Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes

Thöny, Beat; Blau, Nenad

doi:10.1002/(sici)1098-1004(1997)10:1<11::aid-humu2>3.0.co;2-p

Cited by 71 publications

(26 citation statements)

References 49 publications

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“…19 The syndrome is characterized by a deficit of the neurotransmitters dopamine and serotonin and generally presents in childhood with progressive neurological symptoms. 20 The variable presentation reflects a range of mutations in genes encoding the enzymes involved in BH4 biosynthesis 21 or regeneration. 22 A form of BH4 deficiency without hyperphenylalaninemia is also recognized, known as dopa-responsive dystonia, 23 and this is associated with mutations in the gene encoding GTPCH, transmitted in an autosomal-dominant fashion.…”

Section: Tetrahydrobiopterinmentioning

confidence: 77%

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Nicholas

Channon

2004

ATVB

473

361

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Abstract-Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a key signaling molecule in vascular homeostasis. Loss of NO bioavailability due to reduced synthesis and increased scavenging by reactive oxygen species is a cardinal feature of endothelial dysfunction in vascular disease states. The pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of eNOS activity: when BH4 availability is limiting, eNOS no longer produces NO but instead generates superoxide. In vascular disease states, there is oxidative degradation of BH4 by reactive oxygen species. However, augmentation of BH4 concentrations in vascular disease by pharmacological supplementation, by enhancement of its rate of de novo biosynthesis or by measures to reduce its oxidation, has been shown in experimental studies to enhance NO bioavailability. Thus, BH4 represents a potential therapeutic target in the regulation of eNOS function in vascular disease. Key Words: tetrahydrobiopterin Ⅲ nitric oxide synthase Ⅲ superoxide N itric oxide (NO), produced by endothelial NO synthase (eNOS), is a key signaling molecule in vascular homeostasis. 1 Originally identified as endothelium-derived relaxing factor, 2,3 NO is an important regulator of vascular tone and blood pressure. In addition, NO has multiple antiatherogenic roles, including anti-inflammatory, antithrombotic, antiproliferative, and antioxidant effects (reviewed in Ignarro 1 ). Loss of NO bioavailability is a cardinal feature of endothelial dysfunction 4 that precedes the development of overt atherosclerosis and is an independent predictor of adverse cardiovascular risk. 5,6 Several factors contribute to loss of NO bioavailability in endothelial dysfunction states, including both reduced NO synthesis and NO scavenging by reactive oxygen species. 7 The regulation of NO production by eNOS is complex, but the pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of NO synthesis. Indeed, endothelial BH4 availability appears to be a key requirement for maintaining normal endothelial function. In this article, we review the current knowledge on the regulation of eNOS by BH4 and discuss the potential importance of mechanisms linking BH4 availability with endothelial function in vascular disease. TetrahydrobiopterinTetrahydrobiopterin (BH4) is an essential cofactor for all 3 NO synthase (NOS) isoforms and for the aromatic amino acid hydroxylases (phenylalanine hydroxylase, tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase). BH4 biosynthesis proceeds from GTP via 2 intermediates, 7,8-dyhydroneopterin triphosphate and 6-pyruvoyl-5,6,7,8-tetrahydropterin (reviewed in Thony et al 8 ; Figure 1). In endothelial cells (ECs), the first and rate-limiting step in this pathway is GTP cyclohydrolase I (EC 3.5.4.16; GTPCH). The subsequent steps are catalyzed by the enzymes 6-pyruvoyl tetrahydropterin synthase (EC 4.6.1.10; PTPS) and sepiapterin reductase (EC 1.1.1.153; SR). In some cell types (for example, macrophages), inflammatory cytok...

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Section: Tetrahydrobiopterinmentioning

confidence: 77%

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Nicholas

Channon

2004

ATVB

473

361

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“…Purified isoforms A-C consistently exhibit higher molecular masses on SDS-PAGE (39, 45, and 47 kDa, respectively) than the calculated molecular masses (30,34, and 36 kDa, respectively) as noted previously for Drosophila (38), rat (46), and human (47, 48) GTPCH subunits on SDS-PAGE. This discrepancy appears to be due, in part, to the N-terminal extensions of isoforms A-C, which exhibit apparent higher molecular masses (16,17, and 18 kDa, respectively) than expected (8,12, and 13 kDa, respectively), whereas the mobility of the common region is consistent with its expected molecular mass at 24 kDa.…”

Section: Resultsmentioning

confidence: 99%

A typical N-terminal Extensions Confer Novel Regulatory Properties on GTP Cyclohydrolase Isoforms in Drosophila melanogaster

Funderburk¹,

Bowling²,

Xu³

et al. 2006

Journal of Biological Chemistry

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The cofactor tetrahydrobiopterin plays critical roles in the modulation of the signaling molecules dopamine, serotonin, and nitric oxide. Deficits in cofactor synthesis have been associated with several human hereditary diseases. Responsibility for the regulation of cofactor pools resides with the first enzyme in its biosynthetic pathway, GTP cyclohydrolase I. Because organisms must be able to rapidly respond to environmental and developmental cues to adjust output of these signaling molecules, complex regulatory mechanisms are vital for signal modulation. Mammalian GTP cyclohydrolase is subject to end-product inhibition via an associated regulatory protein and to positive regulation via phosphorylation, although target residues are unknown. GTP cyclohydrolase is composed of a highly conserved homodecameric catalytic core and non-conserved N-terminal domains proposed to be regulatory sites. We demonstrate for the first time in any organism that the N-terminal arms of the protein serve regulatory functions. We identify two different modes of regulation of the enzyme mediated through the N-terminal domains. The first is end-product feedback inhibition, catalytically similar to that of the mammalian enzyme, except that feedback inhibition by the cofactor requires sequences in the N-terminal arms rather than a separate regulatory protein. The second is a novel inhibitory interaction between the N-terminal arms and the active sites, which can be alleviated through the phosphorylation of serine residues within the N termini. Both mechanisms allow for acute and highly responsive regulation of cofactor production as required by downstream signaling pathways.

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“…1 Mutations in enzymes associated with BH 4 homeostasis cause BH 4 deficiency, a metabolic disorder associated with symptoms of phenylketonuria (PKU), especially BH 4 -responsive PKU as well as neurodegenerative diseases such as Parkinson disease. [3][4][5][6] Untreated cases of BH 4 -responsive PKU…”

Section: Introductionmentioning

confidence: 99%

Autophagy induction by tetrahydrobiopterin deficiency

et al. 2011

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Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes

Cited by 71 publications

References 49 publications

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

A typical N-terminal Extensions Confer Novel Regulatory Properties on GTP Cyclohydrolase Isoforms in Drosophila melanogaster

Autophagy induction by tetrahydrobiopterin deficiency

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