A Model of Redox Kinetics Implicates the Thiol Proteome in Cellular Hydrogen Peroxide Responses

Article (PDF Available)inAntioxidants & Redox Signaling 13(6):731-43 · September 2010with78 Reads
DOI: 10.1089/ars.2009.2968 · Source: PubMed
Hydrogen peroxide is appreciated as a cellular signaling molecule with second-messenger properties, yet the mechanisms by which the cell protects against intracellular H(2)O(2) accumulation are not fully understood. We introduce a network model of H(2)O(2) clearance that includes the pseudo-enzymatic oxidative turnover of protein thiols, the enzymatic actions of catalase, glutathione peroxidase, peroxiredoxin, and glutaredoxin, and the redox reactions of thioredoxin and glutathione. Simulations reproduced experimental observations of the rapid and transient oxidation of glutathione and the rapid, sustained oxidation of thioredoxin on exposure to extracellular H(2)O(2). The model correctly predicted early oxidation profiles for the glutathione and thioredoxin redox couples across a range of initial extracellular [H(2)O(2)] and highlights the importance of cytoplasmic membrane permeability to the cellular defense against exogenous sources of H(2)O(2). The protein oxidation profile predicted by the model suggests that approximately 10% of intracellular protein thiols react with hydrogen peroxide at substantial rates, with a majority of these proteins forming protein disulfides as opposed to protein S-glutathionylated adducts. A steady-state flux analysis predicted an unequal distribution of the intracellular anti-oxidative burden between thioredoxin-dependent and glutathione-dependent antioxidant pathways, with the former contributing the majority of the cellular antioxidant defense due to peroxiredoxins and protein disulfides.

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Available from: Melissa Kemp, Jun 06, 2014
    • "The authors modelled peroxiredoxin with a detailed enzymatic mechanism (Pannala and Dash, 2015). In contrast, we (Pillay et al., 2011) and others (Adimora et al., 2010) have used mass action kinetics to describe peroxiredoxin because the resulting models described the data sufficiently, the second-order rate constants 160 could be readily measured in vitro, and the peroxiredoxin concentrations are much greater than the hydrogen peroxide concentrations in vivo. Since we used our earlier model (Pillay et al., 2011) as a basis for the current analysis and wanted to compare results, we continued to model peroxiredoxin kinetics with mass action in this paper. "
    [Show abstract] [Hide abstract] ABSTRACT: Thioredoxin, glutaredoxin, and peroxiredoxin systems (collectively called redoxins) play critical roles in a large number of redox-sensitive cellular processes. These systems are linked to each other by coupled redox cycles and by common reaction intermediates into a larger network.
    Full-text · Article · Sep 2016
    • "While kinetic expressions for the thioredoxin [187,188] and glutaredoxin [189] systems appear to be resolved, the appropriate kinetic expression (s) for modeling peroxiredoxin activity has not been settled. The consensus within the field is that peroxiredoxins are peroxidase enzymes with (bi-bi) ping-pong kinetics [190], but peroxiredoxins have been modeled as reactants with mass action kinetics in all computational models of the system published thus far [135,175,176]. Even within these models, peroxiredoxins have been treated either as monomers (e.g. "
    [Show abstract] [Hide abstract] ABSTRACT: Redox signaling is now recognized as an important regulatory mechanism for a number of cellular processes including the antioxidant response, phosphokinase signal transduction and redox metabolism. While there has been considerable progress in identifying the cellular machinery involved in redox signaling, quantitative measures of redox signals have been lacking, limiting efforts aimed at understanding and comparing redox signaling under normoxic and pathogenic conditions. Here we have outlined some of the accepted principles for redox signaling, including the description of hydrogen peroxide as a signaling molecule and the role of kinetics in conferring specificity to these signaling events. Based on these principles, we then develop a working definition for redox signaling and review a number of quantitative methods that have been employed to describe signaling in other systems. Using computational modeling and published data, we show how time- and concentration- dependent analyses, in particular, could be used to quantitatively describe redox signaling and therefore provide important insights into the functional organization of redox networks. Finally, we consider some of the key challenges with implementing these methods.
    Article · May 2016
    • "My controlled titration studies [19] provided an independent confirmation of Helmut's finding that intracellular H 2 O 2 concentration is in the low nanomolar range. More recent modeling studies of H 2 O 2 metabolism also support this interpretation [20]. Thus, the modern view of H 2 O 2 generation and metabolism is largely developed from Helmut's pioneering research published in 1970. "
    [Show abstract] [Hide abstract] ABSTRACT: When Rafael Radi and I wrote about Helmut Sies for the Redox Pioneer series, I was disappointed that the Editor restricted us to the use of “Pioneer” in the title. My view is that Helmut was always ahead of the pioneers: He was a scout discovering paths for exploration and a trailblazer developing strategies and methods for discovery. I have known him for nearly 40 years and greatly enjoyed his collegiality as well as brilliance in scientific scholarship. He made monumental contributions to 20th century physiological chemistry beginning with his first measurement of H2O2 in rat liver. While continuous H2O2 production is dogma today, the concept of H2O2 production in mammalian tissues was largely buried for half a century. He continued this leadership in research on oxidative stress, GSH, selenium, and singlet oxygen, during the timeframe when physiological chemistry and biochemistry transitioned to contemporary 21st century systems biology. His impact has been extensive in medical and health sciences, especially in nutrition, aging, toxicology and cancer. I briefly summarize my interactions with Helmut, stressing our work together on the redox code, a set of principles to link mitochondrial respiration, bioenergetics, H2O2 metabolism, redox signaling and redox proteomics into central redox theory.
    Full-text · Article · Apr 2016
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