GTP cyclohydrolase I

GCH1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FB1
Identifiers
Aliases	GCH1, DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1, HPABH4B, GTP cyclohydrolase 1
External IDs	MGI: 95675 HomoloGene: 132 GeneCards: GCH1
Genetically Related Diseases
obesity, rheumatoid arthritis[1]
Gene ontology Molecular function • nucleotide binding • calcium ion binding • protein homodimerization activity • zinc ion binding • GTP binding • metal ion binding • GTP-dependent protein binding • protein binding • catalytic activity • coenzyme binding • hydrolase activity • GTP cyclohydrolase I activity • translation initiation factor binding Cellular component • cytoplasm • cytosol • nuclear membrane • nucleoplasm • protein complex • cytoplasmic vesicle • nucleus Biological process • nitric oxide biosynthetic process • response to interferon-gamma • neuromuscular process controlling posture • protein heterooligomerization • protein complex assembly • negative regulation of blood pressure • dopamine biosynthetic process • regulation of lung blood pressure • regulation of nitric-oxide synthase activity • vasodilation • pteridine-containing compound biosynthetic process • 7,8-dihydroneopterin 3'-triphosphate biosynthetic process • dihydrobiopterin metabolic process • regulation of blood pressure • response to tumor necrosis factor • tetrahydrofolate biosynthetic process • response to lipopolysaccharide • positive regulation of nitric-oxide synthase activity • response to pain • tetrahydrobiopterin biosynthetic process • metabolic process • protein homooligomerization • regulation of removal of superoxide radicals Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2643	14528
Ensembl	ENSG00000131979	ENSMUSG00000037580
UniProt	P30793	Q05915
RefSeq (mRNA)	NM_000161 NM_001024024 NM_001024070 NM_001024071	NM_008102
RefSeq (protein)	NP_000152.1 NP_001019195.1 NP_001019241.1 NP_001019242.1	NP_032128.1
Location (UCSC)	Chr 14: 54.84 – 54.9 Mb	Chr 14: 47.15 – 47.19 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

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.^[4]

Clinical significance

Mutations in this gene are associated with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as GTP cyclohydrolase I deficiency.^[4] Deficiency of GTP cyclohydrolase I can occur in a recessive and in a dominant form and lead to a lack 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.^[5] 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).^[6]

Function

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

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.

See also

• Guanosine triphosphate (GTP)
• Tetrahydrobiopterin (THB, BH₄)
• Vitamin B₉ (folic acid → folate)

References

1. "Diseases that are genetically associated with GCH1 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. "Entrez Gene: GCH1 GTP Cyclohydrolase 1 (DOPA-Responsive Dystonia).".
5. 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.
6. "Patient registry".

Further reading

• Voet, Judith G.; Voet, Donald (2004). Biochemistry. New York: J. Wiley & Sons. ISBN 0-471-39223-5.

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