The Catalytic Role of Carbon Dioxide in the Decomposition of Peroxynitrite

Pryor, William A.; Lemercier, Jean-Noël; Zhang, Houwen; Uppu, Rao M.; Squadrito, G

doi:10.1016/s0891-5849(97)00121-4

Cited by 97 publications

(64 citation statements)

References 17 publications

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“…The data show that TPH is inactivated by ONOO Ϫ in a manner that depends on the concentrations of both reactants. The IC 50 for inhibition of enzyme activity was approximately 15 or 200 M ONOO Ϫ when the enzyme concentration was 0.625 or 10 M, respectively. Decomposed ONOO Ϫ did not have an effect on TPH activity.…”

Section: Effects Of Onoomentioning

confidence: 97%

“…DISCUSSION TPH is quite sensitive to inactivation by the ONOO Ϫ anion. The approximate IC 50 of ONOO Ϫ for enzyme inhibition was 15…”

Section: Effects Of Tetranitromethane On Tph-in View Of Onoomentioning

confidence: 99%

“…The catalytic core deletion mutant of TPH contains a total of 15 tyrosyl residues (44), so it appears that the secondary structure of the protein and the charge of ONOO Ϫ act in concert to limit accessibility of ONOO Ϫ to tyrosyl residues within TPH. The IC 50 for FIG. 5.…”

Section: Effects Of Tetranitromethane On Tph-in View Of Onoomentioning

confidence: 99%

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Peroxynitrite Inactivates Tryptophan Hydroxylase via Sulfhydryl Oxidation

Kuhn

Geddes

1999

Journal of Biological Chemistry

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Tryptophan hydroxylase, the initial and rate-limiting enzyme in serotonin biosynthesis, is inactivated by peroxynitrite in a concentration-dependent manner. This effect is prevented by molecules that react directly with peroxynitrite such as dithiothreitol, cysteine, glutathione, methionine, tryptophan, and uric acid but not by scavengers of superoxide (superoxide dismutase), hydroxyl radical (Me 2 SO, mannitol), and hydrogen peroxide (catalase). Assuming simple competition kinetics between peroxynitrite scavengers and the enzyme, a second-order rate constant of 3.4 ؋ 10 4 M ؊1 s ؊1 at 25°C and pH 7.4 was estimated. The peroxynitrite-induced loss of enzyme activity was accompanied by a concentration-dependent oxidation of protein sulfhydryl groups. Peroxynitrite-modified tryptophan hydroxylase was resistant to reduction by arsenite, borohydride, and dithiothreitol, suggesting that sulfhydryls were oxidized beyond sulfenic acid. Peroxynitrite also caused the nitration of tyrosyl residues in tryptophan hydroxylase, with a maximal modification of 3.8 tyrosines/monomer. Sodium bicarbonate protected tryptophan hydroxylase from peroxynitrite-induced inactivation and lessened the extent of sulfhydryl oxidation while causing a 2-fold increase in tyrosine nitration. Tetranitromethane, which oxidizes sulfhydryls at pH 6 or 8, but which nitrates tyrosyl residues at pH 8 only, inhibited tryptophan hydroxylase equally at either pH. Acetylation of tyrosyl residues with N-acetylimidazole did not alter tryptophan hydroxylase activity. These data suggest that peroxynitrite inactivates tryptophan hydroxylase via sulfhydryl oxidation. Modification of tyrosyl residues by peroxynitrite plays a relatively minor role in the inhibition of tryptophan hydroxylase catalytic activity.Tryptophan hydroxylase (TPH, 1 EC 1.14.16.4; L-tryptophan,tetrahydrobiopterin:oxygen oxidoreductase (5-hydroxylating)) is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin. The physiological roles for serotonin are diverse and include modulation of sleep, thermoregulation, and food intake (1). From a clinical perspective, alterations in serotonin function have been implicated in several neuropsychiatric disorders such as depression, obsessive-compulsive disorder, and suicide (2). Alterations in TPH activity produce corresponding changes in the synaptic levels of serotonin (3), suggesting that TPH can have influences on serotonin neurochemical function that extend well beyond its role in fulfilling the first step in serotonin synthesis from tryptophan. Drugs that cause long term changes in TPH activity could well change serotonin synaptic function to the detriment of normal physiological and behavioral function. For example, the neurotoxic amphetamines methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") significantly reduce TPH activity and serotonin levels (4). Long term abuse of these drugs produces behavioral and psychiatric conditions indicative of diminished serotonin function (5, 6). Because the...

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Section: Effects Of Onoomentioning

confidence: 97%

“…DISCUSSION TPH is quite sensitive to inactivation by the ONOO Ϫ anion. The approximate IC 50 of ONOO Ϫ for enzyme inhibition was 15…”

Section: Effects Of Tetranitromethane On Tph-in View Of Onoomentioning

confidence: 99%

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Peroxynitrite Inactivates Tryptophan Hydroxylase via Sulfhydryl Oxidation

Kuhn

Geddes

1999

Journal of Biological Chemistry

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“…It is proposed that the protonation of ONOO Ϫ results in a high-energy, reactive intermediate, ONOOH*, which can either decay to give nitrate or react with substrate (2,3). In the presence of bicarbonate, the peroxynitrosocarbonate anion, (ONOOCO 2 Ϫ ) is formed from ONOO Ϫ in a carbon dioxide catalyzed reaction (4)(5)(6)(7). Although ONO-OCO 2 Ϫ has a shorter lifetime than ONOO Ϫ , the former is still a potent oxidizing agent, with a redox potential in excess of ϩ 1 V (4,8).…”

mentioning

confidence: 99%

Peroxynitrite reaction products of 3′,5′-di -O- acetyl-8-oxo-7,8-dihydro-2′-deoxyguanosine

Niles

Burney

Singh

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Of the DNA bases, peroxynitrite (ONOO ؊ ) is most reactive toward 2-deoxyguanosine (dGuo), but even more reactive with 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodGuo), requiring a 1,000-fold excess of dGuo to provide 50% protection against the reaction with 8-oxodGuo. Therefore, it seems reasonable that 8-oxodGuo is a potentially important target in DNA and that the structures of the reaction products with ONOO ؊ should be characterized.

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“…Thus, CO 2 competes with the metal of Fe-SOD for ONOO Ϫ , yielding the secondary derived radicals that may react with solvent-accessible non-critical protein tyrosine residues without causing enzyme inactivation (19,69,70 35 -In order to confirm the preferential nitration of Tyr 35 after peroxynitrite treatment (0 -300 M) of T. cruzi Fe-SODs (8 M), control and treated enzymes were separated by two-dimensional gel electrophoresis, and protein spots were analyzed by nano-LC-nano-SI-MS. One major spot for both Fe-SODA and Fe-SODB and other minor ones were identified in the native enzymes, indicating posttranslational modifications that affect the protein isoelectric point. In the case of the peroxynitrite-treated Fe-SODs, the two-dimensional gels revealed the generation of several more acidic spots in both Fe-SODs with a more drastic shift in the case Fe-SODA, in agreement with its higher susceptibility to peroxynitrite (Fig.…”

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confidence: 99%