Nitration Transforms a Sensitive Peroxiredoxin 2 into a More Active and Robust Peroxidase

Randall, Lía M.; Manta, Bruno; Hugo, Martín; Gil, Magdalena; Batthyány, Carlos; Trujillo, Madia; Poole, Leslie B.; Denicola, Ana

doi:10.1074/jbc.m113.539213

Cited by 45 publications

(39 citation statements)

References 56 publications

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“…Specifically, the k 2f value is consistently smaller for mammalian Prx2 from different studies compared to Prx3 and Prx5 (Table 3). The estimated values are in agreement with the experimentally determined values reported in the literature [58-60]. For example, the pre-steady state kinetic experiments performed on Prx5 in Trujillo et al [58] yielded the rate constant for formation of intramolecular disulfide bond ( k 2f ) as 14.7 s −1 , which is close to the estimated value for Prx5 in our study (Table 3).…”

Section: Discussionsupporting

confidence: 92%

“…In addition to the second order rate constant k 2pf , the rate of Prx overoxidation also depends on the rate constant for the disulfide formation, k 2f . For example, in an independent experiment performed on Prx2 revealed that the nitration of Prx2 increases its catalytic activity and its resistance to overoxidation owing to the increased value of the rate constant for disulfide formation in the catalytic cycle [60]. Thus, this result and our model simulations suggest that for a fixed k 2pf , the rate of overoxidation also depends on the rate of disulfide formation in the catalytic cycle and estimated parameter value of k 2f for Prx2 is lower than the other Prx enzymes indicating a greater chance of overoxidation for Prx2 compared to other Prx enzymes.…”

Section: Discussionmentioning

confidence: 99%

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Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Pannala

Dash

2015

Free Radical Biology and Medicine

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The thioredoxin system, which consists of a family of proteins, including thioredoxin (Trx), peroxiredoxin (Prx) and thioredoxin reductase (TrxR), plays a critical role in the defense against oxidative stress by removing harmful hydrogen peroxide (H2O2). Specifically, Trx donates electrons to Prx to remove H2O2 and then TrxR maintains the reduced Trx concentration with NADPH as the cofactor. Despite a great deal of kinetic information gathered on the removal of H2O2 by the Trx system from various sources/species, a mechanistic understanding of the associated enzymes is still not available. We address this issue by developing a thermodynamically-consistent mathematical model of the Trx system which entails mechanistic details and provides quantitative insights into the kinetics of the TrxR and Prx enzymes. Consistent with experimental studies, the model analyses of the available data show that both enzymes operate by a ping-pong mechanism. The proposed mechanism for TrxR, which incorporates substrate inhibition by NADPH and intermediate protonation states, well describes the available data and accurately predicts the bell-shaped behavior of the effect of pH on the TrxR activity. Most importantly, the model also predicts the inhibitory effects of the reaction products (NADP+ and Trx(SH)2) on the TrxR activity for which suitable experimental data are not available. The model analyses of the available data on the kinetics of Prx from mammalian sources reveal that Prx operates at very low H2O2 concentrations compared to their human parasite counterparts. Furthermore, the model is able to predict the dynamic overoxidation of Prx at high H2O2 concentrations, consistent with the available data. The integrated Prx-TrxR model simulations well describe the NADPH and H2O2 degradation dynamics and also show that the coupling of TrxR- and Prx-dependent reduction of H2O2 allowed ultrasensitive changes in the Trx concentration in response to changes in the TrxR concentration at high Prx concentrations. Thus, the model of this sort is very useful for integration into computational H2O2 degradation models to identify its role in physiological and pathophysiological functions.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Pannala

Dash

2015

Free Radical Biology and Medicine

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“…That such control mechanisms may be widespread is indicated by the variety of in vivo modifications of Prxs that modulate its properties. These include Tyr nitration [91], Ser and Thr phosphorylation, acetylation at the N terminus or near the C terminus, proteolytic truncation, and S-nitrosylation or glutathionylation of catalytic or non-catalytic Cys residues (reviewed in [40, 92]).…”

Section: Potential Roles For Prxs In Stress and Non-stress Related Cementioning

confidence: 99%

Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling

Perkins

Nelson

Parsonage

et al. 2015

Trends in Biochemical Sciences

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494

401

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Peroxiredoxins (Prxs) are a ubiquitous family of cysteine-dependent peroxidase enzymes that play dominant roles in regulating peroxide levels within cells. These enzymes, often present at high levels and capable of rapidly clearing peroxides, display a remarkable array of variations in their oligomeric states and susceptibility to regulation by hyperoxidative inactivation and other post-translational modifications. Key conserved residues within the active site promote catalysis by stabilizing the transition state required for transferring the terminal oxygen of hydroperoxides to the active site (peroxidatic) cysteine residue. Extensive investigations continue to expand our understanding of the scope of their importance as well as the structures and forces at play within these critical defense and regulatory enzymes.

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“…Whether or not PTEN is responsible for this relationship between Prx1 and Prx2 expression in those tissues, is still a question. Nitrosylation of Tyr 193 in the YF motif of Prx2 is an important post-translational modification that plays a critical role in the regulation of disulfide bond formation under oxidative stress conditions [103]. Glutathionylation is another post-translational modification of Prx2, which may affect its localization to extracellular compartment [104].…”

Section: The Srx-prx Axis In Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

Mishra¹,

Jiang²,

Wu³

et al. 2015

Cancer Letters

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Redox signaling is a critical component of cell signaling pathways that is involved in regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Peroxiredoxin (Prx) is a family of thiol-based peroxidases that acts as a regulator of redox signaling. Members of Prx family can act as antioxidants and chaperone. Sulfiredoxin (Srx) is an antioxidant protein that exclusively reduces over-oxidized typical 2-Cys Prx. Srx have different affinities for individual Prx and it also catalyzes deglutathionylation of variety of substrates. Individual components of Srx-Prx system play critical roles in carcinogenesis by modulating cell signaling pathway involved in cell proliferation, migration and metastasis. Expression levels of individual components of Srx-Prx axis has been correlated with patient survival outcome in multiple cancer types. This review will summarize the molecular basis of differences in affinity of Srx for individual Prx and the role of individual components of Srx-Prx system in tumor progression and metastasis. This enhanced understanding of molecular aspects of Srx-Prx interaction and its role in cell signal transduction will help in defining Srx-Prx system as a future therapeutic target in human cancer.

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Nitration Transforms a Sensitive Peroxiredoxin 2 into a More Active and Robust Peroxidase

Cited by 45 publications

References 56 publications

Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Mechanistic characterization of the thioredoxin system in the removal of hydrogen peroxide

Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

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