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GCH1 GTP cyclohydrolase 1 [ Homo sapiens (human) ]

Gene ID: 2643, updated on 11-Apr-2024

Summary

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Official Symbol
GCH1provided by HGNC
Official Full Name
GTP cyclohydrolase 1provided by HGNC
Primary source
HGNC:HGNC:4193
See related
Ensembl:ENSG00000131979 MIM:600225; AllianceGenome:HGNC:4193
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
GCH; DYT5; DYT14; DYT5a; GTPCH1; HPABH4B; GTP-CH-1
Summary
This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]
Expression
Broad expression in liver (RPKM 22.0), bone marrow (RPKM 9.4) and 19 other tissues See more
Orthologs
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Genomic context

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Location:
14q22.2
Exon count:
10
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 14 NC_000014.9 (54842017..54902826, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 14 NC_060938.1 (49047244..49108020, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 14 NC_000014.8 (55308735..55369544, complement)

Chromosome 14 - NC_000014.9Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC112268133 Neighboring gene sterile alpha motif domain containing 4A Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8413 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr14:55116884-55117491 Neighboring gene H3K27ac hESC enhancer GRCh37_chr14:55117492-55118098 Neighboring gene H3K27ac hESC enhancer GRCh37_chr14:55119678-55120414 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8414 Neighboring gene SAMD4A antisense RNA 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5773 Neighboring gene Sharpr-MPRA regulatory region 12509 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8416 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr14:55239710-55240909 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:55271438-55272239 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:55275033-55275533 Neighboring gene Sharpr-MPRA regulatory region 1906 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr14:55337424-55338029 Neighboring gene RNA, U6atac small nuclear 9, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8418 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8419 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8420 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8421 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:55364129-55364629 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5774 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5776 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5775 Neighboring gene microRNA 4308 Neighboring gene farnesyl diphosphate synthase pseudogene 3 Neighboring gene Sharpr-MPRA regulatory region 2393 Neighboring gene WD repeat and HMG-box DNA binding protein 1 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr14:55493639-55494166 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr14:55494167-55494693 Neighboring gene ribosomal protein SA pseudogene 13 Neighboring gene suppressor of cytokine signaling 4

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis. Khairallah A, et al. J Chem Inf Model, 2021 Sep 27. PMID 34450011
  2. Epigenetic silencing of GCH1promotes hepatocellular carcinoma growth by activating superoxide anion-mediated ASK1/p38 signaling via inhibiting tetrahydrobiopterin de novo biosynthesis. Zhong GC, et al. Free Radic Biol Med, 2021 May 20. PMID 33781891
  3. GCH1 mutations in hereditary spastic paraplegia. Varghaei P, et al. Clin Genet, 2021 Jul. PMID 33713342
  4. Increased superoxide in GCH1 mutant fibroblasts points to a dopamine-independent toxicity mechanism. Terbeek J, et al. Parkinsonism Relat Disord, 2021 Jan. PMID 33221620
  5. Brain structural alterations in patients with GCH1 mutations associated DOPA-responsive dystonia. Kostić VS, et al. J Neurol Neurosurg Psychiatry, 2021 Mar. PMID 33087420

See all (223) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.
    Title: Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.
  2. CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis.
    Title: CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis.
  3. Association analysis of SYT11, FGF20, GCH1 rare variants in Parkinson's disease.
    Title: Association analysis of SYT11, FGF20, GCH1 rare variants in Parkinson's disease.
  4. GCH1 mutations in hereditary spastic paraplegia.
    Title: GCH1 mutations in hereditary spastic paraplegia.
  5. Polymorphisms of Nav1.6 sodium channel, Brain-derived Neurotrophic Factor, Catechol-O-methyltransferase and Guanosine Triphosphate Cyclohydrolase 1 genes in trigeminal neuralgia.
    Title: Polymorphisms of Nav1.6 sodium channel, Brain-derived Neurotrophic Factor, Catechol-O-methyltransferase and Guanosine Triphosphate Cyclohydrolase 1 genes in trigeminal neuralgia.
  6. Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP.
    Title: Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP.
  7. Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension.
    Title: Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension.
  8. Increased superoxide in GCH1 mutant fibroblasts points to a dopamine-independent toxicity mechanism.
    Title: Increased superoxide in GCH1 mutant fibroblasts points to a dopamine-independent toxicity mechanism.
  9. GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis.
    Title: GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis.
  10. Association of TOR1A and GCH1 Polymorphisms with Isolated Dystonia in India.
    Title: Association of TOR1A and GCH1 Polymorphisms with Isolated Dystonia in India.
Submit: New GeneRIF Correction See all GeneRIFs (149)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Copy number response

Description
Copy number response
Triplosensitivity

No evidence available (Last evaluated 2023-02-14)

ClinGen Genome Curation Page
Haploinsufficency

Sufficient evidence for dosage pathogenicity (Last evaluated 2023-02-14)

ClinGen Genome Curation PagePubMed

EBI GWAS Catalog

Description
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
EBI GWAS Catalog
Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population.
EBI GWAS Catalog
Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

HIV-1 interactions

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Protein interactions

Protein Gene Interaction Pubs
Tat tat Microarray analysis indicates HIV-1 Tat-induced upregulation of GTP cyclohydrolase 1 (GCH1) in primary human brain microvascular endothelial cells PubMed

Go to the HIV-1, Human Interaction Database

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables GTP binding IBA
Inferred from Biological aspect of Ancestor
more info
  
enables GTP binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables GTP cyclohydrolase I activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables GTP cyclohydrolase I activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables GTP-dependent protein binding IEA
Inferred from Electronic Annotation
more info
  
enables GTPase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables calcium ion binding IEA
Inferred from Electronic Annotation
more info
  
enables identical protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables mitogen-activated protein kinase binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein homodimerization activity IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein-containing complex binding IEA
Inferred from Electronic Annotation
more info
  
enables zinc ion binding IBA
Inferred from Biological aspect of Ancestor
more info
  
enables zinc ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
Process Evidence Code Pubs
involved_in dihydrobiopterin metabolic process IEA
Inferred from Electronic Annotation
more info
  
involved_in dopamine biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in negative regulation of blood pressure IEA
Inferred from Electronic Annotation
more info
  
involved_in negative regulation of cardiac muscle cell apoptotic process IEA
Inferred from Electronic Annotation
more info
  
involved_in negative regulation of cellular senescence IEA
Inferred from Electronic Annotation
more info
  
acts_upstream_of_or_within neuromuscular process controlling posture IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in nitric oxide biosynthetic process NAS
Non-traceable Author Statement
more info
 PubMed 
involved_in positive regulation of heart rate IEA
Inferred from Electronic Annotation
more info
  
involved_in positive regulation of neuron apoptotic process IEA
Inferred from Electronic Annotation
more info
  
involved_in positive regulation of nitric-oxide synthase activity IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in positive regulation of nitric-oxide synthase activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in positive regulation of telomere maintenance via telomerase IEA
Inferred from Electronic Annotation
more info
  
involved_in protein-containing complex assembly IEA
Inferred from Electronic Annotation
more info
  
involved_in pteridine-containing compound biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in regulation of blood pressure IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in regulation of lung blood pressure IEA
Inferred from Electronic Annotation
more info
  
involved_in regulation of removal of superoxide radicals IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in response to lipopolysaccharide IDA
Inferred from Direct Assay
more info
 PubMed 
NOT involved_in response to lipopolysaccharide IEP
Inferred from Expression Pattern
more info
 PubMed 
involved_in response to pain ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in response to tumor necrosis factor IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in response to type II interferon IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in tetrahydrobiopterin biosynthetic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in tetrahydrobiopterin biosynthetic process IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in tetrahydrobiopterin biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in tetrahydrofolate biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
involved_in vasodilation IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
is_active_in cytoplasm IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in cytoplasm IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytoplasmic vesicle IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytosol IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytosol TAS
Traceable Author Statement
more info
  
located_in mitochondrion IEA
Inferred from Electronic Annotation
more info
  
located_in neuron projection terminus TAS
Traceable Author Statement
more info
 PubMed 
located_in nuclear membrane IDA
Inferred from Direct Assay
more info
  
located_in nucleoplasm IDA
Inferred from Direct Assay
more info
  
located_in nucleus IDA
Inferred from Direct Assay
more info
 PubMed 
part_of protein-containing complex IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
GTP cyclohydrolase 1
Names
GTP cyclohydrolase I
GTP-CH-I
dystonia 14
guanosine 5'-triphosphate cyclohydrolase I
NP_000152.1
NP_001019195.1
NP_001019241.1
NP_001019242.1
NP_001411033.1
NP_001411034.1
XP_047287217.1
XP_054231824.1

NCBI Reference Sequences (RefSeq)

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NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_008647.2 RefSeqGene

    Range
    5000..65809
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_000161.3 → NP_000152.1  GTP cyclohydrolase 1 isoform 1

    See identical proteins and their annotated locations for NP_000152.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1), also known as Type I, represents the longest transcript. Variants 1 and 2 encode the longest isoform (1), which is the active enzyme.
    Source sequence(s)
    AL133444, AL160471
    Consensus CDS
    CCDS9720.1
    UniProtKB/Swiss-Prot
    P30793, Q6FHY7, Q9Y4I8
    Related
    ENSP00000419045.2, ENST00000491895.7
    Conserved Domains (2) summary
    cd00642
    Location:66 → 250
    GTP_cyclohydro1; GTP cyclohydrolase I (GTP-CH-I) catalyzes the conversion of GTP into dihydroneopterin triphosphate. The enzyme product is the precursor of tetrahydrofolate in eubacteria, fungi, and plants and of the folate analogs in methanogenic bacteria. In ...
    NF033930
    Location:8 → 56
    pneumo_PspA; pneumococcal surface protein A

  2. NM_001024024.2 → NP_001019195.1  GTP cyclohydrolase 1 isoform 1

    See identical proteins and their annotated locations for NP_001019195.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2), also known as Type V, differs in the 3' UTR, compared to variant 1. Variants 1 and 2 both encode the functional enzyme, isoform 1.
    Source sequence(s)
    AL133444, AL160471
    Consensus CDS
    CCDS9720.1
    UniProtKB/Swiss-Prot
    P30793, Q6FHY7, Q9Y4I8
    Related
    ENSP00000378890.1, ENST00000395514.5
    Conserved Domains (2) summary
    cd00642
    Location:66 → 250
    GTP_cyclohydro1; GTP cyclohydrolase I (GTP-CH-I) catalyzes the conversion of GTP into dihydroneopterin triphosphate. The enzyme product is the precursor of tetrahydrofolate in eubacteria, fungi, and plants and of the folate analogs in methanogenic bacteria. In ...
    NF033930
    Location:8 → 56
    pneumo_PspA; pneumococcal surface protein A

  3. NM_001024070.2 → NP_001019241.1  GTP cyclohydrolase 1 isoform 2

    See identical proteins and their annotated locations for NP_001019241.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3), also known as Type IV, uses alternate, in-frame splice sites in the 3' coding region and 3' UTR, compared to variant 1. The resulting non-functional protein (isoform 2) is shorter and has a distinct C-terminus, compared to isoform 1.
    Source sequence(s)
    AL133444, AL160471
    Consensus CDS
    CCDS41954.1
    UniProtKB/Swiss-Prot
    P30793
    Related
    ENSP00000444011.2, ENST00000543643.6
    Conserved Domains (2) summary
    NF033930
    Location:8 → 56
    pneumo_PspA; pneumococcal surface protein A
    cl00263
    Location:66 → 209
    TFold; Tunnelling fold (T-fold). The five known T-folds are found in five different enzymes with different functions: dihydroneopterin-triphosphate epimerase (DHNTPE), dihydroneopterin aldolase (DHNA) , GTP cyclohydrolase I (GTPCH-1), 6-pyrovoyl ...

  4. NM_001024071.2 → NP_001019242.1  GTP cyclohydrolase 1 isoform 3

    See identical proteins and their annotated locations for NP_001019242.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4), also known as Type II, lacks an alternate in-frame exon in the 3' coding region and uses a downstream stop codon, compared to variant 1. The resulting non-functional protein (isoform 3) is shorter and has a distinct C-terminus, compared to variant 1.
    Source sequence(s)
    AL133444, AL160471
    Consensus CDS
    CCDS45110.1
    UniProtKB/Swiss-Prot
    P30793
    Related
    ENSP00000445246.2, ENST00000536224.2
    Conserved Domains (2) summary
    NF033930
    Location:8 → 56
    pneumo_PspA; pneumococcal surface protein A
    cl00263
    Location:66 → 209
    TFold; Tunnelling fold (T-fold). The five known T-folds are found in five different enzymes with different functions: dihydroneopterin-triphosphate epimerase (DHNTPE), dihydroneopterin aldolase (DHNA) , GTP cyclohydrolase I (GTPCH-1), 6-pyrovoyl ...

  5. NM_001424104.1 → NP_001411033.1  GTP cyclohydrolase 1 isoform 4

    Status: REVIEWED

    Source sequence(s)
    AL133444, AL160471

  6. NM_001424105.1 → NP_001411034.1  GTP cyclohydrolase 1 isoform 5

    Status: REVIEWED

    Source sequence(s)
    AL133444, AL160471

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000014.9 Reference GRCh38.p14 Primary Assembly

    Range
    54842017..54902826 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_047431261.1 → XP_047287217.1  GTP cyclohydrolase 1 isoform X1

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060938.1 Alternate T2T-CHM13v2.0

    Range
    49047244..49108020 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054375849.1 → XP_054231824.1  GTP cyclohydrolase 1 isoform X1

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P30793.1 GenPept UniProtKB/Swiss-Prot:P30793

Gene LinkOut

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