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Information on EC 1.14.16.2 - tyrosine 3-monooxygenase and Organism(s) Homo sapiens

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EC Tree
IUBMB Comments
The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by EC 2.7.11.27, [acetyl-CoA carboxylase] kinase. The 4a-hydroxytetrahydropteridine formed can dehydrate to 6,7-dihydropteridine, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydropteridine must be enzymically reduced back to tetrahydropteridine, by EC 1.5.1.34, 6,7-dihydropteridine reductase, before it slowly rearranges into the more stable but inactive compound 7,8-dihydropteridine.
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This record set is specific for:
Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
tyrosine hydroxylase, cat-2, tyrosine 3-monooxygenase, monophenol monooxygenase, tyrosine-3-monooxygenase, l-tyrosine hydroxylase, tyrosine 3-hydroxylase, tyrosine hydroxylase type 1, tyrosine-3-mono-oxygenase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hTH2
-
-
L-tyrosine hydroxylase
-
-
-
-
oxygenase, tyrosine 3-mono-
-
-
-
-
TH2
-
isoform
tyrosinase
-
tyrosine 3-hydroxylase
-
-
-
-
tyrosine hydroxylase
tyrosine hydroxylase type 1
-
isoform
tyrosine-3-mono-oxygenase
-
-
tyrosine-3-monooxygenase
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
L-tyrosine + a 5,6,7,8-tetrahydropteridine + O2 = L-dopa + a 4a-hydroxy-5,6,7,8-tetrahydropteridine
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
L-tyrosine,tetrahydrobiopterin:oxygen oxidoreductase (3-hydroxylating)
The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by EC 2.7.11.27, [acetyl-CoA carboxylase] kinase. The 4a-hydroxytetrahydropteridine formed can dehydrate to 6,7-dihydropteridine, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase. The 6,7-dihydropteridine must be enzymically reduced back to tetrahydropteridine, by EC 1.5.1.34, 6,7-dihydropteridine reductase, before it slowly rearranges into the more stable but inactive compound 7,8-dihydropteridine.
CAS REGISTRY NUMBER
COMMENTARY hide
9036-22-0
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3,4-dihydroxy-L-phenylalanine + 6,7-dimethyltetrahydropteridine + O2
?
show the reaction diagram
3,4-dihydroxy-L-phenylalanine + tetrahydropterin + O2
?
show the reaction diagram
L-phenylalanine + tetrahydrobiopterin + O2
L-tyrosine + 3-hydroxyphenylalanine + dihydropteridine + H2O
show the reaction diagram
the enzyme prefers L-tyrosine as a substrate over L-phenylalanine by an order of magnitude
-
-
?
L-phenylalanine + tetrahydropteridine + 2 O2
3,4-dihydroxy-L-phenylalanine + dihydropteridine + 2 H2O
show the reaction diagram
-
-
-
?
L-phenylalanine + tetrahydropteridine + O2
L-tyrosine + dihydropteridine + H2O
show the reaction diagram
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
?
show the reaction diagram
the enzyme prefers L-tyrosine as a substrate over L-tryptophan by 25fold
-
-
?
L-tyrosine + (6R)-L-erythro-1',2'-dihydroxypropyltetrahydropterin + O2
?
show the reaction diagram
-
-
-
-
?
L-tyrosine + (6R)-L-erythro-tetrahydrobiopterin + O2
?
show the reaction diagram
L-tyrosine + (6RS)-L-erythro-tetrahydrobiopterin + O2
?
show the reaction diagram
-
-
-
-
?
L-tyrosine + (6S)-L-erythro-tetrahydrobiopterin + O2
?
show the reaction diagram
-
-
-
-
?
L-tyrosine + 2-methyl-4-oxo-5,6,7,8-tetrahydropterin + O2
?
show the reaction diagram
-
recombinant hTH1
-
-
?
L-tyrosine + 5,6,7,8,-tetrahydro-L-biopterin + O2
3,4-dihydroxy-L-phenylalanine + 4a-hydroxytetrahydro-L-biopterin
show the reaction diagram
-
-
-
-
?
L-tyrosine + 5,6,7,8-tetrahydro-L-biopterin + O2
3,4-dihydroxy-L-phenylalanine + 4a-hydroxytetrahydro-L-biopterin
show the reaction diagram
-
-
-
-
?
L-tyrosine + 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine + O2
3,4-dihydroxyphenylalanine + ?
show the reaction diagram
-
-
-
-
?
L-tyrosine + 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine + O2
?
show the reaction diagram
-
-
-
-
?
L-tyrosine + 6-methyltetrahydropterin + O2
?
show the reaction diagram
L-tyrosine + tetrahydrobiopterin + O2
3,4-dihydroxy-L-phenylalanine + 4a-hydroxytetrahydrobiopterin + H2O
show the reaction diagram
L-tyrosine + tetrahydrobiopterin + O2
3,4-dihydroxy-L-phenylalanine + dihydrobiopterin + H2O
show the reaction diagram
L-tyrosine + tetrahydrobiopterin + O2
L-dopa + 4a-hydroxytetrahydrobiopterin + H2O
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
L-tyrosine + (6R)-L-erythro-tetrahydrobiopterin + O2
?
show the reaction diagram
-
probable regulatory role of cosubstrate for all 4 isoforms
-
-
?
L-tyrosine + tetrahydrobiopterin + O2
3,4-dihydroxy-L-phenylalanine + 4a-hydroxytetrahydrobiopterin + H2O
show the reaction diagram
L-tyrosine + tetrahydrobiopterin + O2
3,4-dihydroxy-L-phenylalanine + dihydrobiopterin + H2O
show the reaction diagram
L-tyrosine + tetrahydrobiopterin + O2
L-dopa + 4a-hydroxytetrahydrobiopterin + H2O
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
-
i.e. BH4, complex regulation by the cofactor including both enzyme inactivation and conformational stabilization, competitive inhibition
5,6,7,8-tetrahydro-L-biopterin
-
-
tetrahydrobiopterin
additional information
a non-heme iron enzyme
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cu2+
-
slightly activating
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(6R)-L-erythro-1',2'-dihydroxypropyltetrahydropterin
-
80% inhibition when the enzyme is preincubated with (6R)-L-erythro-1',2'-dihydroxypropyltetrahydropterin. Inhibition was attenuated by simultanious addition of dopamine
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
-
i.e. BH4, cofactor, complex regulation by the cofactor including both enzyme inactivation and conformational stabilization, competitive inhibition, synergistically with DTT
(6S)-L-erythro-1',2'-dihydroxypropyltetrahydropterin
-
80% inhibition when the enzyme is preincubated with (6S)-L-erythro-1',2'-dihydroxypropyltetrahydropterin
1,10-phenanthroline
-
complete
2,4-diamino-6-dihydroxypropyl-5,6,7,8-tetrahydropterin
-
competitive against (6R)-L-erythro-tetrahydrobiopterin
3,4-dihydroxy-L-phenylalanine
3,4-dihydroxyphenylacetaldehyde
3-iodo-L-tyrosine
5(N-phenylthiocarbamoyl)-5,6,7,8-tetrahydropterin
-
-
5-methyl-5,6,7,8-tetrahydropterin
-
competitive against (6R)-L-erythro-tetrahydrobiopterin
6-methyltetrahydropterin
-
80% inhibition when the enzyme is preincubated with 6-methyltetrahydropterin
6-[2-(4-benzoylphenyl)propionyloxymethyl]-5,6,7,8-tetrahydropterin
-
competitive against (6R)-L-erythro-tetrahydrobiopterin
7-amino-3,3a,4,5-tetrahydro-8H-2-oxa-5,6,8,9b-tetraaza-cyclopenta[a]naphthalene-1,9-dione
-
competitive against (6R)-L-erythro-tetrahydrobiopterin
8-methyl-6,7-dimethyl-5,6,7,8-tetrahydropterin
-
competitive against (6R)-L-erythro-tetrahydrobiopterin
adrenaline
-
-
alpha-methyl-p-tyrosine
-
complete inhibition at 0.001 mM
Bathocuproine sulfonate
-
slightly
bathophenanthroline sulfonate
-
-
Catecholamines
CoCl2
-
0.1 mM CoCl2 results in more than 80% inhibition
dihydrobiopterin
-
L-dopa-oxidase activity
dopamine
DTT
-
inactivates the enzyme, synergistically with tetrahydrobiopterin
L-alpha-methyl-p-tyrosine
specific and potent inhibitor
L-Dopa
-
above 0.15 mM inhibiting L-dopa-oxidase activity in presence of tetrahydropterin, but not with 6,7-dimethyltetrahydropterin
L-erythro-7,8-dihydrobiopterin
-
competitive against tetrahydropterin
L-phenylalanine
-
-
L-tyrosine
-
-
Mn2+
-
50% inhibition at 0.01 mM
N-methyl-norsalsolinol
-
noncompetitive with respect to L-tyrosine, N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cerebrospinal fluid of patients with Parkinson’s disease
N-methyl-salsolinol
-
-
Ni2+
-
competitive against Fe2+
noradrenaline
-
-
norsalsolinol
-
N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cerebrospinal fluid of patients with Parkinson’s disease
tyrosine
-
substrate inhibition, with (6R)-L-erythro-tetrahydrobiopterin
Zn2+
-
competitive against Fe2+
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
14-3-3gamma
homodimeric 14-3-3gamma protein is the strongest activator
-
forskolin
-
forskolin selectively increases the phosphorylation of tyrosine hydroxylase at Ser40 by 1.8fold without increasing total tyrosine hydroxylase protein levels
nitric oxide
-
S-nitrosylation by nitric oxide at Cys279 enhances the enzymatic activity by about 25%
thiols
-
activate the L-dopa activity
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.045
6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine
-
0.1 mM L-tyrosine, 0.1 mg/ml catalase, 50 mM HEPES pH 7.0, 0.01 mM ferrous ammonium sulfate, 1 mM dithiothreitol, 25°C
0.06 - 0.1
6-Methyl-5,6,7,8-tetrahydropterin
-
-
0.056 - 0.146
L-Dopa
0.0081 - 0.08
L-tyrosine
0.085
phenylalanine
-
-
0.0056 - 0.507
tetrahydrobiopterin
0.01
Tetrahydropterin
-
recombinant phosphorylated hTH1, L-dopa-oxidase activity
0.011 - 0.166
tyrosine
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.8 - 5.35
L-tyrosine
0.017 - 0.58
tetrahydrobiopterin
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.7 - 89.3
tetrahydrobiopterin
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.07
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
-
pH 7.0, 25°C, versus (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
0.016
2,4-diamino-6-dihydroxypropyl-5,6,7,8-tetrahydropterin
-
-
2.83
5(N-phenylthiocarbamoyl)-5,6,7,8-tetrahydropterin
-
-
0.063
5-methyl-5,6,7,8-tetrahydropterin
-
-
0.001
6-[2-(4-benzoylphenyl)propionyloxymethyl]-5,6,7,8-tetrahydropterin
-
-
0.138
7-amino-3,3a,4,5-tetrahydro-8H-2-oxa-5,6,8,9b-tetraaza-cyclopenta[a]naphthalene-1,9-dione
-
-
0.617
8-methyl-6,7-dimethyl-5,6,7,8-tetrahydropterin
-
-
0.07
L-erythro-7,8-dihydrobiopterin
-
-
0.103
L-phenylalanine
-
0-0.4 mM L-tyrosine, 0-0.2 mM L-phenylalanine, 1 mM 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine, 200 mM Na-HEPES pH 7.0, 100 mM 2-mercaptoethanol, 0.2 mg/ml catalase, 37°C
0.037 - 0.073
L-tyrosine
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0022
3,4-dihydroxy-L-phenylalanine
Homo sapiens
-
at pH 7.0 and 25°C
0.05
3-iodo-L-tyrosine
Homo sapiens
-
pH and temperature not specified in the publication
0.0002 - 0.0136
dopamine
0.0003
N-methyl-norsalsolinol
Homo sapiens
-
-
0.004
N-methyl-salsolinol
Homo sapiens
-
-
0.01
norsalsolinol
Homo sapiens
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0054
-
crude enzyme, at pH 6.8 and 37°C
0.0163
-
purified enzyme, at pH 6.8 and 37°C
0.0447
-
activity in melanosomes
0.16
-
purified recombinant isoform hTH3
0.2
-
purified recombinant isoform hTH4
0.29
-
purified recombinant isoform hTH2
0.33
-
purified recombinant isoform hTH1, tyrosine concentration is 0.2 mM
0.555
-
with 0.05 mM L-tyrosine, at pH 7.0 and 25°C
0.79
-
purified recombinant isoform hTH1, tyrosine concentration is 0.05 mM
1
-
about, purified recombinant enzyme
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 7
-
4 isoforms
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5 - 8.5
-
4 isoforms
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
assay at, crude brain enzyme extract
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
undifferentiated, hydroxylase isoenzyme I mRNA, no detection of isoenzyme 2, 3 and 4
Manually annotated by BRENDA team
-
increased enzyme contents in violent suicidal depressive patients, analysis of postmortem brains of control individuals, non-suicidal depressive patients, and non-violent and violent suicidal depressive patients
Manually annotated by BRENDA team
-
epidermal, hydroxylase isoenzyme I mRNA, no detection of isoenzyme 2, 3 and 4
Manually annotated by BRENDA team
-
37 different tumor samples, analysis of enzyme expression
Manually annotated by BRENDA team
-
a dopaminergic-like, neuroblastoma cell line
Manually annotated by BRENDA team
-
a dopaminergic cell line
Manually annotated by BRENDA team
-
the superior cervical ganglion of the sympathetic nervous system is filled with many neuronal somata and fibers with strong immunoreactivity for tyrosine hydroxylase, TH-positive fibers are not evenly distributed within the nerve bundles of the ganglia, but tend to be located at their circumference
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
mutant enzymes T283M and R306H expressed in Escherichia coli are mainly found in inclusion bodies but a small amount of soluble enzyme is produced
Manually annotated by BRENDA team
-
mutant enzyme T245P and T463 M expressed in Escherichia coli are predominantly soluble. Mutant enzymes T283M and R306H expressed in Escherichia coli are mainly found in inclusion bodies but a small amount of soluble enzyme is produced
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
physiological function
-
The enzyme shows a disruptive effect on cell membranes. Incubation of isolated mitochondria with the enzyme leads to a decrease in the mitochondrial membrane potential
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
TY3H_HUMAN
528
0
58600
Swiss-Prot
other Location (Reliability: 2)
Q15587_HUMAN
111
0
11951
TrEMBL
other Location (Reliability: 3)
Q9NP14_HUMAN
138
0
14498
TrEMBL
other Location (Reliability: 2)
Q7KZ38_HUMAN
106
0
11297
TrEMBL
other Location (Reliability: 3)
Q9UQ57_HUMAN
61
0
6220
TrEMBL
other Location (Reliability: 3)
O43816_HUMAN
134
0
14058
TrEMBL
other Location (Reliability: 3)
Q16846_HUMAN
107
0
11510
TrEMBL
other Location (Reliability: 3)
Q7KZ39_HUMAN
102
0
10856
TrEMBL
other Location (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
24000
-
4 isoforms, gel filtration
300000
gel filtration
34700
-
catalytic domain, gel filtration
56000
-
x * 56000, SDS-PAGE
58000
-
x * 58000, recombinant enzyme, SDS-PAGE
60000
-
4 * 60000, 4 isoforms, SDS-PAGE
70000
4 * 70000, SDS-PAGE
98900
-
recombinant enzyme, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
-
2 * 17044, catalytic domain, calculated from amino acid sequence
homotetramer
tetramer
-
4 * 60000, 4 isoforms, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
nitrosylation
-
the enzyme can be S-nitrosylated at Cys279
phosphoprotein
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
complex of 14-3-3gamma protein and phosphorylated tyrosine hydroxylase(1-43), sitting drop vapor diffusion method, using 30% (w/v) polyethylene glycol 2000 monomethyl ether as precipitant
crystal structure, analysis of tetrahydropterin analogues binding to isoform hTH1
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A297L
D361N
reductions in Vmax are not significantly different from the wild type enzyme
E332A
-
the mutant has 10fold higher Km for 6-methyltetrahydropterin, but reduction of the enzyme by 6-methyltetrahydropterin is similar to the wild type
E332D
active site residue, 10fold reduction in activity, close to the catalytic iron
E332Q
active site residue, no activity, close to the catalytic iron
E362G
the Vmax is reduced compared to the wild type enzyme
E362Q
reductions in Vmax are not significantly different from the wild type enzyme
E362R/E365R
the Vmax is significantly less reduced by dopamine than for the wild type enzyme
E365G
the Vmax is reduced compared to the wild type enzyme
E365Q
the Vmax is significantly less reduced by dopamine than for the wild type enzyme
F184W/W372F
-
4fold lower Km for L-tyrosine compared to the wild-type enzyme. Similar Km for 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine compared to wild-type enzyme
F300A
active site residue
F300Y
active site residue
K170E/L480A
the mutant is inhibited over the same range of dopamine like the wild type enzyme
K366L
reductions in Vmax are not significantly different from the wild type enzyme
L205P
L294A
protrudes into catalytic cleft
L294Y
protrudes into catalytic cleft
Q381K
-
the mutation is associated with tyrosine hydroxylase deficiency
R202H
-
the mutation is associated with tyrosine hydroxylase deficiency
R233H
-
the mutation is associated with tyrosine hydroxylase deficiency
R306H
-
1.2fold decrease in Km-value for L-tyrosine compared to wild-type enzyme, Ki-value for L-tyrosine is nearly identical to wild-type value, 1.3fold decrease in KM-value for tetrahydrobiopterin compared to wild-type enzyme, 1.2fold increase of turnover-number compared to wild-type enzyme. 8.2°C increase in Tm-value compared to wild-type enzyme
R306H/T463M
-
all of the TyrH is insoluble and no enzyme can be purified
R37E/R38E
S31A
-
the mutant is not phosphorlyated
S31E
-
phospho-mimic mutant
S368A
the Vmax is significantly less reduced by dopamine than for the wild type enzyme
S40E
-
the mutant mimics a phosphorylation of S40. The kinetics of reduction and oxidation of the enzyme are similar to the wild type
T245P
-
1.4fold increase in Km-value for L-tyrosine compared to wild-type enzyme, 1.6fold increase in Ki-value for L-tyrosine compared to wild-type enzyme, 1.1fold increase in KM-value for tetrahydrobiopterin compared to wild-type enzyme, 1.6fold increase of turnover-number compared to wild-type enzyme. 3.9°C increase in Tm-value compared to wild-type enzyme
T245P/T283M
-
all of the TyrH is insoluble and no enzyme can be purified
T283M
-
1.2fold decrease in Km-value for L-tyrosine compared to wild-type enzyme, 1.2fold decrease in Ki-value for L-tyrosine compared to wild-type enzyme, 1.3fold decrease in KM-value for tetrahydrobiopterin compared to wild-type enzyme, 4.2fold decrease of turnover-number compared to wild-type enzyme
T463M
-
1.1fold decrease in Km-value for L-tyrosine compared to wild-type enzyme, Ki-value for L-tyrosine is nearly identical to wild-type value compared to wild-type enzyme, 1.4fold decrease in KM-value for tetrahydrobiopterin compared to wild-type enzyme, 1.2fold increase of turnover-number compared to wild-type enzyme. 7.7°C increase in Tm-value compared to wild-type enzyme
W166F/F184W/W233F/W372F
-
mutant protein contains one tryptophan at residue 184 in the middle of a mobile active-site loop. The mutant was generated to perform steady-state fluorescence anisotropy measurements and shows kinetic properties similar to the wild-type enzyme
W166F/F184W/W372F
-
Km for L-tyrosine similar to the wild-type enzyme. 3fold higher Km for 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine compared to wild-type enzyme
W166F/W233F/W372F
-
Km for L-tyrosine similar to the wild-type enzyme. 4fold higher Km for 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine compared to wild-type enzyme
W166F/W372F
-
Km for L-tyrosine similar to the wild-type enzyme. 3fold higher Km for 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine compared to wild-type enzyme
W372F
-
10fold lower Km for L-tyrosine compared to the wild-type enzyme. Similar Km for 6,7-dimethyl-2-amino-4-hydroxy-5,6,7,8-tetrahydopteridine compared to wild-type enzyme
Y371F
active site residue, close to the catalytic iron
additional information
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
-
isoforms, optimal stability at
438705
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
5 h, stable, catecholamine, N-methyl-norsalsolinol, or norsalsolinol binding increases the thermal stability of tyrosine hydroxylase
41
-
Tm-value of mutant enzyme T463M is 44.3°C
44
-
Tm-value of mutant enzyme T245P is 44.3°C
46
-
Tm-value of mutant enzyme R306H is 45.8°C
48
-
Tm-value of wild-type enzyme is 48.2°C
50
-
50% loss of activity after 90 min, 80% loss of activity after 2 h, wild-type enzyme
additional information
-
thermal stability of hTH1 is increased by phosphorylation at Ser-40
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
binding of inhibitor dopamine and of cofactor tetrahydrobioterin stabilizes the enzyme
-
catecholamine binding improves tyrosine hydroxylase's resistance to proteolysis
-
the 14-3-3eta protein regulates tyrosine hydroxylase type 1 stability against degradation by acting on the N-terminus
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, purified wild-type enzyme can be stored indefinetely in absence of glycerol. the mutant enzymes T245P and T463M behave similarly. The removal of glyceryl from the T283M and R306H enzymes results in significant precipitation and loss of the protein
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
4 isoforms, recombinant from Escherichia coli
-
amylose resin column chromatography and HiPrep Q column chromatography
-
GST-Sepharose column chromatography
-
heparin Sepharose chromatography
Hi-TRAP heparin column
-
more than 90% homogeneity
-
Ni-chelating Sepharose fast flow bead chromatography
-
Ni-NTA column chromatography and Superdex 200 gel filtration
one chromatography step
-
Talon column chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
4 isoforms, overexpression in Escherichia coli, phosphorylation-free
-
DNA and amino acid sequence determination and analysis of wild-type enzyme and polymorphic genetic variants, expression in human chromaffin cells
-
enzyme expression by in vitro transcription-translation using a rapid translation system with enhanced Escherichia coli lysate and radio-labeled L-Met, tetrahydrobioterin increases the enzyme protein yield
-
expressed in BEscherichia coli BL21-CodonPlus cells
-
expressed in Escherichia coli BL21 Codon Plus (DE3) cells
expressed in Escherichia coli BL21(DE3)
expressed in Escherichia coli BL21(DE3) cells
expressed in Escherichia coli BL21(DE3) pLysS cells
-
expressed in Escherichia coli strain Rosetta (DE3) pLys and HEK-293T cells
-
expressed in monkey striatum using harmless adeno-associated virus vectors and in PC-12 cells and AtT-20 cells
-
expressed in SH-SY5Y cells
-
expressed in SH-SY5Y, SK-N-BE(2), and IMR-32 cells
GQ403014; GQ403013; GQ403012
expressed in SN4741 cells
expression in Escherichia coli
-
expression in Escherichia coli BL21(DE3)
-
expression in Escherichia coli BL21(DE3) as maltose-binding protein fusion protein
-
expression of gene fragment, comprising positions -495 to +25, which have regulatory promoter function, from a pGL-Basic luciferase reporter vector in MES23.5 cells and MES23.5 alpha-synuclein-overexpressing cells, alpha-synuclein is a negative regulator of the tyrosine hydroxylase expression via trans-acting function on the TH promoter, overview
-
isoform 1 hTH1 and His-tagged truncated mutant, expression in Escherichia coli
-
isozyme DNA and amino acid sequence determination and analysis, RT-PCR analysis of isozyme expression in neuroblastoma tumors, in abdominal and thoracic tumours and foetal adrenal glands, using external and internal primers, 4.0fold lower expression level in adrenal glands than in abdominal tumors, overview, expression of the enzyme mutant lacking exons 2, 8, and 9 in HeLa cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
heterogeneous nuclear ribonucleoprotein K is a transactivator of enzyme transcription
striatal tyrosine hydroxylase shows a 49.8% reduction compared to control values in incidental Lewy body disease cases
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Martinez, A.; Abeygunawardana, C.; Haavik, J.; Flatmark, T.; Mildvan, A.S.
Interaction of substrate and pterin cofactor with the metal of human tyrosine hydroxylase as determined by 1H-NMR
Adv. Exp. Med. Biol.
338
77-80
1993
Homo sapiens
Manually annotated by BRENDA team
Nasrin, S.; Ichinose, H.; Hidaka, H.; Nagatsu, T.
Recombinant human tyrosine hydroxylase types 1-4 show regulatory kinetic properties for the natural (6R)-tetrahydrobiopterin cofactor
J. Biochem.
116
393-398
1994
Homo sapiens
Manually annotated by BRENDA team
Haavik, J.
L-DOPA is a substrate for tyrosine hydroxylase
J. Neurochem.
69
1720-1728
1997
Bos taurus, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Martinez, A.; Haavik, J.; Flatmark, T.; Arrondo, J.L.; Muga, A.
Conformational properties and stability of tyrosine hydroxylase studied by infrared spectroscopy. Effect of iron/catecholamine binding and phosphorylation
J. Biol. Chem.
271
19737-19742
1996
Homo sapiens
Manually annotated by BRENDA team
Almas, B.; Toska, K.; Teigen, K.; Groehn, V.; Pfleiderer, W.; Martinez, A.; Flatmark, T.; Haavik, J.
A kinetic and conformational study on the interaction of tetrahydropteridines with tyrosine hydroxylase
Biochemistry
39
13676-13686
2000
Homo sapiens
Manually annotated by BRENDA team
Marles, L.K.; Peters, E.M.; Tobin, D.J.; Hibberts, N.A.; Schallreuter, K.U.
Tyrosine hydroxylase isoenzyme I is present in human melanosomes: a possible novel function in pigmentation
Exp. Dermatol.
12
61-70
2003
Homo sapiens
Manually annotated by BRENDA team
Royo, M.; Daubner, S.C.; Fitzpatrick, P.F.
Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein
Proteins
58
14-21
2004
Homo sapiens
Manually annotated by BRENDA team
Frantom, P.A.; Seravalli, J.; Ragsdale, S.W.; Fitzpatrick, P.F.
Reduction and oxidation of the active site iron in tyrosine hydroxylase: kinetics and specificity
Biochemistry
45
2372-2379
2006
Homo sapiens
Manually annotated by BRENDA team
Sura, G.R.; Lasagna, M.; Gawandi, V.; Reinhart, G.D.; Fitzpatrick, P.F.
Effects of ligands on the mobility of an active-site loop in tyrosine hydroxylase as monitored by fluorescence anisotropy
Biochemistry
45
9632-9638
2006
Homo sapiens
Manually annotated by BRENDA team
Urano, F.; Hayashi, N.; Arisaka, F.; Kurita, H.; Murata, S.; Ichinose, H.
Molecular mechanism for pterin-mediated inactivation of tyrosine hydroxylase: formation of insoluble aggregates of tyrosine hydroxylase
J. Biochem.
139
625-635
2006
Homo sapiens
Manually annotated by BRENDA team
Ogawa, S.; Ichinose, H.
Effect of metals and phenylalanine on the activity of human tryptophan hydroxylase-2: comparison with that on tyrosine hydroxylase activity
Neurosci. Lett.
401
261-265
2006
Homo sapiens
Manually annotated by BRENDA team
Roma, J.; Saus, E.; Cuadros, M.; Reventos, J.; Sanchez de Toledo, J.; Gallego, S.
Characterisation of novel splicing variants of the tyrosine hydroxylase C-terminal domain in human neuroblastic tumours
Biol. Chem.
388
419-426
2007
Homo sapiens
Manually annotated by BRENDA team
Rao, F.; Zhang, L.; Wessel, J.; Zhang, K.; Wen, G.; Kennedy, B.P.; Rana, B.K.; Das, M.; Rodriguez-Flores, J.L.; Smith, D.W.; Cadman, P.E.; Salem, R.M.; Mahata, S.K.; Schork, N.J.; Taupenot, L.; Ziegler, M.G.; OConnor, D.T.
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo
Circulation
116
993-1006
2007
Homo sapiens
Manually annotated by BRENDA team
Gos, T.; Krell, D.; Bielau, H.; Brisch, R.; Truebner, K.; Steiner, J.; Bernstein, H.G.; Jankowski, Z.; Bogerts, B.
Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive patients
Eur. Arch. Psychiatry Clin. Neurosci.
258
513-520
2008
Homo sapiens
Manually annotated by BRENDA team
Scholz, J.; Toska, K.; Luborzewski, A.; Maass, A.; Schuenemann, V.; Haavik, J.; Moser, A.
Endogenous tetrahydroisoquinolines associated with Parkinsons disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines
FEBS J.
275
2109-2121
2008
Homo sapiens
Manually annotated by BRENDA team
He, D.Y.; Ron, D.
Glial cell line-derived neurotrophic factor reverses ethanol-mediated increases in tyrosine hydroxylase immunoreactivity via altering the activity of heat shock protein 90
J. Biol. Chem.
283
12811-12818
2008
Homo sapiens
Manually annotated by BRENDA team
Kawagishi, K.; Fukushima, N.; Yokouchi, K.; Sumitomo, N.; Kakegawa, A.; Moriizumi, T.
Tyrosine hydroxylase-immunoreactive fibers in the human vagus nerve
J. Clin. Neurosci.
15
1023-1026
2008
Homo sapiens
Manually annotated by BRENDA team
Thoeny, B.; Calvo, A.C.; Scherer, T.; Svebak, R.M.; Haavik, J.; Blau, N.; Martinez, A.
Tetrahydrobiopterin shows chaperone activity for tyrosine hydroxylase
J. Neurochem.
106
672-681
2008
Homo sapiens
Manually annotated by BRENDA team
Gao, N.; Li, Y.H.; Li, X.; Yu, S.; Fu, G.L.; Chen, B.
Effect of alpha-synuclein on the promoter activity of tyrosine hydroxylase gene
Neurosci. Bull.
23
53-57
2007
Homo sapiens
Manually annotated by BRENDA team
Klongpanichapak, S.; Phansuwan-Pujito, P.; Ebadi, M.; Govitrapong, P.
Melatonin inhibits amphetamine-induced increase in alpha-synuclein and decrease in phosphorylated tyrosine hydroxylase in SK-N-SH cells
Neurosci. Lett.
436
309-313
2008
Homo sapiens
Manually annotated by BRENDA team
Beach, T.; Adler, C.; Sue, L.; Peirce, J.; Bachalakuri, J.; Dalsing-Hernandez, J.; Lue, L.; Caviness, J.; Connor, D.; Sabbagh, M.; Walker, D.
Reduced striatal tyrosine hydroxylase in incidental Lewy body disease
Acta Neuropathol.
115
445-451
2008
Homo sapiens
Manually annotated by BRENDA team
Gordon, S.L.; Bobrovskaya, L.; Dunkley, P.R.; Dickson, P.W.
Differential regulation of human tyrosine hydroxylase isoforms 1 and 2 in situ: Isoform 2 is not phosphorylated at Ser35
Biochim. Biophys. Acta
1793
1860-1867
2009
Homo sapiens
Manually annotated by BRENDA team
Warner, L.R.; Babbitt, C.C.; Primus, A.E.; Severson, T.F.; Haygood, R.; Wray, G.A.
Functional consequences of genetic variation in primates on tyrosine hydroxylase (TH) expression in vitro
Brain Res.
1288
1-8
2009
Gorilla gorilla (GQ403009), Gorilla gorilla, Pan troglodytes (GQ403010), Pan troglodytes, Macaca mulatta (GQ403011), Macaca mulatta, Homo sapiens (GQ403014 and GQ403013 and GQ403012), Homo sapiens
Manually annotated by BRENDA team
Nakashima, A.; Hayashi, N.; Kaneko, Y.S.; Mori, K.; Sabban, E.L.; Nagatsu, T.; Ota, A.
Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
J. Neural Transm.
116
1355-1362
2009
Homo sapiens
Manually annotated by BRENDA team
Rosmaninho-Salgado, J.; Araujo, I.M.; Alvaro, A.R.; Mendes, A.F.; Ferreira, L.; Grouzmann, E.; Mota, A.; Duarte, E.P.; Cavadas, C.
Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin-1beta: role of neuropeptide Y and nitric oxide
J. Neurochem.
109
911-922
2009
Homo sapiens
Manually annotated by BRENDA team
Gordon, S.L.; Webb, J.K.; Shehadeh, J.; Dunkley, P.R.; Dickson, P.W.
The low affinity dopamine binding site on tyrosine hydroxylase: the role of the N-terminus and in situ regulation of enzyme activity
Neurochem. Res.
34
1830-1837
2009
Homo sapiens
Manually annotated by BRENDA team
Briggs, G.D.; Gordon, S.L.; Dickson, P.W.
Mutational analysis of catecholamine binding in tyrosine hydroxylase
Biochemistry
50
1545-1555
2011
Homo sapiens (P07101)
Manually annotated by BRENDA team
Vermeer, L.M.; Higgins, C.A.; Roman, D.L.; Doorn, J.A.
Real-time monitoring of tyrosine hydroxylase activity using a plate reader assay
Anal. Biochem.
432
11-15
2013
Homo sapiens
Manually annotated by BRENDA team
Calvo, A.; Pey, A.; Miranda-Vizuete, A.; Dskeland, A.; Martinez, A.
Divergence in enzyme regulation between Caenorhabditis elegans and human tyrosine hydroxylase, the key enzyme in the synthesis of dopamine
Biochem. J.
434
133-141
2011
Caenorhabditis elegans, Homo sapiens, Caenorhabditis elegans N2 Bristol
Manually annotated by BRENDA team
Roberts, K.M.; Fitzpatrick, P.F.
Mechanisms of tryptophan and tyrosine hydroxylase
IUBMB Life
65
350-357
2013
Homo sapiens (P07101)
Manually annotated by BRENDA team
Briggs, G.D.; Bulley, J.; Dickson, P.W.
Catalytic domain surface residues mediating catecholamine inhibition in tyrosine hydroxylase
J. Biochem.
155
183-193
2014
Homo sapiens (P07101)
Manually annotated by BRENDA team
Skjevik, A.A.; Mileni, M.; Baumann, A.; Halskau, O.; Teigen, K.; Stevens, R.C.; Martinez, A.
The N-terminal sequence of tyrosine hydroxylase is a conformationally versatile motif that binds 14-3-3 proteins and membranes
J. Mol. Biol.
426
150-168
2014
Homo sapiens (P07101), Homo sapiens
Manually annotated by BRENDA team
Higgins, C.A.; Vermeer, L.M.; Doorn, J.A.; Roman, D.L.
Expression and purification of recombinant human tyrosine hydroxylase as a fusion protein in Escherichia coli
Protein Expr. Purif.
84
219-223
2012
Homo sapiens
Manually annotated by BRENDA team
Ghorbani, S.; Fossbakk, A.; Jorge-Finnigan, A.; Flydal, M.I.; Haavik, J.; Kleppe, R.
Regulation of tyrosine hydroxylase is preserved across different homo- and heterodimeric 14-3-3 proteins
Amino Acids
48
1221-1229
2016
Bos taurus, Homo sapiens (P07101), Homo sapiens
Manually annotated by BRENDA team
Neira, J.L.; Hornos, F.; Bacarizo, J.; Camara-Artigas, A.; Gomez, J.
The monomeric species of the regulatory domain of tyrosine hydroxylase has a low conformational stability
Biochemistry
55
3418-3431
2016
Homo sapiens
Manually annotated by BRENDA team
Hole, M.; Underhaug, J.; Diez, H.; Ying, M.; R?hr, A.K.; Jorge-Finnigan, A.; Fernandez-Castillo, N.; Garcia-Cazorla, A.; Andersson, K.K.; Teigen, K.; Martinez, A.
Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms
Biochim. Biophys. Acta
1854
1078-1089
2015
Homo sapiens
Manually annotated by BRENDA team
Jorge-Finnigan, A.; Kleppe, R.; Jung-Kc, K.; Ying, M.; Marie, M.; Rios-Mondragon, I.; Salvatore, M.F.; Saraste, J.; Martinez, A.
Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules
J. Biol. Chem.
292
14092-14107
2017
Homo sapiens, Rattus norvegicus (P04177)
Manually annotated by BRENDA team
Nagatsu, T.; Nagatsu, I.
Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinsons disease (PD) historical overview and future prospects
J. Neural Transm.
123
1255-1278
2016
Homo sapiens (P07101), Homo sapiens
Manually annotated by BRENDA team
Banerjee, K.; Wang, M.; Cai, E.; Fujiwara, N.; Baker, H.; Cave, J.W.
Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure
Nat. Commun.
5
5769
2014
Bos taurus, Danio rerio, Cavia porcellus, Felis catus, Gadus morhua, Gorilla gorilla, Oryzias latipes, Meleagris gallopavo, Takifugu rubripes, Taeniopygia guttata, Xenopus tropicalis, Pongo abelii, Tursiops truncatus, Gasterosteus aculeatus, Anolis carolinensis, Latimeria chalumnae, Rattus norvegicus (P04177), Homo sapiens (P07101), Mus musculus (P24529), Canis lupus familiaris (Q68CI2), Gallus gallus (Q9PU40)
Manually annotated by BRENDA team
Leite, F.; Lima, M.; Marino, F.; Cosentino, M.; Ribeiro, L.
Dopaminergic receptors and tyrosine hydroxylase expression in peripheral blood mononuclear cells a distinct pattern in central obesity
PLoS ONE
11
e0147483
2016
Homo sapiens (P07101), Homo sapiens
Manually annotated by BRENDA team
Baumann, A.; Jorge-Finnigan, A.; Jung-Kc, K.; Sauter, A.; Horvath, I.; Morozova-Roche, L.A.; Martinez, A.
Tyrosine hydroxylase binding to phospholipid membranes prompts its amyloid aggregation and compromises bilayer integrity
Sci. Rep.
6
39488
2016
Homo sapiens
Manually annotated by BRENDA team
Wang, Y.; Sung, C.C.; Chung, K.K.
Novel enhancement mechanism of tyrosine hydroxylase enzymatic activity by nitric oxide through S-nitrosylation
Sci. Rep.
7
44154
2017
Homo sapiens
Manually annotated by BRENDA team