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FLASH GENE
Symbol GCH1 contributors: mct/npt - updated : 03-01-2017
HGNC name GTP cyclohydrolase 1
HGNC id 4193
RNA
TRANSCRIPTS type messenger
text alternative splicing at the exon 5/6 boundary of the human gene gives GCH types II (cloned from liver) and IV (from myelomonocytoma cells) and a premature stop yields type III (from liver)
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
6 - 2941 27 250 - 2015 25599448
  • GCH1FL or Type I
  • 6 splicing 1852 - 213 liver 2015 25599448
  • GCH1I2, or Type II
  • has been shown to decrease the level of wild-type enzyme
  • - splicing 810 - 209 liver 2015 25599448
    - splicing 1180 - 241 liver 2015 25599448
    7 - 1995 - 250 - 2015 25599448
  • variant 2 or Type V
  • 7 - 1940 - 233 - 2015 25599448
  • variant 3 or Type IV
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Endocrinepancreas   highly
    Lymphoid/Immunelymph node   highly
    Nervousbrainhindbraincerebellum highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • C-terminal residues contribute to structural elements, intra-ring contacts, catalysis and binding of substrate, GFRP and H4-biopterin
  • mono polymer homomer , dimer , pentamer , polymer
    HOMOLOGY
    interspecies homolog to murine Gch
    homolog to C.elegans F32G8.6
    Homologene
    FAMILY
  • GTP cyclohydrolase I family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • catalyzing the first step of tetrahydrobiopterin (BH4) synthesis
  • essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases
  • protects the heart against diabetic cardiomyopathy and is a modulator of cardiac remodeling and function
  • enzyme critically important for dopamine production in nigrostriatal neurons
  • GCH1, SPR and their downstream metabolite BH4 are critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • toroid-shaped homodecamer, composed of a dimer of pentamers
  • INTERACTION
    DNA
    RNA
    small molecule
    protein splice variants interfere with wild-type GCH1 and inactive variants are incorporated into heterodecamers, decreasing the enzyme stability and activity
    cell & other
    REGULATION
    activated by by phenylalanine through complex formation with the GFRP (GCH feedback regulatory protein)
    inhibited by by H4-biopterin
    ASSOCIATED DISORDERS
    corresponding disease(s) DYT5 , GTPCD
    related resource GTP Cyclohydrolase I deficiency-BIOMED/BIODEF database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa
    Susceptibility
  • to bipolar disorder
  • to pain in advanced cancer
  • to Parkinson disease
  • Variant & Polymorphism other
  • genetic variant delaying cancer pain (Lotsch 2010)
  • rare GCH1 variants are associated with an increased risk for Parkinson disease
  • Candidate gene
    Marker
    Therapy target
  • future possibility of using partial GCH1 blockade or BH4 inhibition as a prophylactic to prevent or delay the development of cancer pain (Lötsch 2010)
  • ANIMAL & CELL MODELS