl-N6-propyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6-dimethyl-N6-propyl-L-lysine + succinate + CO2
-
-
-
?
N6-fluoromethyl-N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6-fluoromethyl-N6,N6-dimethyl-L-lysine + succinate + CO2
Nepsilon-trimethyllysine analogue that contains the fluoromethyl group can be used as a 1H and 19F NMR probe for studies on TMLH catalysis
-
-
?
N7,N7,N7-trimethyl-L-alpha-homolysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N7,N7,N7-trimethyl-L-alpha-homolysine + succinate + CO2
-
-
-
?
additional information
?
-
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
the enzymatic hydroxylation occurs at the C-3 site of (2S)-Nepsilon-trimethyllysine substrate. Comparative NMR spectroscopic studies (with two enantiopure synthetic standards that possess 3R and 3S stereochemistry) on the enzymatically produced (2S)-3-hydroxy-Nepsilon-trimethyllysine reveal that TMLH exclusively catalyzes the formation of (3S)-3-hydroxy-Nepsilon-trimethyl-L-lysine, not forming any (3R)-3-hydroxy-Nepsilon-trimethyl-L-lysine diastereoisomer
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
recognition sites that contribute to the enzymatic activity of the enzyme (TMLH): the Fe(II)-binding H242-D244-H389 residues, R391-R398 involved in 2-oxoglutarate-binding, and several residues (D231, N334, and the aromatic cage comprised of W221, Y217 and Y234) associated with binding of (2S)-Nepsilon-trimethyllysine
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
N6,N6, N6-trimethyl-L-lysine is epsilon-N-trimethyl-L-lysine
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
N6,N6, N6-trimethyl-L-lysine is epsilon-N-trimethyl-L-lysine
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
N6,N6, N6-trimethyl-L-lysine is epsilon-N-trimethyl-L-lysine
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
N6,N6, N6-trimethyl-L-lysine is epsilon-N-trimethyl-L-lysine
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
carnitine biosynthesis
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
first enzyme of the L-carnitine biosynthesis
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
additional information
?
-
determination of the (2S,3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine and N6,N6,N6-trimethyl-L-lysine is performed by ultraperformance liquid chromatographytandem mass spectrometry (UPLC/MS/MS) in positive ion electrospray mode
-
-
?
additional information
?
-
NMR spectrosopic structure analysis of substrates and products
-
-
?
additional information
?
-
NMR spectrosopic structure analysis of substrates and products, substrate specificity, overview. No or poor activity with dimethyllysine, methyllysine, lysine, D-trimethyllysine, 5-trimethylamino-1-aminopentane, trimethyllysine, 6-trimethylaminohexanoic acid, hexamethyllysine, N-acetyltrimethyllysine, trimethyldiaminobutyric acid, triethyllysine, symmetric and asymmetric dimethylarginines, mildronate, and gamma-butyrobetaine, structure-activity relationship study
-
-
?
additional information
?
-
-
NMR spectrosopic structure analysis of substrates and products, substrate specificity, overview. No or poor activity with dimethyllysine, methyllysine, lysine, D-trimethyllysine, 5-trimethylamino-1-aminopentane, trimethyllysine, 6-trimethylaminohexanoic acid, hexamethyllysine, N-acetyltrimethyllysine, trimethyldiaminobutyric acid, triethyllysine, symmetric and asymmetric dimethylarginines, mildronate, and gamma-butyrobetaine, structure-activity relationship study
-
-
?
additional information
?
-
-
enzyme is localized to the mitochondrial matrix, product formation is limited by 6-N-trimethyllysine transport across the mitochondrial inner membrane
-
-
?
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N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
additional information
?
-
-
enzyme is localized to the mitochondrial matrix, product formation is limited by 6-N-trimethyllysine transport across the mitochondrial inner membrane
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
(3S)-3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
carnitine biosynthesis
-
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
first enzyme of the L-carnitine biosynthesis
-
?
N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2
3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2
-
-
-
-
?
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0.109 - 1.97
2-oxoglutarate
0.22
alpha-ketoglutarate
-
-
0.13 - 1.47
N6,N6,N6-Trimethyl-L-lysine
additional information
additional information
Michaelis-Menten kinetics
-
0.109
2-oxoglutarate
-
0.35
2-oxoglutarate
mutant enzyme W221F, pH 7.5, 37°C
0.42
2-oxoglutarate
wild-type enzyme, pH 7.5, 37°C
1.12
2-oxoglutarate
mutant enzyme D244E, pH 7.5, 37°C
1.97
2-oxoglutarate
mutant enzyme T269A, pH 7.5, 37°C
0.13
N6,N6,N6-Trimethyl-L-lysine
-
-
0.32
N6,N6,N6-Trimethyl-L-lysine
mutant enzyme D244E, pH 7.5, 37°C
0.33
N6,N6,N6-Trimethyl-L-lysine
-
-
0.636
N6,N6,N6-Trimethyl-L-lysine
recombinant MBP-tagged enzyme, pH 7.0, 37°C
0.696
N6,N6,N6-Trimethyl-L-lysine
recombinant detagged enzyme, pH 7.0, 37°C
0.7
N6,N6,N6-Trimethyl-L-lysine
mutant enzyme T269A, pH 7.5, 37°C
1.1
N6,N6,N6-Trimethyl-L-lysine
pH 6.7, 37°C
1.18
N6,N6,N6-Trimethyl-L-lysine
wild-type enzyme, pH 7.5, 37°C
1.47
N6,N6,N6-Trimethyl-L-lysine
mutant enzyme W221F, pH 7.5, 37°C
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evolution
the enzyme belongs to the family of 2-oxoglutarate (2OG)-dependent oxygenases
evolution
the enzyme belongs to the family of 2-oxoglutarate (2OG)-dependent oxygenases. Members of Fe(II) and 2-oxoglutarate-dependent oxygenases catalyze stereoselective hydroxylations of unactivated C-H bonds in various (bio)molecules, including proteins, DNA, and small molecule metabolites
evolution
the enzyme belongs to the non-heme Fe(II) and 2-oxoglutarate dependent oxygenases
metabolism
the enzyme catalyzes the first step in the biosynthesis of carnitine
metabolism
-
the enzyme catalyzes the first step in the biosynthesis of carnitine, i.e. L-3-hydroxy-4-N-N-N-trimethylaminobutyrate. Lysine in protein peptide linkages undergoes methylation of the 1-amino group to yield trimethyllysine, TML, which is released upon protein degradation. Muscle is the major source of TML. The released TML is further oxidised to gamma-butyrobetaine by the action of trimethyllysine dioxygenase, 3-hydroxy-N-trimethyllysine aldolase and 4-N-trimethylaminobutyraldehyde dehydrogenase
metabolism
the enzyme catalyses the first step in mammalian biosynthesis of carnitine, which plays a crucial role in fatty acid metabolism. Carnitine biosynthesis patway, overview
metabolism
trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nepsilon-trimethyllysine in the first step of carnitine biosynthesis
metabolism
trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nepsilon-trimethyllysine in the first step of carnitine biosynthesis in humans
metabolism
trimethyllysine hydroxylase (TMLH) catalyses the first step in carnitine biosynthesis, the conversion of N6,N6,N6-trimethyl-L-lysine to 3-hydroxy-N6,N6,N6-trimethyl-L-lysine
metabolism
trimethyllysine hydroxylase (TMLH) is involved in the first step of the physiologically important carnitine biosynthesis pathway. The enzyme catalyzes C-3 hydroxylation of (2S)-Nepsilon-L-trimethyllysine, to produce 3-hydroxy-Nepsilon-L-trimethyllysine, which then undergoes three additional enzymatic steps to the final L-carnitine
physiological function
trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nepsilon-trimethyllysine in the first step of carnitine biosynthesis
physiological function
trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nepsilon-trimethyllysine in the first step of carnitine biosynthesis in humans
physiological function
the enzyme catalyzes the first step in carnitine biosynthesis
additional information
residue Asp131 in TMLHis responsible for specific binding of the alpha-ammonium group of trimethyllysine
additional information
-
residue Asp131 in TMLHis responsible for specific binding of the alpha-ammonium group of trimethyllysine
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Hulse, J.D.; Ellis, S.R.; Henderson, L.M.
Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase
J. Biol. Chem.
253
1654-1659
1978
Rattus norvegicus
brenda
Henderson, L.M.; Nelson, P.J.; Henderson, L.
Mammalian enzymes of trimethyllysine conversion to trimethylaminobutyrate
Fed. Proc.
41
2843-2847
1982
Bos taurus
brenda
Sachan, D.S.; Hoppel, C.L.
Carnitine biosynthesis. Hydroxylation of N6-trimethyl-lysine to 3-hydroxy-N6-trimethyl-lysine
Biochem. J.
188
529-534
1980
Rattus norvegicus
brenda
Sachan, D.S.; Broquist, H.P.
Synthesis of carnitine from epsilon-N-trimethyllysine in post mitochondrial fractions of Neurospora crassa
Biochem. Biophys. Res. Commun.
96
870-875
1980
Neurospora crassa
brenda
Swiegers, J.H.; Vaz, F.M.; Pretorius, I.S.; Wanders, R.J.A.; Bauer, F.F.
Carnitine biosynthesis in neurospora crassa: identification of a cDNA coding for epsilon-N-trimethyllysine hydroxylase and its functional expression in Saccharomyces cerevisiae
FEMS Microbiol. Lett.
210
19-23
2002
Neurospora crassa
brenda
Vaz, F.M.; Ofman, R.; Westinga, K.; Back, J.W.; Wanders, R.J.A.
Molecular and biochemical characterization of rat epsilon-N-trimethyllysine hydroxylase, the first enzyme of carnitine biosynthesis
J. Biol. Chem.
276
33512-33517
2001
Mus musculus (Q91ZE0), Mus musculus, Rattus norvegicus (Q91ZW6), Homo sapiens (Q9NVH6), Homo sapiens
brenda
van Vlies, N.; Wanders, R.J.; Vaz, F.M.
Measurement of carnitine biosynthesis enzyme activities by tandem mass spectrometry: differences between the mouse and the rat
Anal. Biochem.
354
132-139
2006
Mus musculus, Rattus norvegicus
brenda
Monfregola, J.; Cevenini, A.; Terracciano, A.; van Vlies, N.; Arbucci, S.; Wanders, R.J.; DUrso, M.; Vaz, F.M.; Ursini, M.V.
Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting
J. Cell. Physiol.
204
839-847
2005
Homo sapiens, Mus musculus
brenda
Davis, A.T.; Monroe, T.J.
Carnitine deficiency and supplementation do not affect the gene expression of carnitine biosynthetic enzymes in rats
J. Nutr.
135
761-764
2005
Rattus norvegicus
brenda
van Vlies, N.; Ofman, R.; Wanders, R.J.; Vaz, F.M.
Submitochondrial localization of 6-N-trimethyllysine dioxygenase - implications for carnitine biosynthesis
FEBS J.
274
5845-5851
2007
Rattus norvegicus
brenda
Furusawa, H.; Sato, Y.; Tanaka, Y.; Inai, Y.; Amano, A.; Iwama, M.; Kondo, Y.; Handa, S.; Murata, A.; Nishikimi, M.; Goto, S.; Maruyama, N.; Takahashi, R.; Ishigami, A.
Vitamin C is not essential for carnitine biosynthesis in vivo: verification in vitamin C-depleted senescence marker protein-30/gluconolactonase knockout mice
Biol. Pharm. Bull.
31
1673-1679
2008
Mus musculus (Q91ZE0)
brenda
Fischer, M.; Hirche, F.; Kluge, H.; Eder, K.
A moderate excess of dietary lysine lowers plasma and tissue carnitine concentrations in pigs
Br. J. Nutr.
101
190-196
2009
Sus scrofa
brenda
Al Temimi, A.H.; Pieters, B.J.; Reddy, Y.V.; White, P.B.; Mecinovic, J.
Substrate scope for trimethyllysine hydroxylase catalysis
Chem. Commun. (Camb.)
52
12849-12852
2016
Homo sapiens (Q9NVH6), Homo sapiens
brenda
Lesniak, R.; Markolovic, S.; Tars, K.; Schofield, C.
Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-Nepsilon-trimethyllysine
Chem. Commun. (Camb.)
53
440-442
2017
Homo sapiens (Q9NVH6)
brenda
Vijayendar Reddy, Y.; Al Temimi, A.H.; Mecinovic, J.
Fluorinated trimethyllysine as a (19)F NMR probe for trimethyllysine hydroxylase catalysis
Org. Biomol. Chem.
15
1350-1354
2017
Homo sapiens (Q9NVH6)
brenda
Reddy, Y.V.; Al Temimi, A.H.; White, P.B.; Mecinovi?, J.
Evidence that trimethyllysine hydroxylase catalyzes the formation of (2S,3S)-3-hydroxy-N(epsilon)-trimethyllysine
Org. Lett.
19
400-403
2017
Homo sapiens (Q9NVH6), Homo sapiens
brenda
Kazaks, A.; Makrecka-Kuka, M.; Kuka, J.; Voronkova, T.; Akopjana, I.; Grinberga, S.; Pugovics, O.; Tars, K.
Expression and purification of active, stabilized trimethyllysine hydroxylase
Protein Expr. Purif.
104
1-6
2014
Homo sapiens (Q9NVH6)
brenda
Wang, Y.; Vijayendar Reddy, Y.; Al Temimi, A.; Venselaar, H.; Nelissen, F.; Lenstra, D.; Mecinovic, J.
Investigating the active site of human trimethyllysine hydroxylase
Biochem. J.
476
1109-1119
2019
Homo sapiens (Q9NVH6), Homo sapiens
brenda