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Information on EC 1.14.16.4 - tryptophan 5-monooxygenase and Organism(s) Mus musculus and UniProt Accession Q8CGV2
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1.14.16.4 tryptophan 5-monooxygenaseIUBMB Comments
The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by a Ca2+-activated protein 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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Word Map
- 1.14.16.4
- serotonin
-
serotonergic
-
raphe
- 5-hydroxytryptamine
-
monoamine
-
dorsal
- dopamine
-
neurotransmitter
- hippocampus
-
antidepressant
-
reuptake
- 5-hydroxytryptophan
-
anxiety
-
psychiatric
- midbrain
- striatum
- hypothalamus
-
neurochemical
-
5-hydroxyindoleacetic
-
mood
-
enterochromaffin
-
neurotransmission
-
5-hiaa
- p-chlorophenylalanine
- fluoxetine
-
pineal
- brainstem
- alpha-methyl-p-tyrosine
-
monoaminergic
-
5,7-dihydroxytryptamine
- analysis
- methamphetamine
-
autoreceptors
-
slc6a4
-
immobility
- pargyline
- n-acetylserotonin
- neostriatal
-
5-httlpr
- medicine
- citalopram
-
antidepressant-like
- carcinoid
- biopterins
-
impulsivity
-
oxidase-a
- tetrahydropterins
- fenfluramine
-
impulsive
-
8-oh-dpat
- 5-hydroxyindole
- drug development
- 3,4-methylenedioxymethamphetamine
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
+
=
+
+
+
=
+
a 4a-hydroxy-5,6,7,8-tetrahydropteridine
Synonyms
tryptophan hydroxylase, tryptophan hydroxylase 2, tryptophan hydroxylase 1, tph-1, tryptophan hydroxylase-2, tryptophan hydroxylase-1, tph-2, tryptophan-5-hydroxylase, tryptophan 5-monooxygenase, htph2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
indoleacetic acid-5-hydroxylase
-
-
-
-
L-tryptophan hydroxylase
-
-
-
-
oxygenase, tryptophan 5-mono-
-
-
-
-
TPH
TPH1
TPH2
tryptophan 5-hydroxylase
-
-
-
-
tryptophan hydroxylase
tryptophan hydroxylase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
L-tryptophan,tetrahydrobiopterin:oxygen oxidoreductase (5-hydroxylating)
The active centre contains mononuclear iron(II). The enzyme is activated by phosphorylation, catalysed by a Ca2+-activated protein 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
9037-21-2
-
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
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
tryptophan hydroxylase-2 controls brain serotonin synthesis
-
-
?
L-tryptophan + (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + 2-amino-4-hydroxy-6-methyl-tetrahydropteridine + O2
?
-
-
-
-
r
L-tryptophan + 6-methyl-tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 6-methyl-4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + tetrahydrobiopterin
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
L-tyrosine + tetrahydropteridine + O2
?
-
1% of activity with L-tryptophan
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
key enzyme of serotonin synthesis in the brain is tryptophan hydroxylase-2
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
TPH catalyzes the first step and rate-limiting reaction in the biosynthesis of 5-hydroxytryptamine, i.e. serotonin, and plays a role in brain and serotonergic neuron development, overview
-
-
?
L-phenylalanine + tetrahydropteridine + O2
tyrosine + dihydropteridine + H2O
-
-
-
-
?
L-phenylalanine + tetrahydropteridine + O2
tyrosine + dihydropteridine + H2O
-
at a comparable rate of L-tryptophan hydroxylation
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
first and rate-limiting step in serotonin biosynthesis, overview. Serotonin, i.e. 5-hydroxytryptamine, is a neurotransmitter that modulates central and peripheral functions through action on neurons, smooth muscle, and other cell types
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
first and rate-limiting step in serotonin biosynthesis, serotonin, i.e. 5-hydroxytryptamine, is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal sensation, secretion, and motility
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
rate-limiting enzyme in serotonin biosynthesis, mice deficient in peripheral tryptophan hydroxylase and serotonin exhibit a reduced risk of thrombosis and thromboembolism
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
rate-limiting step in serotonin, i.e. 5-hydroxytryptamine, biosynthesis
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
the enzyme is responsible for serotonin biosynthesis
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
TPH catalyzes the first step and rate-limiting reaction in the biosynthesis of 5-hydroxytryptamine, i.e. serotonin, and plays a role in brain and serotonergic neuron development, also TPH1 is involved in behavioural disorders, overview
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
TPH is involved in 5-hydroxytryptamine biosynthesis
-
-
?
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
-
-
-
?
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
-
-
-
?
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
-
cofactor 2-amino-4-hydroxy-6,7-dimethyltetrahydropteridine
-
?
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
-
believed to be the rate-limeting enzyme in the biosynthesis of serotonin in the central nervous system
-
?
additional information
?
-
temporal expression pattern of TPH2 and pathway regulation, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH2 and pathway regulation, overview
-
-
?
additional information
?
-
-
emotional behavior and expression pattern tryptophan hydroxylase is altered in senescence-accelerated prone mouse 6, which show increased serotonin levels, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH1 and pathway regulation, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH1 and pathway regulation, 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
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
tryptophan hydroxylase-2 controls brain serotonin synthesis
-
-
?
L-tryptophan + (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
L-tryptophan + tetrahydropteridine + O2
5-hydroxy-L-tryptophan + dihydropteridine + H2O
-
believed to be the rate-limeting enzyme in the biosynthesis of serotonin in the central nervous system
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
key enzyme of serotonin synthesis in the brain is tryptophan hydroxylase-2
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
TPH catalyzes the first step and rate-limiting reaction in the biosynthesis of 5-hydroxytryptamine, i.e. serotonin, and plays a role in brain and serotonergic neuron development, overview
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
-
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
first and rate-limiting step in serotonin biosynthesis, overview. Serotonin, i.e. 5-hydroxytryptamine, is a neurotransmitter that modulates central and peripheral functions through action on neurons, smooth muscle, and other cell types
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
first and rate-limiting step in serotonin biosynthesis, serotonin, i.e. 5-hydroxytryptamine, is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal sensation, secretion, and motility
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
rate-limiting enzyme in serotonin biosynthesis, mice deficient in peripheral tryptophan hydroxylase and serotonin exhibit a reduced risk of thrombosis and thromboembolism
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
rate-limiting step in serotonin, i.e. 5-hydroxytryptamine, biosynthesis
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
the enzyme is responsible for serotonin biosynthesis
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
TPH catalyzes the first step and rate-limiting reaction in the biosynthesis of 5-hydroxytryptamine, i.e. serotonin, and plays a role in brain and serotonergic neuron development, also TPH1 is involved in behavioural disorders, overview
-
-
?
L-tryptophan + tetrahydrobiopterin + O2
5-hydroxy-L-tryptophan + 4a-hydroxytetrahydrobiopterin
-
TPH is involved in 5-hydroxytryptamine biosynthesis
-
-
?
additional information
?
-
temporal expression pattern of TPH2 and pathway regulation, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH2 and pathway regulation, overview
-
-
?
additional information
?
-
-
emotional behavior and expression pattern tryptophan hydroxylase is altered in senescence-accelerated prone mouse 6, which show increased serotonin levels, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH1 and pathway regulation, overview
-
-
?
additional information
?
-
temporal expression pattern of TPH1 and pathway regulation, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)phenylalanine
-
-
3-amino-3-[4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)phenyl]propanoic acid
-
-
3-[1-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)piperidin-4-yl]alanine
-
-
3-[3-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl]alanine
-
-
3-[5-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)pyridin-2-yl]alanine
-
-
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-2-fluorophenylalanine
-
-
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-a-methylphenylalanine
-
-
4-(5-[[(1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)methyl]amino]pyrazin-2-yl)-L-phenylalanine
-
-
4-(5-[[3-(cyclopentyloxy)-4-methoxybenzyl]amino]pyrazin-2-yl)-L-phenylalanine
-
-
4-[4-amino-6-(2,2,2-trifluoro-1-naphthalen-2-ylethoxy)-1,3,5-triazin-2-yl]-L-phenylalanine
-
-
4-[4-amino-6-(2,2,2-trifluoro-1-[2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]ethoxy)-1,3,5-triazin-2-yl]-L-phenylalanine
-
-
4-[4-amino-6-[2,2,2-trifluoro-1-(2-furan-2-ylphenyl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
-
-
4-[4-amino-6-[2,2,2-trifluoro-1-(3'-methylbiphenyl-2-yl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
-
-
4-[4-amino-6-[2,2,2-trifluoro-1-(5-furan-2-ylthiophen-2-yl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
-
-
D-Dopa
-
noncompetitive vs. L-tryptophan and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
dopamine
-
noncompetitive vs. L-tryptophan and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
L-Dopa
-
noncompetitive vs. L-tryptophan and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
L-tyrosine
-
noncompetitive vs. L-tryptophan and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-L-phenylalanine
-
-
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-L-phenylalanine
-
substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acid, which can selectively reduce serotonin levels in the intestine without affecting levels in the brain. It can selectively inhibit peripheral 5-HT synthesis without effects on the central nervous system because of very poor systemic exposure and the inability to cross the blood-brain barrier
additional information
-
development and pharmacokinetic and pharmacodynamic effects of inhibitors inhibiting specifically the enzyme in the gastrointestinal tract, inhibitory potency on different genotypes, overview
-
additional information
-
development of antithrombotic miniribozymes that target peripheral tryptophan hydroxylase, overview
-
additional information
-
glucocorticoids inhibits TPH2 expression, the suppression is blocked by mifepristone, i.e. RU-486
-
additional information
-
oxidation inhibits activity and leads to the formation of high molecular weight aggregates in a dithiothreitol-reversible manner, only cysteine-less mutants are resistant to this effect
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-mercaptoethylamine
-
30 mM, 93.8% activity compared to activation with dithiothreitol
2-mercaptopropionate
-
30 mM, 11.7% activity compared to activation with dithiothreitol
3-Mercaptopropionate
-
30 mM, 22% activity compared to activation with dithiothreitol
N-acetylcysteine
-
30 mM, 31.2% activity compared to activation with dithiothreitol
2-mercaptoethanol
-
30 mM, 79.3% activity compared to activation with dithiothreitol
dithiothreitol
-
or other sulfhydryl reagents like 2-mercaptoethanol and L-cysteine are essential for activation, 5fold increase in activity
additional information
-
citalopram raises basal extracellular serotonin levels in DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele, but not in C57BL/6J and C57BL/6N mice carrying the 1473C allele, overview
-
additional information
-
enzyme expression and activity are increased in hypoxic rats, the effect is partially reversed by 4-chlorophenylalanine and is reduced in TPH1-deficient rats, overview
-
additional information
-
senescence-accelerated prone mouse 6 show increased serotonin levels, probably due to phosphorylation at Ser58, overview
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.1
L-phenylalanine
-
cofactor 2-amino-4-hydroxy-6-methyltetrahydropteridine
0.0344
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
-
biphasic kinetic, low Km value
0.796
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
-
biphasic kinetic, high Km value
0.055
2-amino-4-hydroxy-6-methyltetrahydropteridine
-
substrate L-tryptophan
0.045
L-tryptophan
-
cofactor 2-amino-4-hydroxy-6-methyltetrahydropteridine
additional information
additional information
kinetic mechanism of isozyme TPH2
-
additional information
additional information
kinetic mechanism of isozyme TPH2
-
additional information
additional information
kinetic mechanism of isozyme TPH1
-
additional information
additional information
kinetic mechanism of isozyme TPH1
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.202
D-Dopa
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with low affinity
0.609
D-Dopa
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with high affinity
0.007
dopamine
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with high affinity
0.0393
dopamine
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with low affinity
0.0803
L-Dopa
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with high affinity
0.0887
L-Dopa
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with low affinity
0.0162
L-tyrosine
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with high affinity
0.306
L-tyrosine
-
vs. (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, component with low affinity
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.011
3-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)phenylalanine
Mus musculus
-
-
0.00377
3-amino-3-[4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)phenyl]propanoic acid
Mus musculus
-
-
0.00077
3-[1-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)piperidin-4-yl]alanine
Mus musculus
-
-
0.0126
3-[3-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl]alanine
Mus musculus
-
-
0.00089
3-[5-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)pyridin-2-yl]alanine
Mus musculus
-
-
0.0002
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-2-fluorophenylalanine
Mus musculus
-
-
0.0111
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-a-methylphenylalanine
Mus musculus
-
-
0.000026 - 0.000032
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-L-phenylalanine
0.000046
4-(5-[[(1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)methyl]amino]pyrazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.000013
4-(5-[[(1-hydroxynaphthalen-2-yl)methyl]amino]pyrazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.00004
4-(5-[[(2'-methylbiphenyl-2-yl)methyl]amino]pyrazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.000031
4-(5-[[(9-ethyl-9H-carbazol-3-yl)methyl]amino]pyrazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.000045
4-(5-[[3-(cyclopentyloxy)-4-methoxybenzyl]amino]pyrazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.00038
4-[4-amino-6-(1-naphthalen-2-ylethoxy)-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.00018
4-[4-amino-6-(2,2,2-trifluoro-1-naphthalen-2-ylethoxy)-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.000029
4-[4-amino-6-(2,2,2-trifluoro-1-[2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]ethoxy)-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.000024
4-[4-amino-6-[2,2,2-trifluoro-1-(2-furan-2-ylphenyl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.00007
4-[4-amino-6-[2,2,2-trifluoro-1-(3'-methylbiphenyl-2-yl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.000054
4-[4-amino-6-[2,2,2-trifluoro-1-(5-furan-2-ylthiophen-2-yl)ethoxy]-1,3,5-triazin-2-yl]-L-phenylalanine
Mus musculus
-
-
0.000026
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-L-phenylalanine
Mus musculus
-
-
0.000032
4-(4-amino-6-[[(1R)-1-naphthalen-2-ylethyl]amino]-1,3,5-triazin-2-yl)-L-phenylalanine
Mus musculus
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.28
additional information
additional information
activities of genetic variants of TPH2 in strains C57BL/6 and CC57BR, and in F2 hybrids of these strains, the C7C genotype shows 2fold higher activity compared to the G/G genotype of the C1473G polymorphism, overview
additional information
-
enzyme activity decreases in 4-, 8-, and 12-week-old mice expressing exon 1 of human huntingtin gene by 62, 61 and 86% respectively compared to control animals
additional information
-
5-HT synthesis rates and tissue contents in normoxic mice harboring the C1473G polymorphism of the Tph2 gene, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
the selective serotonin reuptake inhibitor citalopram has no effect in mice strain that exhibit a reduced 5-hydroxy-L-tryptophan synthesis due to a mutatation in the tryptophan hydroxylase 2
additional information
-
expression pattern of tryptophan hydroxylase in senescence-accelerated prone mouse 6, overview
additional information
-
tissue distribution and expression levels of TPH2 and TPH1 in normoxic and hypoxic wild-type and mutant mice, overview
additional information
-
TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as enterochromaffin cells of the gastrointestinal tract. TPH2, the dominant isozyme in the brain, is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
enzyme-deficient mice have elevated serum tryptophan levels, a normal mast cell compartment and enhanced signaling of mammalian target of rapamycin. Enzyme deficiency exacerbates experimental autoimmune encephalomyelitis
physiological function
-
the enzyme is a potent regulator of immunity regulating immune tolerance and inflammation. The enzyme is essential for the generation of protective T cellmediated antitumor immunity
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). TPH2_MOUSE
488
0
55859
Swiss-Prot
Mitochondrion (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
tryptophan hydroxylase becomes phosphorylated at Ser58 in brain stem of 1-month-old SAMP6
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
P447R
the C1473G naturally occuring polymorphism in gene tph2 is the main factor mediating the genetically defined variability of tryptophan hydroxylase-2 activity in the mouse brain, phenotypes, overview
C110S/C112S/C162S/C234S/C248S/C296S/C315S/C355S/C365S/C394S/C404S/C408S/C476S
-
all 13 cysteine residues mutated
C110S/C162S/C234S/C248S/C296S/C355S/C365S/C394S/C404S/C408S/C476S
-
mutant protein containing a single cysteine residue within the regulatory domain (Cys112) and within the catalytic core domain (Cys315)
C1473G
-
naturally occuring polymorphism of gene Tph2, C57Bl/6 and 129X1/SvJ mice are homozygous for the 1473C allele, whereas DBA/2 and BALB/cJ mice are homozygous for the 1473G allele, comparison of pulmonary hypertension and vascular remodeling of haplotypes, overview
C162S/C234S/C248S/C296S/C315S/C355S/C365S/C394S/C404S/C408S/C476S
-
all cysteine residues of the catalytic core domain mutated
C315S/C355S/C365S/C394S/C404S/C408S/C476S
-
seven C-terminal-most cysteines mutated
G1473C
-
naturally occuring polymorphism, citalopram raises basal extracellular serotonin levels in DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele, but not in C57BL/6J and C57BL/6N mice carrying the 1473C allele, overview
additional information
additional information
-
construction of Tph1 knockout mutant mice, distal pulmonary vessel muscularization is less marked in Tph1-/- than in wild-type mice
additional information
-
generation of Tph1 homozygous null mice from a 129S5/SvEvBrd and C57BL/6J hybrid background
additional information
-
mice deficient in TPH1 and serotonin exhibit a reduced risk of thrombosis and thromboembolism, development of antithrombotic hammerhead miniribozymes with site-specific cleavage activity against short synthetic Tph1 RNA substrates targeting peripheral tryptophan hydroxylase, method development and evaluation, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4
-
complete loss of activity in absence of stabilizing agents after 20 h
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
catalase at a concentration of more than 1 mg/ml is required for stability during reaction at aerobic conditiones
-
NaCl: 1 M, in addition to other stabilizing agents brings a great improvement in stabilization
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, 0.06% Tween 20, 0.05 mM EDTA, 50% ethylene glycol, 1 M NaCl, 5 days, no loss of activity
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant isozymes TPH1 and TPH2 from Escherichia coli by pterin affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
isozyme TPH2, DNA and amino acid sequence determination and analysis, tissue-specific and developmental expression analysis, expression of His6-tagged TPH2 in COS7 cells
genes Tph1 and Tph2, expression analysis in wild-type and mutant mice, overview
-
glutathione S-transferase-fusion protein expressed in Escherichia coli, expressed in HEK293-cell, eGFP-fusion protein expressed in HEK293-cell
-
into pT vector and linearized with Nco I prior to antisense transcription with SP6
-
isozyme TPH1, DNA and amino acid sequence determination and analysis, tissue-specific and developmental expression analysis, expression of His6-tagged TPH1 in COS7 cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is inhibited by a Jak2 inhibitor and partially inhibited by MEK1/2 inhibitor U0126 or PI3K inhibitor LY-294002
-
imipramine increases dorsal raphe TPH2 gene expression in a glucocorticoid-dependent manner, increases are due to relief of inhibitory glucocorticoid signaling
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
-
substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel TPH1 inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hasegawa, H.; Ichiyama, A.
Tryptophan 5-monooxygenase from mouse mastocytoma: high-performance liquid chromatography assay
Methods Enzymol.
142
88-92
1987
Mus musculus
Fujisawa, H.; Nakata, H.
Tryptophan 5-monooxygenase from mouse mastocytoma clone P815
Methods Enzymol.
142
93-96
1987
Mus musculus
Nakata, H.; Fujisawa, H.
Tryptophan 5-monooxygenase from mouse mastocytoma P815. A simple purification and general properties
Eur. J. Biochem.
124
595-601
1982
Mus musculus
Naoi, M.; Maruyama, W.; Takahashi, T.; Ota, M.; Parvez, H.
Inhibition of tryptophan hydroxylase by dopamine and the precursor amino acids
Biochem. Pharmacol.
48
207-211
1994
Mus musculus
Park, D.H.; Stone, D.M.; Kim, K.S.; Joh, T.H.
Characterization of recombinant mouse tryptophan hydroxylase expressed in Escherichia coli
Mol. Cell. Neurosci.
5
87-93
1994
Mus musculus, Rattus norvegicus
Yohrling, I.G.; Jiang, G.C.; DeJohn, M.M.; Robertson, D.J.; Vrana, K.E.; Cha, J.H.
Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease
J. Neurochem.
82
1416-1423
2002
Mus musculus
Walther, D.J.; Peter, J.U.; Bashammakh, S.; Hortnagl, H.; Voits, M.; Fink, H.; Bader, M.
Synthesis of serotonin by a second tryptophan hydroxylase isoform
Science
299
76
2003
Mus musculus (Q8CGV2)
Zhang, X.; Beaulieu, J.M.; Sotnikova, T.D.; Gainetdinov, R.R.; Caron, M.G.
Tryptophan hydroxylase-2 controls brain serotonin synthesis
Science
305
217
2004
Mus musculus (Q8CGV2), Mus musculus
Hasegawa, H.; Ichiyama, A.
Distinctive iron requirement of tryptophan 5-monooxygenase: TPH1 requires dissociable ferrous iron
Biochem. Biophys. Res. Commun.
338
277-284
2005
Homo sapiens, Mus musculus
Zhang, X.; Beaulieu, J.M.; Gainetdinov, R.R.; Caron, M.G.
Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2
Cell. Mol. Life Sci.
63
6-11
2006
Danio rerio, Gallus gallus, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus
Cervo, L.; Canetta, A.; Calcagno, E.; Burbassi, S.; Sacchetti, G.; Caccia, S.; Fracasso, C.; Albani, D.; Forloni, G.; Invernizzi, R.W.
Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression
J. Neurosci.
25
8165-8172
2005
Mus musculus
Izikki, M.; Hanoun, N.; Marcos, E.; Savale, L.; Barlier-Mur, A.M.; Saurini, F.; Eddahibi, S.; Hamon, M.; Adnot, S.
Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice
Am. J. Physiol. Lung Cell. Mol. Physiol.
293
L1045-L1052
2007
Mus musculus
Niimi, K.; Takahashi, E.; Itakura, C.
Emotional behavior and expression patterns of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice
Behav. Brain Res.
188
329-336
2008
Mus musculus
Shi, Z.C.; Devasagayaraj, A.; Gu, K.; Jin, H.; Marinelli, B.; Samala, L.; Scott, S.; Stouch, T.; Tunoori, A.; Wang, Y.; Zang, Y.; Zhang, C.; Kimball, S.D.; Main, A.J.; Sun, W.; Yang, Q.; Nouraldeen, A.; Yu, X.Q.; Buxton, E.; Patel, S.; Nguyen, N.; Swaffield, J.; Powell, D.R.; Wilson, A.; Liu, Q.
Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders
J. Med. Chem.
51
3684-3687
2008
Mus musculus
Calcagno, E.; Canetta, A.; Guzzetti, S.; Cervo, L.; Invernizzi, R.W.
Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity
J. Neurochem.
103
1111-1120
2007
Mus musculus
Liu, Q.; Yang, Q.; Sun, W.; Vogel, P.; Heydorn, W.; Yu, X.Q.; Hu, Z.; Yu, W.; Jonas, B.; Pineda, R.; Calderon-Gay, V.; Germann, M.; ONeill, E.; Brommage, R.; Cullinan, E.; Platt, K.; Wilson, A.; Powell, D.; Sands, A.; Zambrowicz, B.; Shi, Z.C.
Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract
J. Pharmacol. Exp. Ther.
325
47-55
2008
Mus musculus
Peter, J.; Alenina, N.; Bader, M.; Walther, D.J.
Development of antithrombotic miniribozymes that target peripheral tryptophan hydroxylase
Mol. Cell. Biochem.
295
205-215
2007
Mus musculus
Nakamura, K.; Hasegawa, H.
Developmental role of tryptophan hydroxylase in the nervous system
Mol. Neurobiol.
35
45-54
2007
Mus musculus (P17532), Mus musculus (Q8CGV2), Homo sapiens (P17752), Homo sapiens (Q8IWU9)
Clark, J.A.; Flick, R.B.; Pai, L.Y.; Szalayova, I.; Key, S.; Conley, R.K.; Deutch, A.Y.; Hutson, P.H.; Mezey, E.
Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice
Mol. Psychiatry
13
498-506
2008
Homo sapiens (Q8IWU9), Homo sapiens, Mus musculus, Mus musculus C57BL/6, Rattus norvegicus (Q8CGU9)
Kulikov, A.V.; Osipova, D.V.; Popova, N.K.
The C1473G polymorphism in gene tph2 is the main factor mediating the genetically defined variability of tryptophan hydroxylase-2 activity in the mouse brain
Russ. J. Genet.
43
1408-1412
2007
Mus musculus (Q8CGV2)
-
Jin, H.; Cianchetta, G.; Devasagayaraj, A.; Gu, K.; Marinelli, B.; Samala, L.; Scott, S.; Stouch, T.; Tunoori, A.; Wang, Y.; Zang, Y.; Zhang, C.; David Kimball, S.; Main, A.J.; Ding, Z.M.; Sun, W.; Yang, Q.; Yu, X.Q.; Powell, D.R.; Wilson, A.; Liu, Q.; Shi, Z.C.
Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors
Bioorg. Med. Chem. Lett.
19
5229-5232
2009
Mus musculus, Homo sapiens (P17752)
Heydendael, W.; Jacobson, L.
Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphe tryptophan hydroxylase gene expression
Brain Res.
1288
69-78
2009
Mus musculus
Kuhn, D.M.; Sykes, C.E.; Geddes, T.J.; Jaunarajs, K.L.; Bishop, C.
Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: possible link to serotonin deficits and non-motor symptoms in Parkinsons disease
J. Neurochem.
116
426-437
2011
Mus musculus
Matthes, S.; Mosienko, V.; Bashammakh, S.; Alenina, N.; Bader, M.
Tryptophan hydroxylase as novel target for the treatment of depressive disorders
Pharmacology
85
95-109
2010
Homo sapiens, Mus musculus
Nowak, E.C.; de Vries, V.C.; Wasiuk, A.; Ahonen, C.; Bennett, K.A.; Le Mercier, I.; Ha, D.G.; Noelle, R.J.
Tryptophan hydroxylase-1 regulates immune tolerance and inflammation
J. Exp. Med.
209
2127-2135
2012
Mus musculus
Laurent, L.; Deroy, K.; St-Pierre, J.; Cote, F.; Sanderson, J.T.; Vaillancourt, C.
Human placenta expresses both peripheral and neuronal isoform of tryptophan hydroxylase
Biochimie
140
159-165
2017
Homo sapiens, Mus musculus
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