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

Abstract

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. Antioxid. Redox Signal. 13, 731-743.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…In this regard, the nascent field of quantitative redox biology, incorporating in vitro data to guide in silico analysis, may help to provide a broader picture of these interconnections (17,18). In particular, the quantitative association between the redox state of the cell and its biological state (such as quiescence, proliferation, or apoptosis) could help guide therapeutic manipulation of the antioxidant pathways (17).…”

Single-Cell Redox Imaging Demonstrates a Distinctive Response of Dopaminergic Neurons to Oxidative Insults

“…Extensive attention has been dedicated to the role of the small tri-peptide glutathione (GSH) in redox homeostasis. However, it is now very clear that protein thiols (pr-SH)-which are present in specialized proteins such as thioredoxins and in other proteins that possess primary functions other than controlling the redox state-also significantly contribute to redox homeostasis (1,35,59). In several cases, the reversible oxidation of pr-SH also performs a fundamental regulatory function and acts as a molecular switch, whereby protein activity is modulated through oxidation or reduction of thiols in critical positions.…”

“…These sensors measure the redox state of the couple GSH/GSSG, which represents just one aspect of the total intracellular redox state (49). In fact, emerging evidence clearly indicates that intracellular redox state is not solely governed by GSH/GSSG, and that protein thiols provide an essential contribution as well (1,41,57). A further limitation of rsFPs-based redox imaging methods is that the use of rsFPs in association with other fluorescent markers is rarely achievable.…”

Redox Sensitivity of Tyrosine Hydroxylase Activity and Expression in Dopaminergic Dysfunction

“…As oxidative stress increases, a high number of Cys in the protein thiol pool will be oxidized to disulfides. The reversible conversion of thiols to disulfides is one the earliest observable events during radical-mediated oxidation of proteins [50,51]. Thiol oxidation has functional consequences as it may be correlated to protein inactivation [1].…”