Electrophile versus oxidant modification of cysteine residues: Kinetics as a key driver of protein modification

Advances and challenges in therapeutic targeting of NRF2

“…Target specificity Many NRF2 activators are electrophiles that target cysteine 151 in KEAP1 [19][20][21]. However, depending on concentration, the electrophilicity of such molecules confers an ability to affect multiple cysteines within KEAP1 [20] and other proteins [6,22,23] (Figure 3A). Thus, whereas NRF2 activation represents an important component of the efficacy of these compounds, it may not be the only responsible factor.…”

Regulation of immunomodulatory networks by Nrf2-activation in immune cells: Redox control and therapeutic potential in inflammatory diseases

“…The thiol-modifying agents that are currently in existence are potent inducers of the Nrf2-mediated antioxidant response, however, specificity for Keap1 is an ongoing consideration and notwithstanding the possible effects coming from the many Keap1-interacting proteins. Depending on concentration, these agents may affect multiple residues within Keap1 and other proteins [ 171 , 174 ] further contributing to the likelihood of unintended effects. Overall, a better understanding of the crystal structure of KEAP1 alone as well cocrystal structure with the Neh2 domain of Nrf2, and others may help in designing more selective Nrf2 activators.…”

Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer

“…H2O2 oxidises several types of protein residues as a redox switch to signal gene up/downregulation, proliferation, migration and metabolism [97]. Additionally, the lipid oxidation products mentioned earlier can also oxidise protein cysteine residues, resulting in lipid-protein adduct formation [98]. ONOOcan also spontaneously decompose into potent • OH and NO2 • radicals that react with protein tyrosine residues to form tyrosine radicals, inactivating proteins by forming irreversible 3-nitrotyrosine or dityrosine (protein-protein) adducts, or propagating lipid peroxidation [99].…”