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Information on EC 3.5.4.16 - GTP cyclohydrolase I and Organism(s) Mus musculus and UniProt Accession Q05915
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3.5.4.16 GTP cyclohydrolase IIUBMB Comments
The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit; the recyclization may be non-enzymic. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 4.2.3.12 (6-pyruvoyltetrahydropterin synthase) .
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Word Map
- 3.5.4.16
- tetrahydrobiopterin
- bh4
- endothelial
- dystonia
- hydroxylase
-
dopa-responsive
- dopamine
- sepiapterin
- biopterin
- parkinsonism
- pterins
- pteridine
- catecholamine
- dihydrofolate
- serotonin
-
segawa
- interferon-gamma
-
neurotransmitter
- 2,4-diamino-6-hydroxypyrimidine
- folate
- levodopa
- l-dopa
- ptp
- dihydropteridine
-
dopaminergic
-
diurnal
-
nigrostriatal
-
endothelium-dependent
- striatum
- dahp
- phenylketonuria
- hyperphenylalaninemia
-
cytokine-stimulated
- nutrition
- dihydropteroate
-
ido
- n-acetylserotonin
-
6r-l-erythro-5,6,7,8-tetrahydrobiopterin
- 7,8-dihydrobiopterin
- 6-pyruvoyl-tetrahydropterin
- dihydrobiopterin
- molecular biology
- indoleamine
- tetrahydropterin
- biotechnology
- medicine
-
catecholaminergic
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
Synonyms
gtp cyclohydrolase i, gtpch, gtp cyclohydrolase, gtp cyclohydrolase 1, gtp-ch, gtp-cyclohydrolase i, gch-1, gtpch1, gtpch i, guanosine triphosphate cyclohydrolase i, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dihydroneopterin triphosphate synthase
-
-
-
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GTP 8-formylhydrolase
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-
-
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GTP cyclohydrolase
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-
-
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guanosine triphosphate 8-deformylase
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-
-
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guanosine triphosphate cyclohydrolase
-
-
-
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hydrolase, guanosine triphosphate cyclo-
-
-
-
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Punch protein
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
amidine hydrolysis
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
GTP 7,8-8,9-dihydrolase
The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit; the recyclization may be non-enzymic. This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 4.2.3.12 (6-pyruvoyltetrahydropterin synthase) [3].
CAS REGISTRY NUMBER
COMMENTARY
37289-19-3
-
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
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
-
-
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
-
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
the enzyme is rate limiting in the tetrahydrobiopterin biosynthesis in adipose tissue, overview
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-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
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-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
-
-
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
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the enzyme synthesizes the cofactor for the reaction of the phenylalanine hydroxylase
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-
?
additional information
?
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GTPCH1 via tetrahydrobiopterin maintains normal blood pressure and endothelial function in vivo by preserving nitric oxide synthesis by endothelial NO synthase
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-
?
additional information
?
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tetrahydrobiopterin production by GTPCH I occurs in close proximity to endothelial nitric oxide synthase
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-
?
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
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
the enzyme is rate limiting in the tetrahydrobiopterin biosynthesis in adipose tissue, overview
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
-
the enzyme synthesizes the cofactor for the reaction of the phenylalanine hydroxylase
-
-
?
additional information
?
-
-
GTPCH1 via tetrahydrobiopterin maintains normal blood pressure and endothelial function in vivo by preserving nitric oxide synthesis by endothelial NO synthase
-
-
?
additional information
?
-
-
tetrahydrobiopterin production by GTPCH I occurs in close proximity to endothelial nitric oxide synthase
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
GTP-CH1 activity can be inhibited by tetrahydrobiopterin through its protein-protein interactions with GTP-CH1 regulatory protein
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
lipolysaccharide
commercially isolated from Escherichia coli serotype 026:B6, activates and upregulates the enzyme in adipose tissue, but in cultured 3T3-L1 adipocytes lipolysaccharide addition only increases the enzyme expression level in presence of TNFalpha and interferon gamma, overview
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additional information
-
GTPCH expression is regulated by inflammatory stimuli, in association with reduced expression of GTP cyclohydrolase feedback regulatory protein
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additional information
-
reduction in GTP-CH1 regulatory protein expression following proinflammatory stimulation is necessary for optimal GTP-CH1 activity
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
tissue dependent enzyme activity and effects of cytokines
additional information
-
tissue dependent enzyme activity and effects of cytokines
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
cardiac GTP cyclohydrolase 1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins
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transfected with a tet-off plasmid and a plasmid encoding human GCH1, the stable clone is named tet-GCH cell
additional information
cardiomyocyte GTP cyclohydrolase 1 protects the heart against diabetic cardiomyopathy
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
GTPCH I is also co-localized with caveolin-1 to caveolar membrane microdomains of endothelial cells
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
cardiac GTP cyclohydrolase 1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Overexpression of GTP cyclohydrolase 1 decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts
malfunction
-
decreases in GTPCH activity and expression in late stages of acute cardiac rejection due to a deficit in BH4
metabolism
physiological function
metabolism
-
GTPCH I is the rate-limiting enzyme for de novo tetrahydrobiopterin synthesis
metabolism
-
GTP cyclohydrolase I is the rate-limiting enzyme for tetrahydrobiopterin synthesis
physiological function
-
endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing in streptozotocin-induced type 1 diabetic mice through enhanced constitutive NOS activity and suppressed oxidative stress
physiological function
-
GTP cyclohydrolase I is the rate-limiting enzyme for tetrahydrobiopterin synthesis. Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection
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). GCH1_MOUSE
241
0
27014
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
construction of transgenic tomato plants expressing GCHI for engineering of the pteridine branch of folate synthesis in Lycopersicon esculentum by folate biofortification, the transgenic plants accumulate increased levels of folate after application of exogenous 4-aminobenzoate, overview
additional information
-
construction of transgenic mice overexpressing the enzyme specifically in the skin together with phenylalanine hydroxylase, the clearance of phenylalanine from blood is increased in transgenic mice, measured in those with phenylketonuria, mice genotyping, overview
additional information
-
GTP cyclohydrolase feedback regulatory protein overexpression and knockdown in tet-GCH cells does not alter GTPCH activity or tetrahydrobiopterin levels, and GTPCH-specific knockdown in sEnd.1 endothelial cells has no effect on GTP cyclohydrolase feedback regulatory protein
additional information
-
wild-type and transgenic human GTPCH-overexpressing murine donor hearts are transplanted into BALB/c recipient mice via pronuclear injection of oocytes. Cardiac myocyte GTPCH overexpression inhibits cardiac graft rejection, phenotype, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of the enzyme in transgenic Lycopersicon esculentum plants using the Agrobacterium tumefaciens transfection system
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
biotechnology
construction of transgenic tomato plants expressing GCHI for engineering of the peteridine branch of folate synthesis in Lycopersicon esculentum by folate biofortification, overview
medicine
cardiomyocyte GTP cyclohydrolase 1 is a therapeutic target for cardiac remodeling and dysfunction after myocardial infarction
nutrition
construction of transgenic tomato plants expressing GCHI for engineering of the peteridine branch of folate synthesis in Lycopersicon esculentum by folate biofortification, overview
biotechnology
-
creation of a phenylalanine sink by transgenic overexpression of phenylalnine hydroxylase and GTP cyclohydrolase I in the skin to reduce high phenylalanine concentrations in the blood in phenylketonuria metabolic disease
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Cha, K.W.; Jacobson, K.B.; Yim, J.J.
Isolation and characterization of GTP cyclohydrolase I from mouse liver. Comparison of normal and the hph-1 mutant
J. Biol. Chem.
266
12294-12300
1991
Mus musculus
Fujiwara, K.; Mori, K.; Kaneko, Y.S.; Nakashima, A.; Nagasaka, A.; Itoh, M.; Ota, A.
Tetrahydrobiopterin biosynthesis in white and brown adipose tissues is enhanced following intraperitoneal administration of bacterial lipopolysaccharide
Biochim. Biophys. Acta
1670
181-198
2004
Mus musculus (Q05915), Mus musculus
Christensen, R.; Alhonen, L.; Wahlfors, J.; Jakobsen, M.; Jensen, T.G.
Characterization of transgenic mice with the expression of phenylalanine hydroxylase and GTP cyclohydrolase I in the skin
Exp. Dermatol.
14
535-542
2005
Mus musculus
Diaz de la Garza, R.; Quinlivan, E.P.; Klaus, S.M.; Basset, G.J.; Gregory, J.F.; Hanson, A.D.
Folate biofortification in tomatoes by engineering the pteridine branch of folate synthesis
Proc. Natl. Acad. Sci. USA
101
13720-13725
2004
Mus musculus (Q05915)
Eells, J.B.; Misler, J.A.; Nikodem, V.M.
Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice
Brain Res. Bull.
70
186-195
2006
Mus musculus
Liao, S.J.; Lin, L.; Zeng, J.S.; Huang, R.X.; Channon, K.M.; Chen, A.F.
Endothelium-targeted transgenic GTP-cyclohydrolase I overexpression inhibits neointima formation in mouse carotid artery
Clin. Exp. Pharmacol. Physiol.
34
1260-1266
2007
Mus musculus, Mus musculus C57BL/6
Wang, S.; Xu, J.; Song, P.; Wu, Y.; Zhang, J.; Chul Choi, H.; Zou, M.H.
Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure
Hypertension
52
484-490
2008
Bos taurus, Mus musculus
Peterson, T.E.; dUscio, L.V.; Cao, S.; Wang, X.L.; Katusic, Z.S.
Guanosine triphosphate cyclohydrolase I expression and enzymatic activity are present in caveolae of endothelial cells
Hypertension
53
189-195
2009
Mus musculus
Tatham, A.L.; Crabtree, M.J.; Warrick, N.; Cai, S.; Alp, N.J.; Channon, K.M.
GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression
J. Biol. Chem.
284
13660-13668
2009
Mus musculus
Nandi, M.; Kelly, P.; Vallance, P.; Leiper, J.
Over-expression of GTP-cyclohydrolase 1 feedback regulatory protein attenuates LPS and cytokine-stimulated nitric oxide production
Vasc. Med.
13
29-36
2008
Mus musculus
Tie, L.; Li, X.J.; Wang, X.; Channon, K.M.; Chen, A.F.
Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes
Am. J. Physiol. Endocrinol. Metab.
296
E1423-E1429
2009
Mus musculus
Ionova, I.A.; Vasquez-Vivar, J.; Cooley, B.C.; Khanna, A.K.; Whitsett, J.; Herrnreiter, A.; Migrino, R.Q.; Ge, Z.D.; Regner, K.R.; Channon, K.M.; Alp, N.J.; Pieper, G.M.
Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection
Am. J. Physiol. Heart Circ. Physiol.
299
H88-H96
2010
Homo sapiens, Mus musculus, Mus musculus C57BL6
Wu, H.E.; Baumgardt, S.L.; Fang, J.; Paterson, M.; Liu, Y.; Du, J.; Shi, Y.; Qiao, S.; Bosnjak, Z.J.; Warltier, D.C.; Kersten, J.R.; Ge, Z.D.
Cardiomyocyte GTP cyclohydrolase 1 protects the heart against diabetic cardiomyopathy
Sci. Rep.
6
27925
2016
Mus musculus (Q05915), Mus musculus
Liu, Y.; Baumgardt, S.L.; Fang, J.; Shi, Y.; Qiao, S.; Bosnjak, Z.J.; Vasquez-Vivar, J.; Xia, Z.; Warltier, D.C.; Kersten, J.R.; Ge, Z.D.
Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling
Sci. Rep.
7
3093
2017
Mus musculus (Q05915)
EXTERNAL LINKS (specific for EC-Number 3.5.4.16)
Transporter Classification Database (TCDB): 9.B.10.1.1
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