GCH1

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]

Full Name

GTP Cyclohydrolase 1

Function

Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.

Biological Process

7,8-dihydroneopterin 3'-triphosphate biosynthetic process Source: UniProtKB-UniPathway
Dopamine biosynthetic process Source: UniProtKB
Negative regulation of blood pressure Source: Ensembl
Neuromuscular process controlling posture Source: MGI
Nitric oxide biosynthetic process Source: UniProtKB
Positive regulation of heart rate Source: Ensembl
Positive regulation of nitric-oxide synthase activity Source: UniProtKB
protein-containing complex assembly Source: Ensembl
Pteridine-containing compound biosynthetic process Source: UniProtKB
Regulation of blood pressure Source: UniProtKB
Regulation of lung blood pressure Source: Ensembl
Regulation of removal of superoxide radicals Source: BHF-UCL
Response to interferon-gamma Source: UniProtKB
Response to lipopolysaccharide Source: UniProtKB
Response to pain Source: UniProtKB
Response to tumor necrosis factor Source: UniProtKB
Tetrahydrobiopterin biosynthetic process Source: UniProtKB
Tetrahydrofolate biosynthetic process Source: InterPro
Vasodilation Source: Ensembl

Cellular Location

Nucleus; Cytoplasm

Involvement in disease

Hyperphenylalaninemia, BH4-deficient, B (HPABH4B):
A disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.
Dystonia, dopa-responsive (DRD):
A form of dystonia that responds to L-DOPA treatment without side effects. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DRD typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and exercise.

PTM

Phosphorylated by casein kinase II at Ser-81 in HAECs during oscillatory shear stress; phosphorylation at Ser-81 results in increased enzyme activity.