Abstract
Hydrogen peroxide's (H2O2) best characterized signaling actions in mammalian cells involve the oxidation of thiols in cytoplasmic targets within minutes of stimulation. However, these redox targets are orders of magnitude less H2O2-reactive and abundant than cytoplasmic peroxiredoxins (Prx). How can they be oxidized in minutes? Our computational results show that at H2O2 supply rates commensurate with mitogenic signaling a H2O2 concentration gradient of a few tenths of µm is established. Even near supply sites H2O2 concentrations are too low to oxidize typical targets in minutes. Further, any Prx inhibition or increase in H2O2 supply able to strongly increase the local H2O2 concentration would collapse the gradient and/or extensively oxidize PrxI/II, inconsistent with observations. In turn, the local concentrations of Prx sulfenate and disulfide forms strongly exceed those of H2O2. Redox targets reacting with these forms at rate constants much lower than that for thioredoxin could be oxidized in
Highlights
Hydrogen peroxide (H2O2) is a key intermediate in many signaling pathways in mammalian cells [1]
Whereas the redox active thiolates in these targets react with H2O2 with rate constants in the range of 9−164 M−1 s−1 [5,6,9,1], the cell cytoplasm contains very abundant peroxiredoxins I and II (PrxI, PrxII) [10,11], which react with H2O2 with rate constants in the range of 107–108 M−1 s−1 [12,13]
In order to frame this question, we first examine how the maximal cytoplasmic H2O2 concentrations relate to the extracellular concentrations, peroxiredoxin concentrations and cytoplasmic gradients to highlight a fundamental trade-off between signal localization and the maximal cytoplasmic H2O2 concentration
Summary
Hydrogen peroxide (H2O2) is a key intermediate in many signaling pathways in mammalian cells [1]. The first such proposal was the floodgate hypothesis [21], which posits that the oxidation of the less reactive H2O2 targets is facilitated by the oxidation of eukaryotic 2-Cys peroxiredoxins to redox-inactive sulfinic and sulfonic forms (hyperoxidation) This hypothesis is supported by observations that overexpressing 2-Cys peroxiredoxins in mammalian cells blocks peroxide activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [22,23], and that treatment of cells with tumor necrosis factor causes substantial hyperoxidation of PrxII [24]. It can have a dramatic effect on the local concentrations of oxidized forms of the peroxiredoxins, further helping these species outcompete H2O2 for oxidation of redox targets These results suggest that sulfenate and/or disulfide forms of Prx mediate the oxidation of redox targets within ∼1 μm of H2O2 supply sites under conditions consistent with mitogenic signaling. The global floodgate hypothesis may find its place as part of a stress response in this context
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