Electrophilic metabolites targeting the KEAP1/NRF2 partnership.

Anna-Liisa Levonen, Albena T Dinkova-Kostova, Henriikka Hakomäki

Journal: Current opinion in chemical biology 2024;78():102425

PMID: 38241876

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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.

Address: Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, UK; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. Electronic address: [email protected].

DOI: 10.1016/j.cbpa.2024.102425

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https://linkinghub.elsevier.com/retrieve/pii/S1367...

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-OTUB1-1

MeSH Terms: Kelch-Like ECH-Associated Protein 1, NF-E2-Related Factor 2, Oxidative Stress, Oxidation-Reduction, Antioxidants