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the 7th letter of the Roman alphabet (同)g

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/10 16:56:58」(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 L-DOPA (Levodopa)-responsive dystonia.^[1]

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).".

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

UpToDate Contents

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1. ジストニアの分類および評価 classification and evaluation of dystonia
2. 小児における運動過多な運動障害 hyperkinetic movement disorders in children

English Journal

Early replacement therapy in a first Japanese case with autosomal recessive guanosine triphosphate cyclohydrolase I deficiency with a novel point mutation.

Sato H1, Uematsu M2, Endo W1, Nakayama T1, Kobayashi T1, Hino-Fukuyo N1, Sakamoto O1, Shintaku H3, Kure S1.Author information 1Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.2Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan. Electronic address: uematsu@bk9.so-net.ne.jp.3Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.AbstractAutosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatment, a patient with GTPCH deficiency develops complex neurological dysfunctions, including dystonia and developmental delays. The first Japanese patient with GTPCH deficiency was discovered by HPA during asymptomatic newborn screening. The phenylalanine level at the age of 5days was 1273μmol/L (cutoff value, 180.0μmol/L). The high serum phenylalanine level was decreased to normal after adequate BH4 oral supplementation. Serum and urinary pteridine examination revealed very low levels of neopterin and biopterin. Sequence analysis of GCH1 revealed compound heterozygous point mutations, including a novel point mutation (p.R235W). Replacement therapy with BH4 and L-dopa/carbidopa were started at the age of 1month, and 5-hydroxytryptophan (5-HTP) was started at the age of 5months. At 10months of age, the patient showed slight dystonia but no obvious developmental delay. Cerebrospinal fluid should be examined to determine the appropriate dosage of supplement drugs. In conclusion, it is important to control the serum phenylalanine level and perform early replacement of neurotransmitters to prevent neurological dysfunction.
Brain & development.Brain Dev.2014 Mar;36(3):268-71. doi: 10.1016/j.braindev.2013.04.003. Epub 2013 May 6.
Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatme
PMID 23660475

Construction and fed-batch cultivation of Candida famata with enhanced riboflavin production.

Dmytruk K1, Lyzak O1, Yatsyshyn V1, Kluz M2, Sibirny V2, Puchalski C2, Sibirny A3.Author information 1Institute of Cell Biology, NAS of Ukraine, Drahomanov Street, 14/16, Lviv 79005, Ukraine.2University of Rzeszow, Zelwerowicza 4, Rzeszow 35-601, Poland.3Institute of Cell Biology, NAS of Ukraine, Drahomanov Street, 14/16, Lviv 79005, Ukraine; University of Rzeszow, Zelwerowicza 4, Rzeszow 35-601, Poland. Electronic address: sibirny@yahoo.com.AbstractRiboflavin (vitamin B2) is an essential nutrition component serving as a precursor of coenzymes FMN and FAD that are involved mostly in reactions of oxidative metabolism. Riboflavin is produced in commercial scale and is used in feed and food industries, and in medicine. The yeast Candida famata (Candida flareri) belongs to the group of so called "flavinogenic yeasts" which overproduce riboflavin under iron limitation. Three genes SEF1, RIB1 and RIB7 coding for a putative transcription factor, GTP cyclohydrolase II and riboflavin synthase, respectively were simultaneously overexpressed in the background of a non-reverting riboflavin producing mutant AF-4, obtained earlier in our laboratory using methods of classical selection (Dmytruk et al. (2011), Metabolic Engineering 13, 82-88). Cultivation conditions of the constructed strain were optimized for shake-flasks and bioreactor cultivations. The constructed strain accumulated up to 16.4g/L of riboflavin in optimized medium in a 7L laboratory bioreactor during fed-batch fermentation.
Journal of biotechnology.J Biotechnol.2014 Feb 20;172:11-7. doi: 10.1016/j.jbiotec.2013.12.005. Epub 2013 Dec 18.
Riboflavin (vitamin B2) is an essential nutrition component serving as a precursor of coenzymes FMN and FAD that are involved mostly in reactions of oxidative metabolism. Riboflavin is produced in commercial scale and is used in feed and food industries, and in medicine. The yeast Candida famata (Ca
PMID 24361297

The physiological role of riboflavin transporter and involvement of FMN-riboswitch in its gene expression in Corynebacterium glutamicum.

Takemoto N, Tanaka Y, Inui M, Yukawa H.Author information Research Institute of Innovative Technology for the Earth, 9-2 Kizugawadai, Kizugawa, Kyoto, 619-0292, Japan.AbstractRiboflavin is a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which work as cofactors of numerous enzymes. Understanding the supply system of these cofactors in bacteria, particularly those used for industrial production of value added chemicals, is important given the pivotal role the cofactors play in substrate metabolism. In this work, we examined the effect of disruption of riboflavin utilization genes on cell growth, cytoplasmic flavin levels, and expression of riboflavin transporter in Corynebacterium glutamicum. Disruption of the ribA gene that encodes bifunctional GTP cyclohydrolase II/3,4-dihydroxy-2-butanone 4-phosphate synthase in C. glutamicum suppressed growth in the absence of supplemental riboflavin. The growth was fully recovered upon supplementation with 1 μM riboflavin, albeit at reduced intracellular concentrations of FMN and FAD during the log phase. Concomitant disruption of the ribA and ribM gene that encodes a riboflavin transporter exacerbated supplemental riboflavin requirement from 1 μM to 50 μM. RibM expression in FMN-rich cells was about 100-fold lower than that in FMN-limited cells. Mutations in putative FMN-riboswitch present immediately upstream of the ribM gene abolished the FMN response. This 5'UTR sequence of ribM constitutes a functional FMN-riboswitch in C. glutamicum.
Applied microbiology and biotechnology.Appl Microbiol Biotechnol.2014 Feb 16. [Epub ahead of print]
Riboflavin is a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which work as cofactors of numerous enzymes. Understanding the supply system of these cofactors in bacteria, particularly those used for industrial production of value added chemicals, is important given
PMID 24531272

Japanese Journal

NO代謝(テトラヒドロビオプテリンおよびその合成律速酵素GTP cyclohydrolase I)の糖代謝調節機構への関与 (特集血管内皮と糖尿病とその合併症)

藤田義人
内分泌・糖尿病・代謝内科 39(6), 442-448, 2014-12
NAID 40020314340

ビオプテリンの生理機能と病態代謝

一瀬宏
ビタミン 88(3), 131-138, 2014-03-25
… GTP cyclohydrolase I is an enzyme for BH4-biosynthesis and the genetic defect in an allele of GTP cyclohydrolase I gene can cause hereditary dystonia, termed as DYT5, due to partial BH4 deficiency. …
NAID 110009807287

脳性麻痺と診断されていた瀬川病の女性例

村上てるみ,西村敏,舟塚真 [他],新宅治夫,一瀬宏,大澤眞木子
東京女子医科大学雑誌 83(E3), E663-E665, 2013-07-31
… 瀬川病は14q22.1-q22.2に存在するGTPシクロヒドロラーゼI(GCH1)遺伝子異常に起因する常染色体優性遺伝性ジストニーである。 … 髄液中のネオプテリン、バイオプテリンの低値と血球中のGTPシクロヒドラーゼI(GCH1)酵素活性低値、さらにGCH1遺伝子異常を認め瀬川病と確定診断した。 …
NAID 110009604924

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★リンクテーブル★

リンク元	「GTPシクロヒドラーゼ」「GTPシクロヒドロラーゼ」「GCH」
拡張検索	「GTP cyclohydrolase I」「GTP cyclohydrolase I gene mutation」「GTP cyclohydrolase I deficiency」
関連記事	「GTP」「G」「cyclohydrolase」

「GTPシクロヒドラーゼ」

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PMC	articles
PubMed	articles
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; • nucleolus; • cytoplasm; • cytosol; • cytoplasmic vesicle; • nuclear membrane; • protein complex;
Biological process	• GTP catabolic process; • tetrahydrobiopterin biosynthetic process; • nitric oxide biosynthetic process; • metabolic 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
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