It has been reported that corticotropin-releasing factor (CRF) is involved in the regulation of norepinephrine neuron responses to stress such as an immobilized stress. Furthermore, systemic lipopolysaccharide (LPS) injection upregulates the transcription of the genes encoding CRF and CRF type 1 receptor in the paraventricular nucleus of the hypothalamus. We have already reported that an increase in norepinephrine turnover within the murine locus coeruleus is accompanied by septic shock triggered by LPS intraperitoneal injection. We also elucidated that the expression levels of the enzymes involved in the catecholamine biosynthesis were altered by peripheral LPS injection. Collectively, the effects of CRF on the expression levels of the enzymes at murine locus coeruleus were investigated by peripherally injecting CP-154,526, a CRF receptor type 1 antagonist. Pretreatment with CP-154,526 attenuated the increase in expression levels of GTP cyclohydrolase I mRNA due to intraperitoneal LPS injection at 4 h
Tetrahydrobiopterin (BH4) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH4 is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH4 from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH4, but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory ...
The PND association is a disease organization representing children and families who are affected by a pediatric neurotransmitter disease.. As a rare disease advocacy organization our mission is to represent and be a voice for all children affected by dopamine related PNDs. Our goals are to help children and families who are affected by PNDs, support the identification of new PNDs, find better treatments and ultimately a cure for those diseases that are already known. The PND Association was founded in 1998 and is a non-profit, voluntary organization.. All information contained on the PND Association website is intended for informational and educational purposes. The information is not intended to be a replacement or substitute for professional medical treatment or for professional medical advice relative to a specific medical question or condition. ...
Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases.
DOPA responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency are inherited disorders of tetrahydrobiopterin (BH4) metabolism characterized by the signs and symptoms related to monoamine neurotransmitter deficiency. In contrast to classical forms of BH4 deficiency DRD and SR deficiency present without hyperphenylalaninemia and thus cannot be detected by the neonatal screening for phenylketonuria (PKU). While DRD is mostly caused by autosomal dominant mutations in the GTP cyclohydrolase I gene (GCH1), SR deficiency is an autosomal recessive disease. The most important biochemical investigations for the diagnosis of these neurological diseases includes CSF investigations for neurotransmitter metabolites and pterins as well as neopterin and biopterin production in cytokine-stimulated fibroblasts. Discovery of SR deficiency opened new insights into alternative pathways of the cofactor BH4 via carbonyl, aldose, and dihydrofolate reductases. As a consequence of the low dihydrofola
Thus, the two substrates of this enzyme are GTP and H2O, whereas its 3 products are formate, 2,5-diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine, and diphosphate.. This enzyme belongs to the family of hydrolases, those acting on carbon-nitrogen bonds other than peptide bonds, specifically in cyclic amidines. The systematic name of this enzyme class is GTP 7,8-8,9-dihydrolase (diphosphate-forming). Other names in common use include guanosine triphosphate cyclohydrolase II, and GTP-8-formylhydrolase. This enzyme participates in riboflavin metabolism.. ...
TY - JOUR. T1 - C-terminus of heat shock protein 70-interacting protein-dependent GTP cyclohydrolase I degradation in lambs with increased pulmonary blood flow. AU - Sun, Xutong. AU - Fratz, Sohrab. AU - Sharma, Shruti. AU - Hou, Yali. AU - Rafikov, Ruslan. AU - Kumar, Sanjiv. AU - Rehmani, Imran. AU - Tian, Jing. AU - Smith, Anita. AU - Schreiber, Christian. AU - Reiser, Judith. AU - Naumann, Susanne. AU - Haag, Sebastian. AU - Hess, John. AU - Catravas, John D.. AU - Patterson, Cam. AU - Fineman, Jeffery R.. AU - Black, Stephen M.. PY - 2011/7/1. Y1 - 2011/7/1. N2 - We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine ...
AIMS: Clinical markers of cardiac autonomic function, such as heart rate and response to exercise, are important predictors of cardiovascular risk. Tetrahydrobiopterin (BH4) is a required cofactor for enzymes with roles in cardiac autonomic function, including tyrosine hydroxylase and nitric oxide synthase. Synthesis of BH4 is regulated by GTP cyclohydrolase I (GTPCH), encoded by GCH1. Recent clinical studies report associations between GCH1 variants and increased heart rate, but the mechanistic importance of GCH1 and BH4 in autonomic function remains unclear. We investigate the effect of BH4 deficiency on the autonomic regulation of heart rate in the hph-1 mouse model of BH4 deficiency. METHODS AND RESULTS: In the hph-1 mouse, reduced cardiac GCH1 expression, GTPCH enzymatic activity, and BH4 were associated with increased resting heart rate; blood pressure was not different. Exercise training decreased resting heart rate, but hph-1 mice retained a relative tachycardia. Vagal nerve stimulation in vitro
OBJECTIVE: The posttranslational regulation of GTP cyclohydrolase I (GCH-1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, remains elusive. Here, we identified specific phosphorylation sites on GCH-1 and characterized the function of these sites.. METHODS AND RESULTS: Mass spectrometry studies showed overexpressed rat GCH-1 was phosphorylated at serine (S) 51, S167, and threonine (T) 231 in HEK293 cells, whereas a computational analysis of GCH-1 revealed 8 potential phosphorylation sites (S51, S72, T85, T91, T103, S130, S167 and T231). GCH-1 activity and BH4 were significantly decreased in cells transfected with the phospho-defective mutants (S72A, T85A, T91A, T103A, or S130A) and increased in cells transfected with the T231A mutant. BH4 and BH2 were increased in cells transfected with S51E, S72E, T85E, T91E, T103D, or T130D mutants, but decreased in cells transfected with the T231D mutant, whereas cells transfected with the S167A or the S167E mutant had increased BH2. ...
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and nitric oxide (NO) generation. Augmentation of BH4 levels can prevent eNOS uncoupling and improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de-novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell-specific deletion of GCH1, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell-autonomous requirement for endothelial BH4 biosynthesis in vivo.. Mice with a floxed GCH1 allele (GCH1fl/fl) were crossed with Tie2cre mice to delete GCH1 in endothelial cells. GCH1fl/flTie2cre mice demonstrated virtually absent NO bioactivity and significantly greater O2•- production. GCH1fl/flTie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and ...
Fibroblast growth factor receptors (FGFRs) have been implicated in the malignant transformation and chemoresistance of epithelial ovarian cancer; however, the underlying molecular mechanisms are poorly understood. Increased sialyltransferase activity that enhances protein sialylation is an important post‑translational process promoting cancer progression and malignancy. In the present study, α2,6‑sialyltransferase (ST6Gal‑I) overexpression or knockdown cell lines were developed, and FGFR1 was examined to understand the effect of sialylation on migration and drug resistance, and the underlying mechanisms. It was identified that cells with ST6Gal‑I overexpression had increased cell viability and migratory ability upon serum deprivation. Moreover, ST6Gal‑I overexpression cells had strong resistance to paclitaxel, as demonstrated by low growth inhibition rate and cell apoptosis level. A mechanistic study showed that ST6Gal‑I overexpression induced high α2,6‑sialylation of FGFR1 and ...
购买我们的重组人GTP cyclohydrolase 1蛋白。Ab114821为蛋白片段,在小麦胚芽中生产并经过ELISA, SDS-PAGE, Western blot实验验证。Abcam提供免费的实验方案,操作技巧及专业的支持。
Sigma-Aldrich offers abstracts and full-text articles by [Anna Starr, Claire A Sand, Lamia Heikal, Peter D Kelly, Domenico Spina, Mark Crabtree, Keith M Channon, James M Leiper, Manasi Nandi].
Excessive intimal hyperplasia, the principal cause of PCI failure, is associated with reduced endothelial nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS). We investigated the importance of BH4 in regulating intimal hyperplasia using a transgenic mouse with endothelial overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GCH). Angioplasty and stenting was performed on aortic segments from donor transgenic mice crossed onto ApoE-KO background (GCH-Tg/ApoE-KO) or their ApoE-KO littermates (n=16), using a novel model of stenting in mice where the stented donor aortic segment is grafted into the carotid artery of isogenic recipients. Aortic BH4 levels were 8-fold higher in GCH-Tg/ApoE-KO mice compared with ApoE-KO controls. (P,0.01). Despite equal stent expansion and injury scores, intimal hyperplasia was reduced by 47% (P,0.001) in GCH-Tg/ApoE-KO mice. Aortic NO synthesis, ...
GTP cyclohydrolase I (encoded by gene folE) is the first Zn(2+)-dependent enzyme of the de novo tetrahydrofolate biosynthetic pathway. It presents in bacteria, fungi, and plants. It catalyzes the conversion of GTP to 7,8-dihydroneopterin triphosphate. The 2.1A resolution structure of GTP cyclohydrolase I from Yersinia pestis CO92 is a pentomer in the asymmetric unit. The structure contains, in the active site, five GTP molecules and Ca(2+) ions probably from crystallization in place of Zn(2+) determined by atomic distances and fluorescence spectrum ...
OBJECTIVE: When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E-deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. METHODS AND RESULTS: We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4
Endothelial dysfunction in vascular disease states is associated with reduced NO bioactivity and increased superoxide (O2 ) production. Some data suggest that an important mechanism underlying endothelial dysfunction is endothelial NO synthase (eNOS) uncoupling, whereby eNOS generates O2 rather than NO, possibly because of a mismatch between eNOS protein and its cofactor tetrahydrobiopterin (BH4). However, the mechanistic relationship between BH4 availability and eNOS coupling in vivo remains undefined because no studies have investigated the regulation of eNOS by BH4 in the absence of vascular disease states that cause pathological oxidative stress through multiple mechanisms. We investigated the stoichiometry of BH4-eNOS interactions in vivo by crossing endothelialtargeted eNOS transgenic (eNOS-Tg) mice with mice overexpressing endothelial GTP cyclohydrolase 1 (GCH-Tg), the rate-limiting enzyme in BH4 synthesis. eNOS protein was increased 8-fold in eNOS-Tg and eNOS/GCH-Tg mice compared with wild type.
In this study, we have for the first time demonstrated that ONOO− releases zinc from GTPCH1 and that zinc removal lowers GTPCH1 activity. Further, zinc-deleted GTPCH1 exhibits increased ubiquitination and reduced stability. We found that ONOO− generated by high glucose suppresses GTPCH1 activity along with increased ubiquitination and destruction of this enzyme. Finally, GTPCH1 ubiquitination and destruction is markedly increased in parallel with enhanced ONOO− in STZ-induced diabetic mice in vivo. Overall, our results suggest that ONOO− releases zinc, inhibits GTPCH1 activity, and increases GTPCH1 ubiquitination.. The major finding of this study is that ONOO− removes the zinc in GTPCH1, resulting in enzyme inhibition. Several lines of evidence are consistent with the hypothesis that loss of zinc by ONOO− oxidation underlies the inactivation of GTPCH1. First, ONOO− dose-dependently releases zinc from GTPCH1 (Fig. 1B). Second, the effects of ONOO− are mimicked by TPEN, a selective ...
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinsons disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of ...
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinsons disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of ...
Tetrahydrobiopterin (BH4) is an essential co-factor for NO production from NOS enzymes. When BH4 levels become limiting these enzymes can become un-coupled, leading to superoxide production. GTP cyclohydrolase I (GTPCH), encoded by GCH1, is an essential enzyme in the biosynthesis of BH4. BH4 deficiency has been been shown to cause endothelial dysfunction and to exacerbate atherosclerosis in experimental models. However, the role of BH4 in regulating iNOS activity in leukocytes, and the potential impact of this on atherosclerosis is less clear. We have utilised a novel transgenic mouse to address the role of BH4 and iNOS in macrophage biology.. We designed mice harbouring a floxed portion of the GCH1 locus within the active site of the enzyme (GCHfl/fl mice). We crossed these with mice expressing the cre enzyme under control of the Tie2 promoter (GCHfl/fl Tie2cre). Cre expression causes efficient excision of the floxed allele in all leukocytes and endothelial cells, as detected by PCR for the ...
Local overproduction of nitric oxide is seen in early stages of diabetes, which can react with superoxide (O2 −) to form peroxynitrite (ONOO−). The aim of this study was to examine the effect of scavengers for nitric oxide, O2 −, ONOO− and NOS cofactor tetrahydrobiopterin (BH4) on high glucose-induced cardiac contractile dysfunction. Ventricular myocytes were cultured for 24 h with either normal (N, 5.5 mmol/l) or high (25.5 mmol/l) glucose, with or without the nitric oxide scavengers haemoglobin (100 nmol/l), PTIO (100 µmol/l), the NOS inhibitor L-NMMA (100 µmol/l), superoxide dismutase (SOD, 500 U/ml), the ONOO− scavengers urate (100 µmol/l), MnTABP (100 µmol/l), BH4 (10 µmol/l) and its inactive analogue NH4 (10 µmol/l), and the GTP cyclohydrolase I inhibitor DAHP (1 mmol/l). Myocyte mechanics, NOS protein expression and activity were evaluated. High glucose myocytes showed reduced peak shortening, decreased maximal velocity of shortening/relengthening (± dL/dt), prolonged
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BioAssay record AID 3144 submitted by ChEMBL: Percent inhibition was measured against 5,10-Methylene Tetrahydrofolate Cyclohydrolase (L1210 tumor tissue) enzyme at 10E-6 M inhibitory concentration.
During ischemia stage, pHi and pHe were reduced to 5.8 and 6.2 from pre-ischemia stage(pHe 7.4,pHi 7.2), respectively. AP amplitude was also decreased. Sodium overload existed in 10-minutes ischemia stage, compared with pre-ischemia, exacerbating in 10-minutes reperfusion stage. INa 50% block slightly reduced intracellular sodium concertration([Na]i), while CaMKII 50% block and both block groups reduced [Na]i more significantly. Calcium overload were found in control and INa 50% block, while it was reduced significantly in CaMKII 50% block and both block, which reveals that CaMKII is essential to keep calcium overload, not INa. Consistently, we found NCX current were also reduced in CaMKII 50% block and both block,which suggested that NCX played downstream role of CaMKII and calcium overload.. To further explore the mechanisms of CaMKII and INa on MIRI, we analyzed various currents which might be related with sodium and calcium overload. During pre-ischemia stage, we can see that Peak INa keeps ...
MetabolismBiosynthesis of cofactors, prosthetic groups, and carriersRiboflavin, FMN, and FADGTP cyclohydrolase II (TIGR00505; EC 3.5.4.25; HMM-score: 12.4) ...
GCH1 encodes GTPCH1, the rate-limiting enzyme for BH4 synthesis. Im curious to find out if anyone else has a mutation to this gene because low BH4...
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TY - JOUR. T1 - Transcribing the cross-talk of cytokine-induced tetrahydrobiopterin synthesis in endothelial cells. AU - Peterson, Timothy E.. AU - Katusic, Zvonimir S.. PY - 2005/2/4. Y1 - 2005/2/4. KW - Interferon-γ. KW - Nitric oxide. KW - Nitric oxide synthase. KW - Tumor necrosis factor-α. UR - http://www.scopus.com/inward/record.url?scp=13444271566&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=13444271566&partnerID=8YFLogxK. U2 - 10.1161/01.RES.0000156078.12390.44. DO - 10.1161/01.RES.0000156078.12390.44. M3 - Editorial. C2 - 15692091. AN - SCOPUS:13444271566. VL - 96. SP - 141. EP - 143. JO - Circulation Research. JF - Circulation Research. SN - 0009-7330. IS - 2. ER - ...
The autosomal recessive form of GTPCH I deficiency causes no detectable enzyme activity5 6 Patients are normally detected on newborn screening for phenylketonuria but most already have symptoms of dopamine deficiency (personal observations).6 CSF concentrations of homovanillic acid (HVA), 5HIAA, neopterin, and BH4 are all markedly reduced (personal observations).5Heterozygotes do not manifest clinical symptoms and have 30% to 50% residual enzyme activity.5 By contrast, it has been suggested that in the dominant form of GTPCH I deficiency described here residual enzyme activities are 2% to 20% of normal (instead of the 50% expected) implying that the mutation causes dysfunction of the normal gene. In recessively inherited GTPCH I deficiency, heterozygotes have 30% to 46% activity and are normal.7 Biochemical abnormalities in CSF are also more subtle in the dominant form. The only consistent abnormality in the affected patients here is a modest reduction in CSF neopterin to 22% to 30% of mean ...
production by the enzyme.. In other cells, GTPCH-1 has been shown to be mediated by transcriptional mechanisms, posttranslationally by phosphorylation, and by the GTPCH-interacting protein GFRP, which modulates the activity of the enzyme. Cytokines lead to a marked upregulation of GTPCH-1 protein levels in several cells types.18,25-27 Hydrogen peroxide has also been shown to stimulate GTPCH-1 mRNA levels in mouse brain microvascular endothelial cells and in bovine endothelial cells.28 Unlike the cytokines and hydrogen peroxide, we found that laminar shear had no effect on GTPCH-1 protein expression but increased its activity by 30-fold. Of interest, the activity of PTPS and SR were unchanged by shear stress. Our data therefore indicate that the activity of GTPCH-1 is the regulating factor for H4B levels with shear stress. If one compares the relative activities of GTPCH-1, PTPS, and SR at baseline, it is obvious that PTPS activity is ≈10-fold higher than GTPCH-1, whereas SR activity is almost ...
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Riboflavin serves as a precursor for flavocoenzymes (FMN and FAD) and is essential for all living organisms. The two committed enzymatic steps of riboflavin biosynthesis are performed in plants by bifunctional RIBA enzymes comprised of GTP cyclohydrolase II (GCHII) and 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS). Angiosperms share a small RIBA gene family consisting of three members. A reduction of AtRIBA1 expression in the Arabidopsis rfd1mutant and in RIBA1 antisense lines is not complemented by the simultaneously expressed isoforms AtRIBA2 and AtRIBA3. The intensity of the bleaching leaf phenotype of RIBA1 deficient plants correlates with the inactivation of AtRIBA1 expression, while no significant effects on the mRNA abundance of AtRIBA2 and AtRIBA3 were observed. We examined reasons why both isoforms fail to sufficiently compensate for a lack of RIBA1 expression. All three RIBA isoforms are shown to be translocated into chloroplasts as GFP fusion proteins. Interestingly, both AtRIBA2 and
In the present report, the regulation of mRNA abundance and specific activity of PTPS, the second enzyme in the synthesis of BH4, by inflammatory cytokines is described for the first time. GTPCH, the first enzyme in the BH4 synthesis pathway, has been widely described as the rate-limiting step in mammals.9 Up to a 40-fold regulation of GTPCH activity was found in cells treated with inflammatory stimuli,2 8 which is consistent with the strongly elevated GTPCH mRNA level reported in the present article. In humans, PTPS was generally believed to be constitutively present and to become rate limiting on induction of GTPCH, reflected by production of higher neopterin than biopterin concentrations.8 However, the persistent low levels of neopterin in HUVECs even after inflammatory activation (Table⇑), suggest that PTPS is either present with high constitutive activity or that its expression is upregulated by cytokines. We demonstrated that PTPS is upregulated in HUVECs by a combination of inflammatory ...
In this study, we describe a new double-transgenic mouse model in which endothelial-targeted overexpression of GTPCH leads to increased endothelial BH4 levels in mice with endothelial-targeted eNOS overexpression. We used this model to investigate the role of BH4 in the regulation of eNOS coupling in vivo, specifically in the absence of pathological oxidative stress associated with vascular disease states.6 The major findings in this study are as follows. First, eNOS protein levels are markedly elevated in eNOS-Tg and eNOS/GCH-Tg mice but not in GCH-Tg animals, although the proportion of eNOS dimer to monomer is depleted only in eNOS-Tg aortas. Second, endothelial-specific overexpression of GTPCH is sufficient to increase vascular BH4 levels in GCH-Tg and in eNOS/GCH-Tg aortas, whereas BH4 levels are depleted in eNOS-Tg aortas. Third, this increase in BH4 is sufficient to augment vascular eNOS enzymatic activity even in GCH-Tg mice, which have unchanged eNOS protein levels. Indeed, eNOS activity ...
Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine (DA), noradrenaline (NA), serotonin and nitric oxide (NO) synthesis in the brain. Inborn errors of BH4 metabolism including GTP cyclohydrolase 1 (GTP-CH) deficiency are debilitating diseases in which BH4, DA, 5-HT and NO metabolism are impaired. Current treatment for these disorders is typically monoamine replacement +/- BH4. Whilst correction of the primary defect is the ideal, BH4 treatment is problematic as it is expensive and inefficacious. One approach to treat BH4 disorders is to use gene therapy as a more permanent, effective alternative. In this thesis the potential of gene therapy in an animal model of partial BH4 deficiency, the hph-1 mouse, was examined. These mice show many neurochemical similarities associated with BH4 deficient states, including impaired BH4 (-69%), DA (-14%), NA (-23%), serotonin turnover (-55%) and NO metabolites in the brain. In cultured astrocytes from hph-1 mice BH4 was significantly lower than ...
B Chronic oral tetrahydrobiopterin treatment in patients with coronary artery disease elevates total biopterin levels but does not improve biopterin redox status or vascular function: a randomised placebo-controlled trial ...
Overproduction of nitric oxide (NO) is thought to be a key mediator of the vascular dysfunction and severe hypotension in patients with endotoxaemia and septic shock. The contribution of NO produced directly in the vasculature by endothelial cells to the hypotension seen in these conditions, vs. the broader systemic increase in NO, is unclear. To determine the specific role of endothelium derived NO in lipopolysaccharide (LPS)-induced vascular dysfunction we administered LPS to mice deficient in endothelial cell tetrahydrobiopterin (BH4), the essential co-factor for NO production by NOS enzymes. Mice deficient in endothelial BH4 production, through loss of the essential biosynthesis enzyme Gch1 (Gch1(fl/fl)Tie2cre mice) received a 24hour challenge with LPS or saline control. In vivo LPS treatment increased vascular GTP cyclohydrolase and BH4 levels in aortas, lungs and hearts, but this increase was significantly attenuated in Gch1(fl/fl)Tie2cre mice, which were also partially protected from the LPS
Sengupta S and Chandra T.S , Molecular and structural characterization of GTP-cyclohydrolase II in Eremothecium ashbyi NRRL Y-1363: cDNA cloning, comparative sequence analysis and molecular modeling . Fungal Biology 2010 doi:10.1016/j.funbio.2010.06.006 Copyright © 2010 The British Mycological Society Published by Elsevier Ltd (originally called Mycological Research ...
After living the first 33 years of my life thinking I had Spastic Diplegia, I was correctly diagnosed with Dopa Responsive Dystonia (DRD). I am on new medication and doing things that I never imagined possible. This has changed the lives of my husband and two daughters. I truly believe that I am living a miracle each and every day. Life cant get any better than this. ...
TY - JOUR. T1 - Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. AU - Rodriguez-Miguelez, Paula. AU - Gregg, Justin. AU - Seigler, Nichole. AU - Bass, Leon. AU - Thomas, Jeffrey. AU - Pollock, Jennifer S.. AU - Sullivan, Jennifer C. AU - Dillard, Thomas A. AU - Harris, Ryan A.. PY - 2018/9/1. Y1 - 2018/9/1. N2 - Background: Cardiovascular diseases represent a hallmark characteristic in COPD, and endothelial dysfunction has been observed in these patients. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthesis and a regulator of endothelial function. The goal of this study was to test the hypothesis that a single dose of BH4 would improve endothelial function in patients with COPD via an increase in NO bioavailability. Methods: Seventeen patients with COPD completed a randomized, double-blind, placebo (PLC)-controlled, crossover trial with an acute dose of either BH4 (Kuvan; BioMarin Pharmaceutical Inc) or PLC. Flow-mediated dilation ...
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Biopterin is a coenzyme thats used to make several important neurotransmitters in the body. Problems with biopterin levels can...
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The aim of this study was to establish levels of the enzymes involved in tetrahydrobiopterin (BH4) metabolism in human and rat brain preparations; to determine whether BH4 metabolism is altered in dementia, particularly in relation to senile dementia of the Alzheimer type (SDAT); and to examine the effect of aluminium on BH4 metabolism. Overall BH4 synthesis and dihydropteridine reductase (DHPR) activity were greater in the locus coeruleus than in the neocortex of elderly subjects. Sepiapterin reductase and DHPR activity showed a linear correlation with age in the temporal cortex. DHPR activity in the frontal cortex was relatively constant until the mid 60s and then fell with age. Overall BH4 synthesis showed a non-significant decline in temporal cortex and was significantly reduced in locus coeruleus preparations from SDAT subjects compared to control subjects. As DHPR, sepiapterin reductase and GTP cyclohydrolase activity were unaltered in SDAT we suggested that there is a lesion on the ...
Age at onset of the dystonia is mostly between 1 and 10 years. There is a great variability in the severity of the disorder. The dystonia starts in the lower extremities, mostly with gait difficulties, and often remains limited to the extremities (e.g., writers cramp) with no or minimal axial dystonia. About 25% of affected children have clinical signs suggestive of spastic diplegia. In most patients there is a marked diurnal fluctuation of symptoms characterized by worsening of symptoms and increasing fatigue throughout the day and marked benefit of sleep. Symptoms noted in ...