GTP cyclohydrolase I

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).

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
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 47,153,895 bp[2] End 47,189,413 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • calcium ion binding • protein homodimerization activity • zinc ion binding • GTP binding • metal ion binding • GO:0001948 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 • not the membrane • nucleoplasm • cytoplasmic vesicle • cell nucleus • neuron projection terminus • macromolecular 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 • macromolecular 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: 47.15 – 47.19 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5]

Clinical significance

Mutations in this gene are associated with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as GTP cyclohydrolase I deficiency.[5] Deficiency of GTP cyclohydrolase I can occur in a recessive and in a dominant form 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.[6] 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).[7]

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 / 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.

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. [8]

See also

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

References

1. GRCh38: Ensembl release 89: ENSG00000131979 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037580 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: GCH1 GTP Cyclohydrolase 1 (DOPA-Responsive Dystonia)".
6. Longo N (June 2009). "Disorders of biopterin metabolism". Journal of Inherited Metabolic Disease. 32 (3): 333–42. doi:10.1007/s10545-009-1067-2. PMID 19234759. S2CID 13117236.
7. "Patient registry".
8. Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. (January 2020). "GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling". ACS Central Science. 6 (1): 41–53. doi:10.1021/acscentsci.9b01063. PMC 6978838. PMID 31989025.

Further reading

• Voet JG, Voet D (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
• Overview of all the structural information available in the PDB for UniProt: P30793 (Human GTP cyclohydrolase 1) at the PDBe-KB.