Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1

The protein Kelch-like ECH-associated protein 1 (Keap1) is a cysteine-rich regulatory and scaffold protein. Human Keap1 contains 27 cysteines. Some of these cysteines are believed to mediate derepression of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which subsequently upregulates phase 2 enzymes, in response to electrophilic/oxidative assault. Some current models depict a highly select group of two and possibly a few more cysteine residues as key sensors. The assumptions and approaches undergirding these models are commented upon. The chemical reactivity of the cysteines of Keap1 toward an array of electrophiles and one oxidant is reviewed. A number of reports in the recent literature of molecules that putatively modify cysteines of Keap1 are also included. Insights into the current molecular basis of electrophile/oxidant activation of the Nrf2 pathway via reaction at cysteines of Keap1 are discussed. Finally, important knowns and unknowns are summarized.