Information on EC 3.5.4.16 - GTP cyclohydrolase I and Organism(s) Rattus norvegicus and UniProt Accession P22288

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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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This record set is specific for:
Rattus norvegicus
UNIPROT: P22288
Word Map
The taxonomic range for the selected organisms is: Rattus norvegicus
The enzyme appears in selected viruses and cellular organisms
Synonyms
dihydroneopterin triphosphate synthase, FelE, folE, GCH, GCH-1, GCH1, GCHI, GCYH-IA, GCYH-IB, GTP 8-formylhydrolase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dihydroneopterin triphosphate synthase
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-
-
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GTP 8-formylhydrolase
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-
-
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GTP cyclohydrolase
-
-
-
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GTP-cyclohydrolase 1
296405
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GTP-cyclohydrolase I
248
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GTPCH1
296405
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GTPCHI
248
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guanosine triphosphate 8-deformylase
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-
-
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guanosine triphosphate cyclohydrolase
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-
-
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guanosine triphosphate cyclohydrolase I
248
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hydrolase, guanosine triphosphate cyclo-
-
-
-
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Punch protein
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
GTP + H2O = formate + 7,8-dihydroneopterin 3'-triphosphate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
amidine hydrolysis
-
-
-
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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
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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
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-
-
?
GTP + H2O
dihydroneopterin triphosphate + formate
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 + 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
-
-
-
-
?
GTP + H2O
formate + D-erythro-dihydroneopterin triphosphate
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
GTP + H2O
dihydroneopterin triphosphate + formate
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 + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
show the reaction diagram
GTP + H2O
formate + D-erythro-dihydroneopterin triphosphate
show the reaction diagram
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first step of the biosynthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, i.e. BH4
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-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
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activates
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
2,4-Diamino-6-hydroxypyrimidine
dihydrobiopterin
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induction of feedback inhibition, binding site structure
GTP
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substrate inhibition above 0.2 mM
GTP cyclohydrolase I feedback regulatory protein GFRP
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natural inhibitor, inhibition mechanism, in vitro inhibition together with 2,4-diamino-6-hydroxypyrimidine, the inhibition is fully reversible by L-phenylalanine, regulatory function in physiological feedback inhibition, overview
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GTPCH feedback regulatory protein
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GFRP, the allosteric regulatory protein GFRP triggers a noncompetitive attenuation of GTPCH activity, an allosteric effector is unnecessary for GFRP to influence GTPCH activity. GFRP-mediated allosteric regulation by small molecule effectors is indistinguishable for truncated mutant DELTA45-GTPCH and wild-type GTPCH
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L-erythro-5,6,7,8-tetrahydrobiopterin
streptozotocin
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the expression of GCH-I is decreased by streptozotocin treatment (60 mg/kg iv, 7 weeks)
tetrahydrobiopterin
additional information
-
the N-terminal peptide of mammalian GTP cyclohydrolase I is an autoinhibitory control element and contributes to binding the allosteric regulatory protein GFRP. The autoinhibitory peptide provides a molecular mechanism for physiological up-regulation of GTPCH activity
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
17beta-estradiol
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can regulate GTPCH gene expression via transcriptional mechanisms
L-phenylalanine
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0179 - 0.075
GTP
additional information
additional information
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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inhibition kinetics
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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
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assay at
additional information
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
Uniprot
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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multimeric assemblies of wild-type GTPCH and truncation mutant DELTA45-GTPCH on their own display markedly different banding patterns
metabolism
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
GCH1_RAT
241
0
27057
Swiss-Prot
other Location (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
260000
-
GTP cyclohydrolase I
30000
-
SDS-PAGE
50000
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GFRP
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 30000, SDS-PAGE
decamer
pentamer
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GTP cyclohydrolase I feedback regulatory protein, i.e. GFRP
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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GCH-1 has 8 potential phosphorylation sites (Ser51, Ser72, Thr85, Thr91, Thr103, Ser130, Ser167, and Thr231). Overexpressed rat GCH-1 is phosphorylated at Ser51, Ser167, and Thr231 in HEK-293 cells
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
5 mg/ml enzyme subunit GTP cyclohydrolase I feedback regulatory protein, i.e. GFRP, free and complexed with the human catalytic subunit of the enzyme, batch procedure, at 4°C overnight, total reflection X-ray fluorescence spectrometry, structure determination and analysis at 2.6 A resolution, modeling
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crystallization of purified recombinant enzyme and protein GFRP forming a BH2-induced inhibitory complex, involving dGTP, in 14% isopropanol, 0.2 M ammonium sulfate, 10% PEG 300, 10% ethylene glycol, 0.1 M MES-Na, pH 6.0, rapid freezing of crystals in liquid nitrogen, X-ray diffraction structure determination and analysis at 2.8 A resolution
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purified recombinant enzyme complexed with recombinant wild-type and selenomethionine derivatized GFRP, the complex with the latter being used as CH3HGCl derivative, 5 mg/ml protein complex in 24% v/v 2-methyl-2,4-pentanediol, 75 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM phenylalanine, X-ray diffraction structure determination and analysis at 2.7-2.8 A resolution, model building
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S130A
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phospho-defective mutant with significantly decreased GCH-1 activity
S72A
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phospho-defective mutant with significantly decreased GCH-1 activity
T103A
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phospho-defective mutant with significantly decreased GCH-1 activity
T231A
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mutant with 23% increased GCH-1 activity but reduced GCH-1 nuclear localization and nuclear GCH-1 activity
T85A
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phospho-defective mutant with 67% decreased GCH-1 activity
T91A
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phospho-defective mutant with significantly decreased GCH-1 activity
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
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no significant loss of activity after 5 h
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, 6 months, stable
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
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GCH1 in complexes with cellular proteins from organs liver, heart, brain, and kidney, by immunoaffinity chromatography, isolation of mitochondria from liver, heart and kidney
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recombinant His-tagged wild-type GTPCH maltose-binding protein fusion protein from Escherichia coli by amylose affinity chromatography and cleavage of the fusion tag by TEV protease, purification of His-tagged DELTA45-GTPCH mutant from HEK-293 cells by metal affinity chromatography
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recombinant maltose binding protein fusion enzyme fromn Escherichia coli strain DH5alpha
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in HEK-293 cells
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expressed in PC-12 cells
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expression in Escherichia coli
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expression of His-tagged wild-type GTPCH as maltose-binding protein fusion protein in Escherichia coli, expression of a His-tagged GTPCH truncation mutant, devoid of 45 N-terminal amino acids, DELTA45-GTPCH, in HEK-293 cells
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expression of the enzyme in Escherichia coli strain DH5alpha as maltose binding protein fusion protein
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transient co-expression of the enzyme with estrogen receptors in PC12 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
tetracycline stimulation substantially increases GCH-1 activity about 20fold
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the autoinhibitory peptide provides a molecular mechanism for physiological up-regulation of GTPCH activity
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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.
GTP-cyclohydrolases: a review
J. Clin. Chem. Clin. Biochem.
23
169-176
1985
Geobacillus stearothermophilus, Comamonas sp., Escherichia coli, Lactiplantibacillus plantarum, Mammalia, Rattus norvegicus, Serratia indica
Manually annotated by BRENDA team
Blau, N.; Niederwieser, A.
GTP-cyclohydrolases: mini-review
Biochem. Clin. Aspects Pteridines
3
77-92
1984
Geobacillus stearothermophilus, Gallus gallus, Comamonas sp., Drosophila melanogaster, Escherichia coli, Lactiplantibacillus plantarum, Rattus norvegicus, Serratia indica
-
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
Xie, L.; Smith, J.A.; Gross, S.S.
GTP cyclohydrolase I inhibition by the prototypic inhibitor 2,4-diamino-6-hydroxypyrimidine
J. Biol. Chem.
273
21091-21098
1998
Rattus norvegicus
Manually annotated by BRENDA team
Yoneyama, T.; Brewers, J.M.; Hatakeyama, K.
GTP cyclohydrolase I feedback regulatory protein is a pentamer of identical subunits
J. Biol. Chem.
272
9690-9696
1997
Rattus norvegicus
Manually annotated by BRENDA team
Milstien, S.; Jaffe, H.; Kowlessu, D.; Bonner, T.I.
Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein, GFRP
J. Biol. Chem.
271
19743-19751
1996
Rattus norvegicus
Manually annotated by BRENDA team
Hattori, Y.; Gross, S.S.
GTP cyclohydrolase I mRNA is induced by LPS in vascular smooth muscle: Characterization, sequence and relationship to nitric oxide synthase
Biochem. Biophys. Res. Commun.
195
435-441
1993
Rattus norvegicus
Manually annotated by BRENDA team
Maita, N.; Hatakeyama, K.; Okada, K.; Hakoshima, T.
Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory proteins
J. Biol. Chem.
279
51534-51540
2004
Rattus norvegicus
Manually annotated by BRENDA team
Bader, G.; Schiffmann, S.; Herrmann, A.; Fischer, M.; Gutlich, M.; Auerbach, G.; Ploom, T.; Bacher, A.; Huber, R.; Lemm, T.
Crystal structure of rat GTP cyclohydrolase I feedback regulatory protein, GFRP
J. Mol. Biol.
312
1051-1057
2001
Rattus norvegicus
Manually annotated by BRENDA team
Maita, N.; Okada, K.; Hatakeyama, K.; Hakoshima, T.
Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP
Proc. Natl. Acad. Sci. USA
99
1212-1217
2002
Rattus norvegicus
Manually annotated by BRENDA team
Yoneyama, T.; Hatakeyama, K.
Ligand binding to the inhibitory and stimulatory GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complexes
Protein Sci.
10
871-878
2001
Rattus norvegicus
Manually annotated by BRENDA team
Hung, Y.C.; Tsai, P.S.; Huang, C.J.; Yang, S.; Skimming, J.W.; Hsieh, M.C.
Change in expression of the guanosine triphosphate cyclohydrolase I in LPS-stimulated rats is tissue specific
Acta Anaesthesiol. Taiwan.
42
23-31
2004
Rattus norvegicus
Manually annotated by BRENDA team
Kolinsky, M.A.; Gross, S.S.
The mechanism of potent GTP cyclohydrolase I inhibition by 2,4-diamino-6-hydroxypyrimidine: requirement of the GTP cyclohydrolase I feedback regulatory protein
J. Biol. Chem.
279
40677-40682
2004
Rattus norvegicus
Manually annotated by BRENDA team
Serova, L.I.; Filipenko, M.; Schilt, N.; Veerasirikul, M.; Sabban, E.L.
Estrogen-triggered activation of GTP cyclohydrolase 1 gene expression: Role of estrogen receptor subtypes and interaction with cyclic AMP
Neuroscience
140
1253-1263
2006
Rattus norvegicus
Manually annotated by BRENDA team
Seujange, Y.; Eiam-Ong, S.; Tirawatnapong, T.; Eiam-Ong, S.
Role of angiotensin II on dihydrofolate reductase, GTP-cyclohydrolase 1 and nitric oxide synthase expressions in renal ischemia-reperfusion
Am. J. Nephrol.
28
692-700
2008
Rattus norvegicus (P22288), Rattus norvegicus
Manually annotated by BRENDA team
Wenzel, P.; Schulz, E.; Oelze, M.; Mueller, J.; Schuhmacher, S.; Alhamdani, M.S.; Debrezion, J.; Hortmann, M.; Reifenberg, K.; Fleming, I.; Muenzel, T.; Daiber, A.
AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats
Free Radic. Biol. Med.
45
619-626
2008
Rattus norvegicus
Manually annotated by BRENDA team
Du, J.; Wei, N.; Xu, H.; Ge, Y.; Vasquez-Vivar, J.; Guan, T.; Oldham, K.T.; Pritchard, K.A.; Shi, Y.
Identification and functional characterization of phosphorylation sites on GTP cyclohydrolase I
Arterioscler. Thromb. Vasc. Biol.
29
2161-2168
2009
Rattus norvegicus
Manually annotated by BRENDA team
Du, J.; Xu, H.; Wei, N.; Wakim, B.; Halligan, B.; Pritchard, K.A.; Shi, Y.
Identification of proteins interacting with GTP cyclohydrolase I
Biochem. Biophys. Res. Commun.
385
143-147
2009
Rattus norvegicus
Manually annotated by BRENDA team
Higgins, C.E.; Gross, S.S.
The N-terminal peptide of mammalian GTP cyclohydrolase I is an autoinhibitory control element and contributes to binding the allosteric regulatory protein GFRP
J. Biol. Chem.
286
11919-11928
2011
Rattus norvegicus
Manually annotated by BRENDA team
Du, J.; Teng, R.J.; Lawrence, M.; Guan, T.; Xu, H.; Ge, Y.; Shi, Y.
The protein partners of GTP cyclohydrolase I in rat organs
PLoS ONE
7
e33991
2012
Rattus norvegicus, Rattus norvegicus Sprague Dawley
Manually annotated by BRENDA team
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