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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/27 01:35:12」(JST)

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GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH₂-3'-TP).

Gene

GTPCH is encoded by the gene GCH1. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all of the variants give rise to a functional enzyme.^[1]

Clinical significance

Mutations in this gene are associated with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as GTP cyclohydrolase I deficiency.^[1] Deficiency of GTP cyclohydrolase I can occur in a recessive and in a dominant form and lead to a lacl of certain neurotrasmitters (dopamine, norepinephrine, epinephrine and serotonin). The dominant form, with mutation in only one of the two alleles for GTP cyclohydrolase I, causes dopamine-responsive dystonia, characterized by childhood-onset dystonia. Patients with the recessive form have mutations in both alleles for GTP cyclohydrolase I. Patients present with developmental delays and neurological dysfunction with trunk hypotonia, hypertonia of the extremities, abnormal movements, tremors, convulsions, and sometimes autonomic dysfunction. ^[2] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). ^[3]

Function

The transcribed protein is the first and rate-limiting enzyme in tetrahydrobiopterin (THB, BH₄) biosynthesis, catalyzing the conversion of GTP into 7,8-DHNP-3'-TP. THB is an essential cofactor required by the aromatic amino acid hydroxylase (AAAH) and nitric oxide synthase (NOS) enzymes in the biosynthesis of the monoamine neurotransmitters serotonin (5-hydroxytryptamine (5-HT)), melatonin, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and nitric oxide (NO), respectively.

References

^ ^a ^b "Entrez Gene: GCH1 GTP Cyclohydrolase 1 (DOPA-Responsive Dystonia).".
^ Longo N (June 2009). "Disorders of biopterin metabolism". J Inherit Metab Dis 32 (2): 333–342. doi:10.1007/s10545-009-1067-2. PMID 19234759.
^ "Patient registry".

External links

GTP Cyclohydrolase I at the US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia

Molecular and Cellular Biology portal

English Journal

Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid.

Gao L, Siu KL, Chalupsky K, Nguyen A, Chen P, Weintraub NL, Galis Z, Cai H.SourceDivision of Molecular Medicine, Cardiovascular Research Laboratories, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E Young Dr, Los Angeles, CA 90095, USA.
Hypertension.Hypertension.2012 Jan;59(1):158-66. doi: 10.1161/HYPERTENSIONAHA.111.181644. Epub 2011 Nov 14.
It has been shown that endothelial NO synthase (eNOS) uncoupling occurs in hypertension and atherosclerosis. However, its causal role in vascular pathogenesis has not been characterized previously. Here, we challenged eNOS preuncoupled hyperphenylalaninemia (hph)-1 mice (deficient in eNOS cofactor t
PMID 22083158

H(2)O(2) increases de novo synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo.

Chavan B, Beazley W, Wood JM, Rokos H, Ichinose H, Schallreuter KU.SourceClinical and Experimental Dermatology/Department of Biomedical Sciences, University of Bradford, Bradford, UK.
Journal of inherited metabolic disease.J Inherit Metab Dis.2009 Feb;32(1):86-94. doi: 10.1007/s10545-008-0971-1. Epub 2008 Dec 22.
Patients with vitiligo accumulate up to 10(-3) mol/L concentrations of H(2)O(2) in their epidermis, which in turn affects many metabolic pathways in this compartment, including the synthesis and recycling of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH(4)). De novo synthesis of 6BH(4
PMID 19101819

Characterization of an Fe(2+)-dependent archaeal-specific GTP cyclohydrolase, MptA, from Methanocaldococcus jannaschii.

Grochowski LL, Xu H, Leung K, White RH.SourceDepartment of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Biochemistry.Biochemistry.2007 Jun 5;46(22):6658-67. Epub 2007 May 12.
The first step in the biosynthesis of pterins in bacteria and plants is the conversion of GTP to 7,8-dihydro-d-neopterin triphosphate catalyzed by GTP cyclohydrolase I (GTPCHI). Although GTP has been shown to be a precursor of pterins in archaea, homologues of GTPCHI have not been identified in most
PMID 17497938

「GTPシクロヒドロラーゼI」

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NCBI	proteins

	The chemical reaction performed by GTPCH. The important carbons relative to the transformation are numbered for reference.
Identifiers
EC number	3.5.4.16
CAS number	37289-19-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins

GTP cyclohydrolase 1
	PDB rendering based on 1fb1.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1FB1
Identifiers
Symbols	GCH1 ; DYT14; DYT5; DYT5a; GCH; GTP-CH-1; GTPCH1; HPABH4B
External IDs	OMIM: 600225 MGI: 95675 HomoloGene: 132 GeneCards: GCH1 Gene
EC number	3.5.4.16
Gene ontology
Molecular function	• GTP cyclohydrolase I activity; • calcium ion binding; • protein binding; • GTP binding; • zinc ion binding; • GTP-dependent protein binding; • protein homodimerization activity; • coenzyme binding;
Cellular component	• nucleus; • nucleoplasm; • cytoplasm; • cytosol; • cytoplasmic vesicle; • nuclear membrane; • protein complex;
Biological process	• tetrahydrobiopterin biosynthetic process; • nitric oxide biosynthetic process; • regulation of blood pressure; • regulation of lung blood pressure; • response to lipopolysaccharide; • response to interferon-gamma; • response to tumor necrosis factor; • 7,8-dihydroneopterin 3'-triphosphate biosynthetic process; • vasodilation; • dopamine biosynthetic process; • pteridine-containing compound biosynthetic process; • small molecule metabolic process; • negative regulation of blood pressure; • nitric oxide metabolic process; • tetrahydrofolate biosynthetic process; • response to pain; • neuromuscular process controlling posture; • regulation of nitric-oxide synthase activity; • positive regulation of nitric-oxide synthase activity; • protein homooligomerization; • protein heterooligomerization;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;