Nonequilibrium thermodynamics of thiol/disulfide redox systems: A perspective on redox systems biology

Abstract

Understanding the dynamics of redox elements in biologic systems remains a major challenge for redox signaling and oxidative stress research. Central redox elements include evolutionarily conserved subsets of cysteines and methionines of proteins which function as sulfur switches and labile reactive oxygen species (ROS) and reactive nitrogen species (RNS) which function in redox signaling. The sulfur switches depend upon redox environments in which rates of oxidation are balanced with rates of reduction through the thioredoxins, glutathione/glutathione disulfide and cysteine/cystine redox couples. These central couples, which we term redox control nodes, are maintained at stable but non-equilibrium steady states, are largely independently regulated in different subcellular compartments and are quasi-independent from each other within compartments. Disruption of the redox control nodes can differentially affect sulfur switches, thereby creating a diversity of oxidative stress responses. Systems biology provides approaches to address the complexity of these responses. In the present review, we summarize thiol/disulfide pathway, redox potential and rate information as a basis for kinetic modeling of sulfur switches. The summary identifies gaps in knowledge especially related to redox communication between compartments, definition of redox pathways and discrimination between types of sulfur switches. A formulation for kinetic modeling of GSH/GSSG redox control indicates that systems biology could encourage novel therapeutic approaches to protect against oxidative stress by identifying specific redox-sensitive sites which could be targeted for intervention.

Radical-free biology of oxidative stress

“…In addition to containing active site and/or structural thiols, many proteins contain Cys which regulate activity by an allosteric mechanism. This type of regulation can provide a "rheostat" rather than an "on-off" switch (88), thereby providing a means to throttle processes by GS-ylation or S-nitrosylation (Fig. 2).…”

“…Evidence is also available to show that protein trafficking, protein synthesis and degradation, and cytoskeletal structure are redox sensitive, but these are not addressed due to space limitations. Accumulating experimental evidence for nonequilibrium conditions of thiol-disulfide couples (88) is summarized, with discussion of the methods and potential artifacts. Finally, available evidence to support nonradical mechanisms of oxidative stress is reviewed.…”

A Novel Fluorescent Sensor Protein for Visualization of Redox States in the Cytoplasm and in Peroxisomes

“…Therefore, the redox state is considered to reflect the overall metabolic status. While the standard redox potential (E 0 Ј) is a general index used to express the redox state of a compound, it cannot be used to describe the intracellular redox state because it does not take into account various physiological considerations, such as the cytosol, where many compounds coexist in a mixture of various redox states (14). Therefore, the equilibrium redox state in living cells has been estimated from indices such as the ratio of oxidized and reduced forms of glutathione, from indirect indices of the redox state, such as the NAD(P)H ratio (12,40), or from the level of the expression of antioxidant enzymes.…”

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

“…Further reduction of the intra-subunit disulfide bond in mCRP unlocks the CBM, thereby unmasking pro-inflammatory activities, which may accelerate disease progression and trigger acute events. This result is also the first demonstration of a sulfur switch (i.e., Cys36), an essential component of redox regulation [106], in an acute phase reactant, expressing an "on" state in the reduced form. Such a cascading mechanism would ensure prompt and localized responses and determine the expression of anti-or pro-inflammatory activities of CRP, mCRP and reduced mCRP during inflammation.…”