Disease	Score

Substances	Interaction	Organism	Category

Substances	Interaction	Organism	Category

     dopa-responsive dystonia More than 140 mutations in the GCH1 gene have been found to cause dopa-responsive dystonia. This condition is characterized by a pattern of involuntary muscle contractions (dystonia), tremors, and other uncontrolled movements and usually responds to treatment with a medication called L-Dopa. Dopa-responsive dystonia results when one copy of the GCH1 gene is mutated in each cell. Most GCH1 gene mutations that cause this condition change single amino acids in the GTP cyclohydrolase 1 enzyme. Researchers believe that the abnormal enzyme may interfere with the activity of the normal version of GTP cyclohydrolase 1 that is produced from the copy of the gene with no mutation. As a result, the amount of working enzyme in affected individuals is reduced by 80 percent or more. A reduction in functional GTP cyclohydrolase 1 enzyme causes less dopamine and serotonin to be produced, leading to the movement problems and other characteristic features of dopa-responsive dystonia. tetrahydrobiopterin deficiency At least seven mutations in the GCH1 gene have been found to cause tetrahydrobiopterin deficiency. When this condition is caused by GCH1 gene mutations, it is known as GTP cyclohydrolase 1 (GTPCH1) deficiency. GTPCH1 deficiency accounts for about 4 percent of all cases of tetrahydrobiopterin deficiency. GTPCH1 deficiency results when two copies of the GCH1 gene are mutated in each cell. Most of the mutations responsible for this condition change single amino acids in GTP cyclohydrolase 1. These mutations greatly reduce or eliminate the activity of this enzyme. Without enough GTP cyclohydrolase 1, little or no tetrahydrobiopterin is produced. As a result, this cofactor is not available to participate in chemical reactions such as the conversion of phenylalanine to tyrosine. If phenylalanine is not converted to tyrosine, it can build up to toxic levels in the blood and other tissues. Nerve cells in the brain are particularly sensitive to phenylalanine levels, which is why excessive amounts of this substance can cause brain damage. Additionally, a reduction in GTP cyclohydrolase 1 activity disrupts the production of certain neurotransmitters in the brain. Because neurotransmitters are necessary for normal brain function, changes in the levels of these chemicals contribute to intellectual disability in people with GTPCH1 deficiency. Tetrahydrobiopterin deficiency is more severe than dopa-responsive dystonia likely because both copies of the GCH1 gene are mutated, which leads to a more severe enzyme shortage than in dopa-responsive dystonia, in which only one copy of the gene has a mutation.

     The GCH1 gene provides instructions for making an enzyme called GTP cyclohydrolase 1. This enzyme is involved in the first of three steps in the production of a molecule called tetrahydrobiopterin (BH4). Other enzymes help carry out the second and third steps in this process. Tetrahydrobiopterin plays a critical role in processing several protein building blocks (amino acids) in the body. For example, it works with the enzyme phenylalanine hydroxylase to convert an amino acid called phenylalanine into another amino acid, tyrosine. Tetrahydrobiopterin is also involved in reactions that produce chemicals called neurotransmitters, which transmit signals between nerve cells in the brain. Specifically, tetrahydrobiopterin is involved in the production of two neurotransmitters called dopamine and serotonin . Among their many functions, dopamine transmits signals within the brain to produce smooth physical movements, and serotonin regulates mood, emotion, sleep, and appetite. Because it helps enzymes carry out chemical reactions, tetrahydrobiopterin is known as a cofactor.

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

The following transcription factors affect gene expression:

• GR
• GR-alpha
• GR-beta
• p53
• AP-1
• c-Jun

Tissue specificity:

In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level).

Induction:

Up-regulated by IFNG/IFN-gamma, TNF, IL1B/interleukin-1 beta, bacterial lipopolysaccharides (LPS) and phenylalanine, and down-regulated by dibutyryl-cAMP, iloprost and 8-bromo-cGMP in HUVEC cells. Up-regulation of GCH1 expression, in turn, stimulates production of tetrahydrobiopterin, with subsequent elevation of endothelial nitric oxide synthase activity. Cytokine-induced GCH1 up-regulation in HUVECs in response to TNF and IFNG/IFN-gamma involves cooperative activation of both the NF-kappa-B and JAK2/STAT pathways. Also up-regulated by hydrogen peroxide in human aorta endothelial cells (HAECs).

Enzyme Regulation:

GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+).

Molecular Function:

• Calcium Ion Binding
• Coenzyme Binding
• Gtp Binding
• Gtp Cyclohydrolase I Activity
• Protein Homodimerization Activity
• Zinc Ion Binding

Biological Processes:

• 7,8-Dihydroneopterin 3'-Triphosphate Biosynthetic Process
• Dopamine Biosynthetic Process
• Negative Regulation Of Blood Pressure
• Neuromuscular Process Controlling Posture
• Nitric Oxide Biosynthetic Process
• Positive Regulation Of Nitric-Oxide Synthase Activity
• Protein Heterooligomerization
• Protein Homooligomerization
• Pteridine-Containing Compound Biosynthetic Process
• Regulation Of Blood Pressure
• Regulation Of Lung Blood Pressure
• Regulation Of Nitric-Oxide Synthase Activity
• Regulation Of Removal Of Superoxide Radicals
• Response To Interferon-Gamma
• Response To Lipopolysaccharide
• Response To Pain
• Response To Tumor Necrosis Factor
• Tetrahydrobiopterin Biosynthetic Process
• Tetrahydrofolate Biosynthetic Process
• Vasodilation

Drug Bank:

• Isopropyl Alcohol

*synonyms