Electrophilic metabolites targeting the KEAP1/NRF2 partnership

Albena Dinkova-Kostova (Lead / Corresponding author), Henriikka Hakomäki, Anna-Liisa Levonen (Lead / Corresponding author)

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    Abstract

    Numerous electrophilic metabolites are formed during cellular activity, particularly under conditions of oxidative, inflammatory and metabolic stress. Among them are lipid oxidation and nitration products, and compounds derived from amino acid and central carbon metabolism. Here we focus on one cellular target of electrophiles, the Kelch-like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2 p45-related factor 2 (NRF2) partnership. Many of these reactive compounds modify C151, C273 and/or C288 within KEAP1. Other types of modifications include S-lactoylation of C273, N-succinylation of K131, and formation of methylimidazole intermolecular crosslink between two KEAP1 monomers. Modified KEAP1 relays the initial signal to transcription factor NRF2 and its downstream targets, the ultimate effectors that provide means for detoxification, adaptation and survival. Thus, by non-enzymatically covalently modifying KEAP1, the electrophilic metabolites discussed here serve as chemical signals connecting metabolism with stress responses.
    Original languageEnglish
    Article number102425
    Number of pages11
    JournalCurrent Opinion in Chemical Biology
    Volume78
    Early online date18 Jan 2024
    DOIs
    Publication statusPublished - Feb 2024

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Biochemistry

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