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Information on EC 3.5.4.16 - GTP cyclohydrolase I and Organism(s) Homo sapiens

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EC Tree
IUBMB 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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Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
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
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dihydroneopterin triphosphate synthase
-
-
-
-
GTP 8-formylhydrolase
-
-
-
-
GTP cyclohydrolase
-
-
-
-
GTP cyclohydrolase 1
GTP cyclohydrolase I
-
-
GTP cyclohydrolase-1
-
-
GTP-cyclohydrolase I
-
-
GTPCH I
-
-
GTPCH-1
-
-
GTPCHI
-
-
guanosine triphosphate 8-deformylase
-
-
-
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guanosine triphosphate cyclohydrolase
-
-
-
-
hydrolase, guanosine triphosphate cyclo-
-
-
-
-
Punch protein
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
GTP + H2O = formate + 7,8-dihydroneopterin 3'-triphosphate
show the reaction diagram
The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit, the recyclization may be non-enzymic, reaction mechanism
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
amidine hydrolysis
-
-
-
-
C-N bond cleavage
-
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 hide
37289-19-3
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
show the reaction diagram
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
show the reaction diagram
GTP + H2O
formate + 7,8-dihydroneopterin 3'-triphosphate
show the reaction diagram
-
-
-
?
additional information
?
-
-
GTPCH I is the rate-limiting enzyme for de novo tetrahydrobiopterin synthesis
-
-
?
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
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
show the reaction diagram
-
rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, important in the regulation of monoamine neurotransmitters such a s dopamine, norepinephrine, and serotonin
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
show the reaction diagram
-
first step in biosynthesis of tetrahydrobiopterin, BH4
-
?
GTP + H2O
formate + 7,8-dihydroneopterin 3'-triphosphate
show the reaction diagram
-
-
-
?
additional information
?
-
-
GTPCH I is the rate-limiting enzyme for de novo tetrahydrobiopterin synthesis
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
8-Aminoguanosine triphosphate
-
-
Co2+
-
inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, overview
GTP cyclohydrolase feedback regulatory protein
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i.e. GFRP, GTP cyclohydrolase I, GTPCH-1, undergoes negative feedback regulation by its endproduct tetrahydrobiopterin via interaction with the GTP cyclohydrolase feedback regulatory protein, GFRP. GFRP binding increased the apparent Km of GTPCH-1, which also contributes to inhibition and increases the cooperativity of substrate binding in the wild-type but not the S81D mutant. GFRP both inhibits and stimulates GTPCH-1 activity in vitro depending on interactions with either tetrahydrobiopterin or phenylalanine. GTPCH-1 phosphorylation reduces its binding to GFRP
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H2O2
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more than 0.3 mM H2O2 result in a decrease in activity of GTPCHI, the function of the GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complex is not affected by H2O2
L-erythro-5,6,7,8-tetrahydrobiopterin
-
-
L-erythro-7,8-dihydrobiopterin
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-
L-Sepiapterin
-
-
Mg2+
-
inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, formation of Mg-GTP, overview
Mn2+
-
inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, overview
tetrahydrobiopterin
-
GTP cyclohydrolase I, GTPCH-1, undergoes negative feedback regulation by its endproduct tetrahydrobiopterin via interaction with the GTP cyclohydrolase feedback regulatory protein, GFRP
Zn2+
-
inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, overview
additional information
-
no inhibition by EGTA
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
H2O2
-
0.1 mM H2O2 is the optimum concentration for the activation of GTPCHI
interferon-gamma
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GCH1 expression is strongly induced by a mixture of interleukin-1beta, tissue necrosis factor-alpha, and interferon-gamma released by microglia under brain-damaging conditions
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interleukin-1beta
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GCH1 expression is strongly induced by a mixture of interleukin-1beta, tissue necrosis factor-alpha, and interferon-gamma released by microglia under brain-damaging conditions
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L-phenylalanine
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feedback regulation via L-phenylalanine
tissue necrosis factor-alpha
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GCH1 expression is strongly induced by a mixture of interleukin-1beta, tissue necrosis factor-alpha, and interferon-gamma released by microglia under brain-damaging conditions
-
additional information
-
S81 phosphorylation enhances GTPCH-1 enzyme activity
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.031
GTP
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-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
additional information
-
adult cardiac myocytes despite expression of GTPCH mRNA and protein have a defective basal and cytokine-stimulated synthesis of BH4 via the de novo synthesis pathway and impaired synthesis via the salvage pathway in contrast with that typically seen in neonatal cardiac myocytes
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
GCH1_HUMAN
250
0
27903
Swiss-Prot
other Location (Reliability: 2)
Q96T74_HUMAN
78
0
8837
TrEMBL
other Location (Reliability: 4)
Q8IZH7_HUMAN
101
0
11324
TrEMBL
other Location (Reliability: 4)
Q8IZH8_HUMAN
158
0
17880
TrEMBL
other Location (Reliability: 4)
Q8IZH9_HUMAN
177
0
19971
TrEMBL
other Location (Reliability: 4)
A0A024R642_HUMAN
250
0
27903
TrEMBL
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
400000
-
low molecular weight form, gel filtration
41000
-
x * 41000, SDS-PAGE
600000
-
high molecular weight form, gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
x * 41000, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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S81 phosphorylation enhances GTPCH-1 enzyme activity, GFRP modulates phosphorylation of GTPCH-1, and GTPCH-1 phosphorylation reduces its binding to GFRP, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
4.6 mg/ml purified recombinant DELTA42-hGTP-CH-I in 0.1 M potassium phosphate, pH 7.0, 0.02% NaN3, mixed with precipitation solution containing 6% PEG 6000, 150 mM KCl, 100 mM MOPS, pH 7.0, equilibration against precipitant solution, X-ray diffraction strcuture determination and analysis at 3.1 A resolution, modeling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C265T
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mutation results in the loss of the 177 C-terminal amino acids
G155S
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the mutation is associated with Dopa-responsive dystonia in Chines Han population
G201E
M211I
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low activity at 0.1 mM GTP
R184H
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very low activity at 0.1 mM GTP
R88W
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very low activity at 0.1 mM GTP
S81A
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site-directed mutagenesis, the mutant shows enhanced interaction with GFRP both in the presence of BH4 and GTP compared to the wild-type enzyme
S81D
-
site-directed mutagenesis, phospho-mimetic mutant that shows increased enzyme activity, reduced binding to GFRP, and resistance to inhibition by GFRP compared to wild-type GTPCH-1
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
no significant loss of activity after 5 h
80
-
human liver enzyme, half-life: 2 min
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70°C
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-80°C, 6 months, stable
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4°C, extreme instability of purified enzyme
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of wild-type and mutant proteins in Escherichia coli
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recombinant DELTA42-hGTP-CH-I from Escherichia coli M15
two forms
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 cells
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expressed in Escherichia coli, baby hamster kidney cells, and NIH-293 cells
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expressed in Mus musculus
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expressed in Mus musculus microvascular endothelial cells
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expression in Escherichia coli
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expression of DELTA42-hGTP-CH-I in Escherichia coli M15
expression of GTPCH under the control of a 935-bp fragment of the mouse myosin heavy chain gene promoter
-
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
denaturation of the purified recombinant enzyme by 4 M guanidine hydrochloride for 30 min, refolding of denatured enzyme by 100fold dilution in presence of GroE, a chaperone protein, effects of ZnSO4 and EGTA on refolding and activity
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schoedon, G.; Curtis, H.C.; Niederwieser, A.
Localization of GTP cyclohydrolase I in human peripheral blood smears using a specific monoclonal antibody and an immune-alkaline phosphatase labeling technique
Biochem. Biophys. Res. Commun.
148
1232-1236
1987
Homo sapiens
Manually annotated by BRENDA team
Sawada, M.; Horikoshi, T.; Masada, M.; Akino, M.; Sugimoto, T.M.; Matsuura, S.; Nagatsu, T.
A sensitive assay of GTP cyclohydrolase I activity in rat and human tissues using radioimmunoassay of neopterin
Anal. Biochem.
154
361-366
1986
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Blau, N.; Niederwieser, A.
The application of 8-aminoguanosine triphosphate, a new inhibitor of GTP cyclohydrolase I, to the purification of the enzyme from human liver
Biochim. Biophys. Acta
880
26-31
1986
Homo sapiens
Manually annotated by BRENDA team
Hatakeyama, K.; Harada, T.; Kagamiyama, H.
IMP dehydrogenase inhibitors reduce intracellular tetrahydrobiopterin levels through reduction of intracellular GTP levels
J. Biol. Chem.
267
20734-20739
1992
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Sakamoto, H.; Fujita, K.; Idegame, M.; Teradaira, R.; Kuzuya, H.
Different complex forms of human liver GTP cyclohydrolase I
Biogenic Amines
12
55-67
1996
Homo sapiens
-
Manually annotated by BRENDA team
Suzuki, T.; Ohye, T.; Inagaki, H.; Nagatsu, T.; Ichinose, H.
Characterization of wild-type and mutants of recombinant human GTP-cyclohydrolase I: Relationship to etiology of dopa-responsive dystonia
J. Neurochem.
73
2510-2516
1999
Homo sapiens
Manually annotated by BRENDA team
Suzuki, T.; Kurita, H.; Ichinose, H.
GTP cyclohydrolase I utilizes metal-free GTP as its substrate
Eur. J. Biochem.
271
349-355
2004
Homo sapiens
Manually annotated by BRENDA team
Auerbach, G.; Herrmann, A.; Bracher, A.; Bader, G.; Gutlich, M.; Fischer, M.; Neukamm, M.; Garrido-Franco, M.; Richardson, J.; Nar, H.; Huber, R.; Bacher, A.
Zinc plays a key role in human and bacterial GTP cyclohydrolase I
Proc. Natl. Acad. Sci. USA
97
13567-13572
2000
Escherichia coli, Homo sapiens (P30793), Homo sapiens
Manually annotated by BRENDA team
Zhang, L.; Rao, F.; Zhang, K.; Khandrika, S.; Das, M.; Vaingankar, S.M.; Bao, X.; Rana, B.K.; Smith, D.W.; Wessel, J.; Salem, R.M.; Rodriguez-Flores, J.L.; Mahata, S.K.; Schork, N.J.; Ziegler, M.G.; OConnor, D.T.
Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk
J. Clin. Invest.
117
2658-2671
2007
Homo sapiens (P30793), Homo sapiens
Manually annotated by BRENDA team
Lopez-Laso, E.; Camino, R.; Mateos, M.E.; Perez-Navero, J.L.; Ochoa, J.J.; Lao-Villadoniga, J.I.; Ormazabal, A.; Artuch, R.
Dopa-responsive infantile hypokinetic rigid syndrome due to dominant guanosine triphosphate cyclohydrolase 1 deficiency
J. Neurol. Sci.
256
90-93
2007
Homo sapiens
Manually annotated by BRENDA team
Wang, W.; Zolty, E.; Falk, S.; Summer, S.; Zhou, Z.; Gengaro, P.; Faubel, S.; Alp, N.; Channon, K.; Schrier, R.
Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1
Am. J. Physiol. Renal Physiol.
294
F571-F576
2008
Homo sapiens
Manually annotated by BRENDA team
Chiou, Y.W.; Hwu, W.L.; Lee, Y.M.
Hsp27 decreases inclusion body formation from mutated GTP-cyclohydrolase I protein
Biochim. Biophys. Acta
1782
169-179
2008
Homo sapiens
Manually annotated by BRENDA team
Du, Y.H.; Guan, Y.Y.; Alp, N.J.; Channon, K.M.; Chen, A.F.
Endothelium-specific GTP cyclohydrolase I overexpression attenuates blood pressure progression in salt-sensitive low-renin hypertension
Circulation
117
1045-1054
2008
Homo sapiens
Manually annotated by BRENDA team
Souza, C.P.; Valadares, E.R.; Trindade, A.L.; Rocha, V.L.; Oliveira, L.R.; Godard, A.L.
Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family
Genet. Mol. Res.
7
687-694
2008
Homo sapiens
Manually annotated by BRENDA team
Chavan, B.; Beazley, W.; Wood, J.M.; Rokos, H.; Ichinose, H.; Schallreuter, K.U.
H2O2 increases de novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo
J. Inherit. Metab. Dis.
32
86-94
2009
Homo sapiens
Manually annotated by BRENDA team
Chiarini, A.; Armato, U.; Pacchiana, R.; Dal Pra, I.
Proteomic analysis of GTP cyclohydrolase 1 multiprotein complexes in cultured normal adult human astrocytes under both basal and cytokine-activated conditions
Proteomics
9
1850-1860
2009
Homo sapiens
Manually annotated by BRENDA team
Hu, F.Y.; Xu, Y.M.; Yu, L.H.; Ma, M.Y.; He, X.H.; Zhou, D.
A novel missense mutation in GTP cyclohydrolase I (GCH1) gene causes dopa-responsive dystonia in Chinese Han population
Eur. J. Neurol.
18
362-364
2011
Homo sapiens
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
Li, L.; Rezvan, A.; Salerno, J.; Husain, A.; Kwon, K.; Jo, H.; Harrison, D.; Chen, W.
GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide
Circ. Res.
106
328-336
2010
Homo sapiens
Manually annotated by BRENDA team
Wolkow, P.P.; Kosiniak-Kamysz, W.; Osmenda, G.; Wilk, G.; Bujak-Gizycka, B.; Ignacak, A.; Kanitkar, M.; Walus-Miarka, M.; Harrison, D.G.; Korbut, R.; Malecki, M.T.; Guzik, T.J.
GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus
PLoS ONE
9
e108587
2014
Homo sapiens (P30793), Homo sapiens
Manually annotated by BRENDA team