Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control

Redox mechanisms function in control of gene expression, cell proliferation, and apoptosis, but the circuitry for redox signaling remains unclear. Cysteine and methionine are the only amino acids in proteins that undergo reversible oxidation/reduction under biologic conditions and, as such, provide a means for control of protein activity, protein-protein interaction, protein trafficking, and protein-DNA interaction. Hydrogen peroxide and other reactive oxygen species (ROS) provide a mechanism to oxidize signaling proteins. However, oxidation of sulfur-containing side chains of cysteine and methionine by ROS can result in oxidation states of sulfur (e.g., sulfinate, sulfonate, sulfone) that are not reducible under biologic conditions. Thus, mechanisms for oxidation that protect against over-oxidation of these susceptible residues and prevent irreversible loss of activity would be advantageous. The present study shows that the steady-state redox potential of the cysteine/cystine couple (E-h = -145 mV) in cells is sufficiently oxidized (>90 mV) relative to the GSH/GSSG (-250 mV) and thioredoxin (Trx1, -280 mV) redox couples for the cysteine/cystine couple to function as an oxidant in redox switching. Consequently, the cysteine/cystine couple provides a means to oxidize proteins without direct involvement of more potent oxidants. A circuitry model incorporating cysteine as a redox node, along with Trx1 and GSH, reveals how selective interactions between the different thiol/disulfide couples and reactive protein thiols could differentially regulate metabolic functions. Moreover, inclusion of cysteine/cystine as a signaling node distinct from GSH and Trx1 significantly expands the redox range over which protein thiol/disulfide couples may operate to control physiologically relevant processes.