Reactive oxygen species and protein disulfide bonds

Reactive oxygen species (ROS) and protein disulfide bonds are central components of the cellular redox environment, governing protein folding, stability, and signaling. ROS serve as secondary messengers that facilitate the formation of disulfide bridges between cysteine residues, a post-translational modification primarily managed by the thioredoxin and protein disulfide isomerase (PDI) systems [1, 2]. While this process is vital for the structural integrity of proteins in the secretory pathway, an imbalance—often termed oxidative stress—leads to aberrant disulfide bond formation and protein misfolding [3]. This dysregulation is a key driver in various pathologies; for instance, cancer cells often hijack redox signaling to promote proliferation, while in neurodegeneration, excessive disulfide cross-linking contributes to the formation of insoluble protein aggregates [4]. Pharmacological strategies targeting this axis include antioxidants that neutralize ROS and small-molecule inhibitors of redox enzymes like thioredoxin reductase (e.g., auranofin) or PDI [5]. The primary therapeutic challenge lies in achieving selectivity, as broad inhibition can disrupt essential homeostatic redox processes, leading to systemic toxicity [6]. Sources: [1] Sies, H., et al. (2020) Nature Reviews Molecular Cell Biology; [2] Wang, L., & Wang, C. C. (2023) Free Radical Biology and Medicine; [3] Bulleid, N. J., & Ellgaard, L. (2011) Chemical Reviews; [4] Zeeshan, H. M., et al. (2016) Free Radical Biology and Medicine; [5] Holmgren, A., & Lu, J. (2010) Free Radical Biology and Medicine; [6] Forman, H. J., & Zhang, H. (2021) Archives of Biochemistry and Biophysics.

Other names

Redox-mediated protein foldingThiol-disulfide exchangeOxidative protein foldingROS-induced disulfide formationRedox signaling pathway

Modulation of cellular redox homeostasis through the scavenging of reactive oxygen species or the inhibition of enzymes (such as Protein Disulfide Isomerase or Thioredoxin Reductase) that catalyze the formation, reduction, or isomerization of protein disulfide bonds.