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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
    mouse all
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    Genomic context

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    See GCH1 in Genome Data Viewer
    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

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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