Information on EC 3.5.4.16 - GTP cyclohydrolase I and Organism(s) Homo sapiens and UniProt Accession P30793

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This record set is specific for:
Homo sapiens
UNIPROT: P30793


The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
3.5.4.16
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RECOMMENDED NAME
GeneOntology No.
GTP cyclohydrolase I
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
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C-N bond cleavage
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amidine hydrolysis
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-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
6-hydroxymethyl-dihydropterin diphosphate biosynthesis I
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6-hydroxymethyl-dihydropterin diphosphate biosynthesis IV (Plasmodium)
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drosopterin and aurodrosopterin biosynthesis
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erythro-tetrahydrobiopterin biosynthesis I
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erythro-tetrahydrobiopterin biosynthesis II
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preQ0 biosynthesis
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tetrahydromonapterin biosynthesis
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threo-tetrahydrobiopterin biosynthesis
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sulfopterin metabolism
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tetrahydrofolate metabolism
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Folate biosynthesis
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Metabolic pathways
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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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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus
malfunction
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decreases in GTPCH activity and expression in late stages of acute cardiac rejection due to a deficit in BH4. Mechanism of the decreased rejection appears related to decreased T cell proliferation and modulation of immune function by higher expression of genes involved in hematopoietic/stromal cell development and recruitment
metabolism
physiological function
additional information
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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
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 + 7,8-dihydroneopterin 3'-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 + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
show the reaction diagram
additional information
?
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GTPCH I is the rate-limiting enzyme for de novo tetrahydrobiopterin synthesis
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
GTP + H2O
formate + 7,8-dihydroneopterin 3'-triphosphate
show the reaction diagram
-
-
-
-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)-dihydropteridine triphosphate
show the reaction diagram
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rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, important in the regulation of monoamine neurotransmitters such a s dopamine, norepinephrine, and serotonin
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-
?
GTP + H2O
formate + 2-amino-4-hydroxy-6-(erythro-1,2,3-trihydroxypropyl)dihydropteridine triphosphate
show the reaction diagram
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first step in biosynthesis of tetrahydrobiopterin, BH4
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?
additional information
?
-
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GTPCH I is the rate-limiting enzyme for de novo tetrahydrobiopterin synthesis
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zn2+
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essential for activity, coordinated to a His-side chain of the active site, mechanistic role
Zn2+
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absolutely required, e.g. for activity and reconstitution of the denatured enzyme, 1 Zn2+ bound per subunit of the decameric enzyme
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
8-Aminoguanosine triphosphate
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Co2+
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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
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L-erythro-7,8-dihydrobiopterin
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L-Sepiapterin
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Mg2+
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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+
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inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, overview
tetrahydrobiopterin
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GTP cyclohydrolase I, GTPCH-1, undergoes negative feedback regulation by its endproduct tetrahydrobiopterin via interaction with the GTP cyclohydrolase feedback regulatory protein, GFRP
Zn2+
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inhibition by elimination of the required metal-free GTP when present at high concentration with respect to the GTP concentration, overview
additional information
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no inhibition by EGTA
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
H2O2
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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
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additional information
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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
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
P30793
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
41000
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x * 41000, SDS-PAGE
400000
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low molecular weight form, gel filtration
600000
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high molecular weight form, gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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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
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
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no significant loss of activity after 5 h
80
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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
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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
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expression of GTPCH under the control of a 935-bp fragment of the mouse myosin heavy chain gene promoter
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ENGINEERING
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
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
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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
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
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine