Disease relevance of Gch1

• Mutations in GTP-cyclohydrolase I (GTP-CH) have been identified as causing a range of inborn errors of metabolism, including dopa-responsive dystonia [1].
• We identified missense mutations in patients with GTP cyclohydrolase I deficiency and expressed mutated enzymes in Escherichia coli to confirm alterations in the enzyme activity [2].
• The biosynthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH4) in murine erythroleukemia (MEL) cells is almost completely inhibited by 10 mM, 2,4-diamino-6-hydroxypyrimidine (DAHP), which targets GTP cyclohydrolase [3].
• One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis [4].
• The mouse mutant HPH-1, previously generated by chemical mutagenesis, shows a phenylketonuria due to decreased hepatic GTP cyclohydrolase I activity [5].

High impact information on Gch1

• Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression [6].
• We have now investigated the importance and mechanisms of BH4 availability in vivo using a novel transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, guanosine triphosphate-cyclohydrolase I (GTPCH) [6].
• Our finding of much higher levels of BH4 and GTP cyclohydrolase, the first enzyme of de novo BH4 biosynthesis, in rat reticulocytes compared to mature erythrocytes raised the possibility that BH4 might play a role in erythrocyte maturation [7].
• To investigate the pathophysiology, we have begun to characterize biogenic amine and BH4 metabolism in the GTP cyclohydrolase deficient hph-1 mouse [8].
• In vitro data demonstrate that NAMDA inhibited GTP cyclohydrolase I, the rate-limiting enzyme for BH4 biosynthesis, and reduced nitrite accumulation, an oxidative metabolite of NO, without directly inhibiting NOS activity [9].

Chemical compound and disease context of Gch1

• Tetrahydrobiopterin biosynthesis in C6 glioma cells: induction of GTP cyclohydrolase I gene expression by lipopolysaccharide and cytokine treatment [10].
• Tetrahydrobiopterin (BH4) levels and GTP cyclohydrolase activity (GTP-CH) were measured in tissues from mutants and controls of 24 different mouse strains to identify mutants that might be suitable models for diseases which are characterized by a deficiency of the biopterin cofactor, such as parkinsonism and atypical phenylketonuria [11].

Biological context of Gch1

• GTP cyclohydrolase I gene expression in the brains of male and female hph-1 mice [12].
• The 5' flanking region of the GTPCH gene was cloned and sequenced and shown to be identical for both wild-type and hph-1 genomic DNA [12].
• These results suggest that GTP cyclohydrolase I upregulation alone is enough to modulate tetrahydrobiopterin production in the locus coeruleus [13].
• Our research establishes genetic linkage between the hph-1 mutation and the GTP-CH I structural gene [14].
• With the long-term goal of using gene transfer to the skin to remove phenylalanine, we have previously shown that overexpression of PAH, catalyzing the hydroxylation of phenylalanine, and GTP cyclohydrolase (GTP-CH), involved in the formation of the necessary cofactor BH4,are required [15].

Anatomical context of Gch1

• This study was performed to address whether the increase in GTP cyclohydrolase I protein is dependent on the de novo synthesis of GCH in the locus coeruleus [13].
• Stimulation of macrophages with recombinant human interferon-gamma and neutralization of the effect of T cell supernatants by addition of a monoclonal antibody specific for human interferon-gamma showed that immune interferon induced the alterations in GTP cyclohydrolase I activity and neopterin concentration [16].
• Exogenous tetrahydrobiopterin added to the culture medium of stimulated T cells and macrophages suppressed the elevation of GTP cyclohydrolase I activity and neopterin concentration, but not the elevation of intracellular GTP [16].
• These results suggest that other enzymes than GTP-CH, involved in BH4 synthesis and/or regeneration, can be rate-limiting in the genetically modified keratinocytes [15].
• In a concerted action kit ligand and interleukin 3 control the synthesis of serotonin in murine bone marrow-derived mast cells. Up-regulation of GTP cyclohydrolase I and tryptophan 5-monooxygenase activity by the kit ligand [17].

Associations of Gch1 with chemical compounds

• Analysis of the mice showed that no phenotypic effect was observed in mice expressing PAH and GTP-CH from the INV promoter [18].
• Together, these data suggest that Nurr1 may function to modify TH and GTPCH expression and dopamine synthesis [19].
• GTP-CH catalyses the first step in the biosynthesis of tetrahydrobiopterin (BH4), a cofactor necessary for the synthesis of catecholamines and serotonin [1].
• In wild-type male and female animals the highest levels of GTPCH mRNA expression were observed within serotonin neurons, followed by norepinephrine and then dopamine neurons [12].
• In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein [20].

Regulatory relationships of Gch1

• In addition, type-2 cationic amino acid transporter (CAT-2) and guanosine triphosphate cyclohydrolase I (GTPCH) also regulate iNOS activity [21].
• In the wild type mouse (C57BL/6), interferon-gamma and kit ligand induce GTP cyclohydrolase I activity in primed T-cells and in bone marrow-derived mast cells, respectively [5].
• These results demonstrate that LPS and TNF-alpha stimulate de-novo BH4 biosynthesis and suggest that C6 cells offer a model system for studying the molecular events that control the induction of GTPCH gene expression and BH4 synthesis in glial cells [10].

Other interactions of Gch1

• Characterization of transgenic mice with the expression of phenylalanine hydroxylase and GTP cyclohydrolase I in the skin [18].
• The effect on TH expression was only observed at birth, while reduced GTP cyclohydrolase was also observed in the adult ventral tegemental area [19].
• Overall, these results indicate that not only are basal levels of GTPCH mRNA expression heterogeneous across wild-type murine monoamine cell types but that gene expression is also modified in a sex-linked and cell-specific fashion by the hph-1 gene locus [12].
• Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined [16].
• Cardiovascular Control: Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice [22].
• These changes in GTPCH and BH4 had no effect on GFRP expression or protein levels [23].

Analytical, diagnostic and therapeutic context of Gch1

• A quantitative double-label in situ hybridization technique was used to examine CNS GTPCH mRNA expression within serotonin, dopamine, and norepinephrine neurons of male and female wild-type and hph-1 mice [12].
• In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form [24].
• Small interfering RNA targeted against Nurr1 decreases GTPCH expression in MC3T3-E1 osteoblasts in cell culture [25].
• Northern blot analysis demonstrates a marked decrease in the steady state mRNA level specific for GTP cyclohydrolase I [5].
• PCR amplification of the ORF from chromosomal DNA and sequencing showed the existence of a 101 bp intron in the GTP-CH gene of Dictyostelium discoideum [26].

References