GCH1

Protein identityUniProt · HPA

UniProt accession

P30793

Gene

GCH1

Ensembl

ENSG00000131979

Chromosome

14

Canonical length

250 aa

Protein class

Disease related genes, Enzymes, Human disease related genes, Metabolic proteins, Potential drug targets, Predicted intracellular proteins

Subcellular location

Nucleoplasm,Nuclear membrane,Cytosol

Quaternary structure

Homodecamer

OverviewNCBI Gene

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]

Canonical amino-acid sequenceUniProt

250 residues, UniProt reviewed canonical sequence.

>P30793|GCH1
     1  MEKGPVRAPA EKPRGARCSN GFPERDPPRP GPSRPAEKPP RPEAKSAQPA DGWKGERPRS
    61  EEDNELNLPN LAAAYSSILS SLGENPQRQG LLKTPWRAAS AMQFFTKGYQ ETISDVLNDA
   121  IFDEDHDEMV IVKDIDMFSM CEHHLVPFVG KVHIGYLPNK QVLGLSKLAR IVEIYSRRLQ
   181  VQERLTKQIA VAITEALRPA GVGVVVEATH MCMVMRGVQK MNSKTVTSTM LGVFREDPKT
   241  REEFLTLIRS

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against GCH1 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.39

Highest tissue expression

58 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about GCH1.

Disease | AllUniProt

Conditions GCH1 is implicated in, by any mechanism.

• Hyperphenylalaninemia, BH4-deficient, B (HPABH4B) MIM:233910
• Dystonia, dopa-responsive (DRD) MIM:128230

Disease | GeneticClinVar

117 pathogenic / likely-pathogenic of 619 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Dystonia 5
• GTP cyclohydrolase I deficiency
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia
• Dystonic disorder
• Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.4

gnomAD pLI

0.9

gnomAD missense Z

1.52

DepMap mean gene effect

-0.13

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• dopamine biosynthetic process
• neuromuscular process controlling posture
• nitric oxide biosynthetic process
• positive regulation of heart rate
• positive regulation of nitric-oxide synthase activity
• regulation of blood pressure
• regulation of lung blood pressure
• regulation of removal of superoxide radicals
• response to lipopolysaccharide
• response to pain
• response to tumor necrosis factor
• response to type II interferon
• tetrahydrobiopterin biosynthetic process
• tetrahydrofolate biosynthetic process
• pteridine-containing compound biosynthetic process

Molecular functions

• GTP binding
• GTPase activity
• identical protein binding
• mitogen-activated protein kinase binding
• protein homodimerization activity
• zinc ion binding
• GTP cyclohydrolase I activity

Cellular components

• cytoplasm
• cytoplasmic vesicle
• cytosol
• neuron projection terminus
• nuclear membrane
• nucleoplasm
• nucleus
• protein-containing complex

Protein domainsUniProt · Pfam · InterPro

• GTP cyclohydrolase I
• GTP cyclohydrolase I, conserved site
• GTP cyclohydrolase I domain
• GTP cyclohydrolase I, C-terminal/NADPH-dependent 7-cyano-7-deazaguanine reductase
• GTP cyclohydrolase I, N-terminal domain
• GTP cyclohydrolase I

KeywordsUniProt

• Allosteric enzyme
• Cytoplasm
• Dystonia
• GTP-binding
• Hydrolase
• Metal-binding
• Nucleotide-binding
• Nucleus
• Parkinsonism
• Phenylketonuria
• Phosphoprotein
• Tetrahydrobiopterin biosynthesis
• Zinc

InteractionsUniProt · HPA

Protein binding partners of GCH1 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• AHSA1
• GCHFR
• YWHAZ