Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only difference being that nucleotides like GTP have phosphates on their ribose sugar. GTP has the guanine nucleobase attached to the 1' carbon of the ribose and it has the triphosphate moiety attached to ribose's 5' carbon.
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.
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 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).
10-Formyltetrahydrofolate (10-CHO-THF) is a form of tetrahydrofolate that acts as a donor of formyl groups in anabolism. In these reactions 10-CHO-THF is used as a substrate in formyltransferase reactions.
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.
Riboflavin synthase is an enzyme that catalyzes the final reaction of riboflavin biosynthesis. It catalyzes the transfer of a four-carbon unit from one molecule of 6,7-dimethyl-8-ribityllumazine onto another, resulting in the synthesis of riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione:
In enzymology, a formate—tetrahydrofolate ligase is an enzyme that catalyzes the chemical reaction
The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the following chemical reaction:
In enzymology, a GTP cyclohydrolase II (EC 3.5.4.25) is an enzyme that catalyzes the chemical reaction
In enzymology, a GTP cyclohydrolase IIa (EC 3.5.4.29) is an enzyme that catalyzes the chemical reaction
MTHFD1 is a gene located in humans on chromosome 14 that encodes for a protein with three distinct enzymatic activities. C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase is an enzyme that in humans is encoded by the MTHFD1 gene.
GTP cyclohydrolase 1 feedback regulatory protein is an enzyme that in humans is encoded by the GCHFR gene.
The enzyme 3,4-dihydroxy-2-butanone 4-phosphate synthase (RibB) EC 4.1.99.12 catalyses the conversion of D-ribulose 5-phosphate to formate and 3,4-dihydroxy-2-butanone 4-phosphate, the latter serving as the biosynthetic precursor for the xylene ring of riboflavin. In Photobacterium leiognathi, the riboflavin synthesis genes ribB, ribE, ribH and ribA all reside in the lux operon. RibB is sometimes found as a bifunctional enzyme with GTP cyclohydrolase II that catalyses the first committed step in the biosynthesis of riboflavin. No sequences with significant homology to DHBP synthase are found in the metazoa.
2,5-diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine is a metabolite in the purine metabolism, formed by the hydrolysis of GTP by GTP cyclohydrolase II. Alternatively two separate enzymes can carry out this reaction, initially GTP cyclohydrolase IIa hydrolyses the 8,9 bond to form 2-Amino-5-formylamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one, followed by de-formylation by 2-amino-5-formylamino-6-ribosylaminopyrimidin-4(3H)-one 5'-monophosphate deformylase. 2,5-diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine is deaminated by Diaminohydroxyphosphoribosylaminopyrimidine deaminase to form 5-amino-6-(5-phosphoribosylamino)uracil.
2-Amino-5-formylamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one is a metabolite in the riboflavin biosynthesis pathway. It is formed from GTP by the enzyme GTP cyclohydrolase IIa which catalyzes the hydrolysis of the 8,9 bond in the guanine group and loss of the beta and gamma phosphate groups. The molecule is deformylated by 2-amino-5-formylamino-6-ribosylaminopyrimidin-4(3H)-one 5'-monophosphate deformylase as the second step in the archaeal riboflavin biosynthetic pathway.
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.
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.
