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	OMIM: 600225; MGI: 95675; HomoloGene: 132; GeneCards: GCH1; OMA:GCH1 - orthologs
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q22.2 Start 54,842,008 bp[1] End 54,902,826 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 C1|14 24.6 cM Start 47,391,352 bp[2] End 47,426,870 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte beta cell jejunal mucosa kidney tubule cartilage tissue palpebral conjunctiva mononuclear cell monocyte epithelium of nasopharynx right lobe of liver Top expressed in superior cervical ganglion pineal gland left lobe of liver islet of Langerhans zygote gastrula pyloric antrum secondary oocyte cumulus cell tibiofemoral joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding calcium ion binding protein homodimerization activity zinc ion binding GTP binding metal ion binding protein binding catalytic activity hydrolase activity GTP cyclohydrolase I activity mitogen-activated protein kinase binding GTPase activity GTP-dependent protein binding translation initiation factor binding Cellular component cytoplasm cytosol nuclear membrane nucleoplasm cytoplasmic vesicle nucleus neuron projection terminus protein-containing complex Biological process nitric oxide biosynthetic process response to interferon-gamma neuromuscular process controlling posture protein heterooligomerization negative regulation of blood pressure dopamine biosynthetic process regulation of lung blood pressure 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 metabolism protein homooligomerization regulation of removal of superoxide radicals positive regulation of heart rate protein-containing complex assembly Sources:Amigo / QuickGO
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 NP_001019195 NP_001019241 NP_001019242 NP_032128 Location (UCSC) Chr 14: 54.84 – 54.9 Mb Chr 14: 47.39 – 47.43 Mb PubMed search [3] [4]
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).

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.^[5]

At least 94 disease-causing mutations in this gene have been discovered.^[6] Mutations in this gene are associated with two disorders: autosomal recessive GTP cyclohydrolase I deficiency and autosomal dominant GTP cyclohydrolase I deficiency. These may present with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA)^[5] and lead to a lack of certain neurotransmitters (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.^[7] 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).^[8]

The chemical reaction performed by GTPCH. The important carbons relative to the transformation are numbered for reference.
Identifiers
EC no.	3.5.4.16
CAS no.	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 / QuickGO
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.^{[citation needed]}

GTPCH (GCH1) and tetrahydrobiopterin were found to protect against cell death by ferroptosis. Tetrahydrobiopterin (BH₄) acts as a potent, diffusable antioxidant that resists oxidative stress and enables cancer cell survival.^[9]

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

• GTP+Cyclohydrolase+I at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia
• Overview of all the structural information available in the PDB for UniProt: P30793 (Human GTP cyclohydrolase 1) at the PDBe-KB.