Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate

Patel, Kantilal B.; Stratford, Michael R.L.; Wardman, Peter; Everett, Steven A.

doi:10.1016/s0891-5849(01)00777-8

Cited by 91 publications

(57 citation statements)

References 46 publications

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“…These latter isoforms produce considerably less O 2 À than the enzyme found in macrophages and neutrophils and that generated by mitochondrial respiration. The roles of the nonphagocytic NADPH oxidase are not completely understood, GSH 9 Â 10 9 2 Â 10 2 2 Â 10 7 5 Â 10 6 6 Â 10 2 Cysteine 2 Â 10 10 5 Â 10 7 5 Â 10 7 6 Â 10 3 Ascorbate 1 Â 10 9 5 Â 10 4 4 Â 10 7 1 Â 10 9 b 5 Â 10 1 Urate 7 Â 10 9 2 Â 10 7 5 Â 10 2c Tyrosine 1 Â 10 10 o1 Â 10 1 3 Â 10 5 5 Â 10 7 Tryptophan 1 Â 10 10 o2 Â 10 1 o5 Â 10 5 7 Â 10 8 4 Â 10 1c Methionine 9 Â 10 9 o1 1 Â 10 8 b 2 Â 10 2 NADH 2 Â 10 10 1 Â 10 5 4 Â 10 3 1 Â 10 9 Tetrahydrobiopterin 9 Â 10 9 1 Â 10 9 5 Â 10 9 Aconitase 3 Â 10 7 1 Â 10 5 Cytochrome c (Fe(II)) 41 Â 10 10 1 Â 10 6 3 Â 10 4 Mn-SOD 2 Â 10 9 1 Â 10 5 CO 2 3 Â 10 4 a Most rate constants are from the NIST database (Ross et al, 1998) or references mentioned in the text (Radi et al, 2000;Ford et al, 2002a;Kirsch et al, 2002;Patel et al, 2002;Radi et al, 2002 (Majander et al, 1994). Cellular SOD converts the O 2 À anion to H 2 O 2, which is then further reduced to water by catalases and peroxidases in the cytoplasm and in the mitochondria by an NADPH-dependent glutathione peroxidase.…”

Section: Cellular Mechanisms Of Ros Homeostasismentioning

confidence: 99%

Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms

2003

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In the past few years, nuclear DNA damage-sensing mechanisms activated by ionizing radiation have been identified, including ATM/ATR and the DNA-dependent protein kinase. Less is known about sensing mechanisms for cytoplasmic ionization events and how these events influence nuclear processes. Several studies have demonstrated the importance of cytoplasmic signaling pathways in cytoprotection and mutagenesis. For cytoplasmic signaling, radiation-stimulated reactive oxygen species (ROS) and reactive nitrogen species (RNS) are essential activators of these pathways. This review summarizes recent studies on the chemistry of radiation-induced ROS/ RNS generation and emphasizes interactions between ROS and RNS and the relative roles of cellular ROS/ RNS generators as amplifiers of the initial ionization events. Cellular mechanisms for regulating ROS/RNS levels are discussed. The mechanisms by which cells sense ROS/RNS are examined in terms of how ROS/RNS modify protein structure and function, for example, interactions with metal-thiol clusters, protein tyrosine nitration, protein cysteine oxidation, S-thiolation and Snitrosylation. We propose that radiation-induced ROS are the initiators and that nitric oxide (NO ) or derivatives are the effectors activating these signal transduction pathways. In responding to cellular ionization events, the cell converts an oxidative signal to a nitrosative one because ROS are too reactive and unspecific in their reactions for regulatory purposes and the cell is equipped to precisely modulate NO levels.

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Section: Cellular Mechanisms Of Ros Homeostasismentioning

confidence: 99%

Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms

2003

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“…Although O 2 •− can oxidize BH 4 , ONOO − and •OH are known to be more potent BH 4 oxidizers (22)(23)(24). Because ONOO − is formed when O 2…”

Section: H 2 O 2 Activates Not Only Enos But Also the Omentioning

confidence: 99%

Early determinants of H2O2-induced endothelial dysfunction

Boulden

Widder

Allen

et al. 2006

Free Radical Biology and Medicine

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Reactive oxygen species (ROS) can stimulate nitric oxide (NO•) production from the endothelium by transient activation of endothelial nitric oxide synthase (eNOS). With continued or repeated exposure, NO• production is reduced, however. We investigated the early determinants of this decrease in NO• production. Following an initial H 2 O 2 exposure, endothelial cells responded by increasing NO• production measured electrochemically. NO• concentrations peaked by 10 min with a slow reduction over 30 min. The decrease in NO• at 30 min was associated with a 2.7 fold increase O 2•− production (p<0.05) and a 14 fold reduction of the eNOS cofactor, tetrahydrobiopterin (BH 4 , p<0.05). Used as a probe for endothelial dysfunction, the integrated NO• production over 30 min upon repeat H 2 O 2 exposure was attenuated by 2.1 fold (p=0.03). Endothelial dysfunction could be prevented by BH 4 cofactor supplementation, by scavenging O 2•− or peroxynitrite (ONOO − ), or by inhibiting the NADPH oxidase. Hydroxyl radical (•OH) scavenging did not have an effect. In summary, early H 2 O 2 -induced endothelial dysfunction was associated with a decreased BH 4 level and increased O 2•− production. Dysfunction required O 2 •− , ONOO − , or a functional NADPH oxidase. Repeated activation of the NADPH oxidase by ROS may act as a feed forward system to promote endothelial dysfunction.

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“…, CO 3 . , ⅐ NO 2 , HO ⅐ , and GS ⅐ , oxidize H4B have been elucidated (18,39). Superoxide has been proposed to react according the following reaction sequences.…”

Section: Discussionmentioning

confidence: 99%

“…acts as an one-electron oxidant for H4B, the produced radical cation of which, H4B . ϩ , undergoes rapid deprotonation at neutral pH (39). Disproportionation of the H3B ⅐ radical leads to the formation of a quinoid form (qH2B) of dihydrobiopterin, which further rearranges to the normal H2B structure (Scheme 1 .…”

Section: H4bmentioning

confidence: 99%

The Autoxidation of Tetrahydrobiopterin Revisited

Kirsch

Korth

Stenert

et al. 2003

Journal of Biological Chemistry

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It has been known for quite some time that tetrahydrobiopterin (H4B) is prone to autoxidation in the presence of molecular oxygen. Evidence has been presented that in this process superoxide radicals may be released, although their intermediacy never has been directly proven. In the present study, the autoxidation of H4B was reinvestigated with the aim to find direct evidence for superoxide formation. By means of two specific assays, namely elicitation of luminescence from lucigenin and ESR-spectrometric detection of the DEPMPO-OOH radical adduct, the release of free superoxide radicals was unequivocally demonstrated. The production of superoxide radicals was further corroborated by interaction with nitric oxide. The kinetics of the autoxidation process was established. Our data fully confirm earlier conclusions that the direct reaction between H4B and oxygen serves as an initiation reaction for the further, rapid reaction of the thus formed superoxide with H4B, thereby very likely establishing a chain reaction process involving reduction of molecular oxygen by the intermediary tetrahydrobiopterin radical. Conclusively, because H4B can per se induce oxidative stress, an in vivo overproduction of this pterin, as is evident in various diseases, may be responsible for the observed acceleration of pathophysiological pathways.

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Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate

Cited by 91 publications

References 46 publications

Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms

Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms

Early determinants of H2O2-induced endothelial dysfunction

The Autoxidation of Tetrahydrobiopterin Revisited

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