GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).
GTPCH is encoded by the gene GCH1. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all of the variants give rise to a functional enzyme. [5]
At least 94 disease-causing mutations in this gene have been discovered. [6] Mutations in this gene are associated with two disorders: autosomal recessive GTP cyclohydrolase I deficiency and autosomal dominant GTP cyclohydrolase I deficiency. These may present with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA) [5] and lead to a lack of certain neurotransmitters (dopamine, norepinephrine, epinephrine and serotonin). The dominant form, with mutation in only one of the two alleles for GTP cyclohydrolase I, causes dopamine-responsive dystonia, characterized by childhood-onset dystonia. Patients with the recessive form have mutations in both alleles for GTP cyclohydrolase I. Patients present with developmental delays and neurological dysfunction with trunk hypotonia, hypertonia of the extremities, abnormal movements, tremors, convulsions, and sometimes autonomic dysfunction. [7] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). [8]
 The chemical reaction performed by GTPCH. The important carbons relative to the transformation are numbered for reference. | |||||||||
| Identifiers | |||||||||
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| EC no. | 3.5.4.16 | ||||||||
| CAS no. | 37289-19-3 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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The transcribed protein is the first and rate-limiting enzyme in tetrahydrobiopterin (THB, BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-DHNP-3'-TP. THB is an essential cofactor required by the aromatic amino acid hydroxylase (AAAH) and nitric oxide synthase (NOS) enzymes in the biosynthesis of the monoamine neurotransmitters serotonin (5-hydroxytryptamine (5-HT)), melatonin, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and nitric oxide (NO), respectively.[ citation needed ]
GTPCH (GCH1) and tetrahydrobiopterin were found to protect against cell death by ferroptosis. Tetrahydrobiopterin (BH4) acts as a potent, diffusable antioxidant that resists oxidative stress and enables cancer cell survival. [9]
l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.
Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).
Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, as a group, are compounds related to pterin with additional substituents. Pterin itself is of no biological significance.
Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.
6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors, monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).
GTP cyclohydrolases are enzymes that catalyze imidazole ring opening of guanosine triphosphate (GTP). This reaction is the committed step in the biosynthesis of multiple coenzymes, tRNA bases, and the phytotoxin toxoflavin. Several GTP cyclohydrolases exist, which sometimes synthesize different products for different pruposes:
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).
Queuine (Q) is a hypermodified nucleobase found in the first position of the anticodon of tRNAs specific for Asn, Asp, His, and Tyr, in most eukaryotes and prokaryotes. Because it is utilized by all eukaryotes but produced exclusively by bacteria, it is a putative vitamin.
Biopterins are pterin derivatives which function as endogenous enzyme cofactors in many species of animals and in some bacteria and fungi. The prototypical compound of the class is biopterin, as shown in the infobox. Biopterins act as cofactors for aromatic amino acid hydroxylases (AAAH), which are involved in synthesizing a number of neurotransmitters including dopamine, norepinephrine, epinepherine, and serotonin, along with several trace amines. Nitric oxide synthesis also uses biopterin derivatives as cofactors. In humans, tetrahydrobiopterin (BH4) is the endogenous cofactor for AAAH enzymes.
Sepiapterin reductase is an enzyme that in humans is encoded by the SPR gene.
The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the following chemical reaction:
GTP cyclohydrolase 1 feedback regulatory protein is an enzyme that in humans is encoded by the GCHFR gene.
Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.
Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures. Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma.
Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.
Catecholamines up (Catsup) is a dopamine regulatory membrane protein that functions as a zinc ion transmembrane transporter (orthologous to ZIP7), and a negative regulator of rate-limiting enzymes involved in dopamine synthesis and transport: Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) in Drosophila melanogaster.
Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene.
Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD) is a disorder associated with the deficient operation of the enzyme GTP cyclohydrolase I. The condition leads to insufficient production of the cofactor tetrahydrobiopterin necessary for the proper synthesis of dopamine and serotonin and for maintenance of adequate levels of phenylalanine. As of 2020, autosomal recessive GTP cyclohydrolase I deficiency was one of the six known causes of tetrahydrobiopterin deficiency. It is also considered part of the spectrum of dopa-responsive dystonias.
Autosomal dominant GTP cyclohydrolase I deficiency (AD-GTPCHD) is a disease caused by dysfunction of GTP cyclohydrolase I, an enzyme that plays an important role in the synthesis of tetrahydrobiopterin, and, as a consequence, of dopamine. This condition is one of the six known causes of tetrahydrobiopterin deficiency and is the most frequently-reported cause of dopa-responsive dystonia.
Tyrosine hydroxylase deficiency (THD) is a disorder caused by disfunction of tyrosine hydroxylase, an enzyme involved in the biosynthesis of dopamine. This condition is one of the causes of dopa-responsive dystonia.
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