The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2

Manta, Bruno; Hugo, Martín; Ortiz, Cecilia; Ferrer-Sueta, Gerardo; Trujillo, Madia; Denicola, Ana

doi:10.1016/j.abb.2008.11.017

Cited by 191 publications

(230 citation statements)

References 61 publications

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“…The observed concentration-dependent inhibition of HRP oxidation (Fig. 3a) gave a second order rate constant (k 1 in Table 2 (18,19). The rate constant for Reaction 2 between the sulfenic acid and H 2 O 2 (hyperoxidation) was measured by adding concentrations of catalase that were sufficient to give progressive inhibition of Reaction 2 but not enough to inhibit Reaction 1 and modeling with varying k 2 to give the best fit of the data in Fig.…”

Section: Resultsmentioning

confidence: 98%

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Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

Peskin

Pace

Behring

et al. 2016

Journal of Biological Chemistry

106

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Peroxiredoxin 2 (Prx2) is a thiol protein that functions as an antioxidant, regulator of cellular peroxide concentrations, and sensor of redox signals. Its redox cycle is widely accepted to involve oxidation by a peroxide and reduction by thioredoxin/ thioredoxin reductase. Interactions of Prx2 with other thiols are not well characterized. Here we show that the active site Cys residues of Prx2 form stable mixed disulfides with glutathione (GSH). Glutathionylation was reversed by glutaredoxin 1 (Grx1), and GSH plus Grx1 was able to support the peroxidase activity of Prx2. Prx2 became glutathionylated when its disulfide was incubated with GSH and when the reduced protein was treated with H 2 O 2 and GSH. The latter reaction occurred via the sulfenic acid, which reacted sufficiently rapidly (k ‫؍‬ 500 M ؊1 s ؊1 ) for physiological concentrations of GSH to inhibit Prx disulfide formation and protect against hyperoxidation to the sulfinic acid. Glutathionylated Prx2 was detected in erythrocytes from Grx1 knock-out mice after peroxide challenge. We conclude that Prx2 glutathionylation is a favorable reaction that can occur in cells under oxidative stress and may have a role in redox signaling. GSH/Grx1 provide an alternative mechanism to thioredoxin and thioredoxin reductase for Prx2 recycling.

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Section: Resultsmentioning

confidence: 98%

“…The sulfenic acid can also be further oxidized by H 2 O 2 (hyperoxidized) to the sulfinic acid, which will be present as the sulfinate (-SO 2 Ϫ ) because of its low pK a . The rate constants for the H 2 O 2 reactions are 1-2 ϫ 10 7 M Ϫ1 s Ϫ1 for reduced Prx2 (18,19) and ϳ10…”

mentioning

confidence: 99%

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

Peskin

Pace

Behring

et al. 2016

Journal of Biological Chemistry

106

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“…Whereas plasma urate reacts stoichiometrically with oxidants, catalase, superoxide dismutase, glutathione peroxidase, and Prx2 in RBC react catalytically and far more rapidly, conferring an immense capacity to consume H 2 O 2 generated by the auto-oxidation of hemoglobin, as well as H 2 O 2 and other oxidants, including peroxynitrite, produced within the vasculature. For example, the apparent second-order rate constant for the reaction of urate with peroxynitrite is ∼5 × 10 2 M −1 ·s −1 (46), compared with ≥10 7 M −1 ·s −1 for the reactions of Prx2 with H 2 O 2 and peroxynitrite (30). The concentration of erythrocyte Prx2 in blood is ∼240 μM, close to that of plasma urate and high enough to scavenge H 2 O 2 noncatalytically (28-30).…”

Section: Discussionmentioning

confidence: 99%

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

Hershfield

Roberts²,

Ganson³

et al. 2010

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

124

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A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associations. Pegloticase therapy generates H 2 O 2 while depleting urate, offering an in vivo test of the antioxidant hypothesis. We show that erythrocytes can efficiently eliminate H 2 O 2 derived from urate oxidation to prevent cell injury in vitro; during therapy, disulfide-linked peroxiredoxin 2 dimer did not accumulate in red blood cells, indicating that their peroxidase capacity was not exceeded. To assess oxidative stress, we monitored F2-Isoprostanes (F2-IsoPs) and protein carbonyls (PC), products of arachidonic acid and protein oxidation, in plasma of 26 refractory gout patients receiving up to five infusions of pegloticase at 3-wk intervals. At baseline, PUA was markedly elevated in all patients, and plasma F2-IsoP concentration was elevated in most. Pegloticase infusion rapidly lowered mean PUA to ≤1 mg/dL in all patients, and PUA remained low in 16 of 21 patients who completed treatment. F2-IsoP levels did not correlate with PUA and did not increase during 15 wk of sustained urate depletion. There also was no significant change in the levels of plasma PC. Because refractory gout is associated with high oxidative stress in spite of high PUA, and profoundly depleting uric acid did not increase lipid or protein oxidation, we conclude that urate is not a major factor controlling oxidative stress in vivo.

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“…In the case of hydrogen peroxide, another possible target is glutathione peroxidase 3, which, at a concentration of 175 nM, reacts with a rate constant of 1.8 x 10 8 M -1 s -1 (20,21). However, the scarcity of glutathione in plasma questions its significance in vivo.…”

Section: Reactivity Of the Albumin Thiolmentioning

confidence: 99%

Oxidation of the albumin thiol to sulfenic acid and its implications in the intravascular compartment

Turell

Carballal

Botti

et al. 2009

Braz J Med Biol Res

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Human serum albumin (HSA) is the most abundant protein in the intravascular compartment. It possesses a single thiol, Cys34, which constitutes ~8 0% of the total thiols in plasma. This thiol is able to scavenge plasma oxidants. A central intermediate in this potential antioxidant activity of human serum albumin is sulfenic acid (HSA-SOH). Work from our laboratories has demonstrated the formation of a relatively stable sulfenic acid in albumin through complementary spectrophotometric and mass spectrometric approaches. Recently, we have been able to obtain quantitative data that allowed us to measure the rate constants of sulfenic acid reactions with molecules of analytical and biological interest. Kinetic considerations led us to conclude that the most likely fate for sulfenic acid formed in the plasma environment is the reaction with low molecular weight thiols to form mixed disulfides, a reversible modification that is actually observed in ~2 5% of circulating albumin. Another possible fate for sulfenic acid is further oxidation to sulfinic and sulfonic acids. These irreversible modifications are also detected in the circulation. Oxidized forms of albumin are increased in different pathophysiological conditions and sulfenic acid lies in a mechanistic junction, relating oxidizing species to final thiol oxidation products.

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The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2

Cited by 191 publications

References 61 publications

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

Oxidation of the albumin thiol to sulfenic acid and its implications in the intravascular compartment

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