Projects per year
Abstract
Numerous small molecules (termed inducers), many of which are electrophiles, upregulate cytoprotective responses and inhibit pro-inflammatory pathways by activating nuclear factor-erythroid 2 p45-related factor 2 (NRF2). Key to NRF2 activation is the ability to chemically modifying critical sensor cysteines in the main negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), of which C151, C273 and C288 are best characterized. This study aimed to establish the requirement for these cysteine sensor(s) for the biological activities of the most potent NRF2 activators known to date, the cyclic cyanoenones, some of which are in clinical trials. It was found that C151 in KEAP1 is the main cysteine sensor for this class of inducers, irrespective of molecular size or shape. Furthermore, in primary macrophage cells expressing C151S mutant KEAP1, at low concentrations, the tricyclic cyanoenone TBE-31 is inactive as an activator of NRF2 as well as an inhibitor of lipopolysaccharide-stimulated gene expression of the pro-inflammatory cytokines IL6 and IL1β. However, at high inducer concentrations, NRF2 activation proceeds in the absence of C151, albeit at a lower magnitude. Our findings highlight the intrinsic flexibility of KEAP1 and emphasize the critical importance of establishing the precise dose of NRF2 activators for maintaining on-target selectivity.
Original language | English |
---|---|
Article number | 8037 |
Pages (from-to) | 1-12 |
Number of pages | 12 |
Journal | Scientific Reports |
Volume | 8 |
Issue number | 1 |
DOIs | |
Publication status | Published - 23 May 2018 |
Keywords
- Mechanism of action
- Pharmacology
ASJC Scopus subject areas
- General
Fingerprint
Dive into the research topics of 'C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape'. Together they form a unique fingerprint.Projects
- 1 Finished
-
The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)
Dinkova-Kostova, A. (Investigator)
Biotechnology and Biological Sciences Research Council
30/09/14 → 27/02/18
Project: Research
Research output
- 58 Citations
- 1 Comment/debate
-
Author Correction: C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape
Dayalan Naidu, S., Muramatsu, A., Saito, R., Asami, S., Honda, T., Hosoya, T., Itoh, K., Yamamoto, M., Suzuki, T. (Lead / Corresponding author) & Dinkova-Kostova, A. T. (Lead / Corresponding author), 27 Feb 2024, In: Scientific Reports. 14, 1, 2 p., 4774.Research output: Contribution to journal › Comment/debate › peer-review
Open AccessFile63 Downloads (Pure)
Profiles
-
Dinkova-Kostova, Albena
- Cancer Research - Professor (Teaching and Research) of Chemical Biology
Person: Academic