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• W1994014539 endingPage "6244" @default.
• W1994014539 startingPage "6232" @default.
• W1994014539 abstract "Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized “electrophile toolbox” with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2–ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2–ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background." @default.
• W1994014539 created "2016-06-24" @default.
• W1994014539 creator A5012739930 @default.
• W1994014539 creator A5042005906 @default.
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• W1994014539 creator A5088715619 @default.
• W1994014539 creator A5089679931 @default.
• W1994014539 date "2015-05-05" @default.
• W1994014539 modified "2023-09-27" @default.
• W1994014539 title "A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling" @default.
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• W1994014539 doi "https://doi.org/10.1021/ja5132648" @default.
• W1994014539 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4528680" @default.
• W1994014539 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25909755" @default.
• W1994014539 hasPublicationYear "2015" @default.
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