The Autoxidation of Tetrahydrobiopterin Revisited

Kirsch, Michael; Korth, Hans‐Gert; Stenert, Verena; Sustmann, Reiner; Groot, Herbert de

doi:10.1074/jbc.m211779200

Cited by 80 publications

(47 citation statements)

References 69 publications

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“…Given that the present study was performed to simulate the clinical setting, the use of a chronically instrumented conscious animal model was believed to be essential, because open-chest preparations are associated with a number of potentially confounding factors that may interfere with myocardial infarction 14 and/or ischemic PC. 15 Moreover, because BH 4 is auto-oxidized in a radical reaction 16 and is oxidized by NO 17 and peroxynitrite, 18,19 it seemed important to avoid experimental conditions, such as surgical trauma, that may lead to exaggerated generation of free radicals. 20 Accordingly, all of the studies reported herein were performed in closed-chest, awake animals in an effort to test the effect of hypercholesterolemia on late PC under conditions that were Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits

et al. 2005

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Background-Although the late phase of ischemic preconditioning (PC) is known to confer cardioprotection in healthy animal models, it is unknown whether this phenomenon exists in the presence of hypercholesterolemia. The goal of this study was to determine whether the infarct-sparing effect of late PC is affected by hypercholesterolemia and, if so, whether a tetrahydrobiopterin (BH 4 )-dependent mechanism is responsible for the loss of late PC. Methods and Results-Conscious rabbits fed a normal diet or a 1% cholesterol diet for 6 weeks were subjected to ischemic PC (six 4-minute coronary occlusion/4-minute reperfusion cycles) and, 24 hours later, underwent a 30-minute occlusion followed by 3 days of reperfusion. A total of 125 rabbits were used. In normocholesterolemic rabbits, ischemic PC reduced infarct size, an effect that was abrogated by administration of the BH 4 synthesis inhibitor N-acetylserotonin (15 mg/kg IV) before the 30-minute occlusion. In hypercholesterolemic rabbits, however, ischemic PC failed to reduce infarct size. Myocardial BH 4 levels in the ischemic zone increased 24 hours after ischemic PC in normocholesterolemic rabbits but not in hypercholesterolemic rabbits. In addition, in normocholesterolemic rabbits, pretreatment with N-acetylserotonin completely abolished the ischemic PC-induced increase in myocardial BH 4 levels. Conclusions-This study demonstrates that (1) hypercholesterolemia abrogates both the infarct-sparing effect of late PC and the concomitant upregulation of myocardial BH 4 , and (2)

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Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits

et al. 2005

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“…Superoxide is formed in vivo by NADPH oxidase in phagocytic cells MS 20120387 Submitted 2/13/2012, Accepted 5/23/2012. Authors Denev andKratchanova are with Laboratory of Biologically Active Substances, 139 Ruski Blvd, Plovdiv-4000, Bulgaria, Author Kratchanov is with Vitanea Ltd., 20 d-r G.M.Dimitrov str., Plovdiv-4000, Bulgaria, andAuthors Ciz andLojek are with Inst. of Biophysics of the Academy of Sciences of the Czech Republic,v.v.i.,Kralovopolska 135,612 65 Brno, by other enzymes like xanthine oxidase and xanthine dehydrogenase which reduce O 2 to O 2 ·− and by the auto-oxidation of many biomolecules like glyceraldehydes, FMNH 2 , FADH 2 , adrenalin, noradrenalin, and dopamine (Kirsch 2003). The most important source of O 2 ·− in vivo is the mitochondrial electron transport chain and hemoglobin in human erythrocytes, which also could be a source of superoxide radicals (Rifkind 2004).…”

Section: Introductionmentioning

confidence: 99%

Bioavailability and Antioxidant Activity of Black Chokeberry (Aronia melanocarpa) Polyphenols: in vitro and in vivo Evidences and Possible Mechanisms of Action: A Review

Denev

Kratchanov

Čı́ž

et al. 2012

Comp Rev Food Sci Food Safe

212

176

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Black chokeberry (Aronia melanocarpa) is a distinctive berry with a high content of polyphenol compounds and possesses one of the highest in vitro antioxidant activities among fruits. The bioavailability of aronia polyphenols seems to be low, but there is ample evidence for chokeberry health benefits including antidiabetic, cardioprotective, hepatoprotective, antimutagenic, and anticarcinogenic effects. This review presents the available information for the bioavailability and antioxidant activity of chokeberry polyphenols and explains the possible mechanisms of action in vivo in the prevention and treatment of oxidative stress-related diseases. The review shows the available data for chokeberry antioxidant activity in vitro, in isolated cells and cell lines, and in vivo, in both human subjects and animals. It is evident that in vivo antioxidant action of chokeberry extends far beyond radical scavenging and includes suppression of reactive oxygen and nitrogen species formation, inhibition of prooxidant enzymes, restoration of antioxidant enzymes, and probably cellular signaling to regulate the level of antioxidant compounds and enzymes. The original contribution of this work is that it compiles the available information up to date and outlines the gaps and future directions in the assessment of chokeberry antioxidant action in vivo.

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“…In vitro, oxygen and peroxynitrite can oxidize BH4 to quinonoid dihydrobiopterin, which readily rearranges to BH2 (50,51), and in vivo it has been shown that BH2 rapidly forms in the circulation following administration of BH4 (15). The authors consider changes to intracellular homeostasis as the most probable explanation for the increased oxidation of tetrahydrobiopterin as queuine deficiency has previously been suggested to affect the activity of a number of antioxidant systems (52,53) and to influence the metabolic state of the cell (33,52,54).…”

Section: Discussionmentioning

confidence: 99%

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Rakovich

Boland

Bernstein

et al. 2011

Journal of Biological Chemistry

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Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet (Marks, T., and Farkas, W. R. (1997) Biochem. Biophys. Res. Commun. 230, 233-237). Here, we show that human HepG2 cells deficient in queuine and mice made deficient in queuosine-modified transfer RNA, by disruption of the tRNA guanine transglycosylase enzyme, are compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease phenylketonuria, which arises from mutation in the enzyme phenylalanine hydroxylase or from a decrease in the supply of its cofactor tetrahydrobiopterin (BH4). Immunoblot and kinetic analysis of liver from tRNA guanine transglycosylase-deficient animals indicates normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels are significantly decreased in the plasma, and both plasma and urine show a clear elevation in dihydrobiopterin, an oxidation product of BH4, despite normal activity of the salvage enzyme dihydrofolate reductase. Our data suggest that queuosine modification limits BH4 oxidation in vivo and thereby potentially impacts on numerous physiological processes in eukaryotes.Bacteria and humans have co-evolved for millennia, and many examples exist of how various symbiotic and commensal partnerships contribute to human health and nutrition ranging from the metabolism of complex carbohydrates to the provision of vital micronutrients (1). Queuosine is an example of a micronutrient, synthesized exclusively by bacteria but which, for poorly defined reasons, is utilized by almost all eukaryotic species with the exception of the baker's yeast, Saccharomyces cerevisiae (2).Bacterial queuosine biosynthesis occurs in two stages. First, a series of five enzymatic steps convert guanosine triphosphate nucleoside (GTP) to the soluble 7-aminomethyl-7-deazaguanine molecule. Subsequently, 7-aminomethyl-7-deazaguanine is inserted into the wobble position of tRNA containing a GUN consensus sequence (Tyr, Asp, Asn, and His) by means of the single enzyme species, tRNA guanine transglycosylase (TGT), and is further remodeled in situ to queuosine (3). Eukaryotes must acquire queuosine or its free nucleobase, queuine, from food and the gut microflora. Curiously, both cytosolic and mitochondrial tRNA species are modified by queuosine (2). The eukaryotic enzyme that performs this reaction, queuine tRNA ribosyltransferase, has recently been identified as a heterodimeric complex, consisting of the eukaryotic homologue of the catalytic TGT subunit and a related protein called queuine tRNA ribosyltransferase domain containing 1 (QTRTD1), both of which localize to the mitochondria (4, 5).Stu...

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The Autoxidation of Tetrahydrobiopterin Revisited

Cited by 80 publications

References 69 publications

Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits

Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits

Bioavailability and Antioxidant Activity of Black Chokeberry (Aronia melanocarpa) Polyphenols: in vitro and in vivo Evidences and Possible Mechanisms of Action: A Review

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

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