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Published on: May 21, 2020

A small-molecule inducer of the antioxidant response element

Wooyoung Hur1, Zheng Sun, Tao Jiang

  • 1Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.

Chemistry & Biology
|June 11, 2010
PubMed

Insights

Researchers discovered AI-1, a novel compound that activates the Nrf2 pathway by modifying Keap1. This activation enhances cellular antioxidant responses and holds therapeutic potential for various diseases.

Area of Science:

  • Molecular Biology
  • Cellular Stress Response

Background:

  • Eukaryotic cells utilize the Nrf2-ARE pathway to combat oxidative stress.
  • Nrf2 controls protective enzyme expression by binding to the antioxidant response element (ARE).
  • Electrophilic molecules activating Nrf2 show therapeutic promise in tumor models.

Purpose of the Study:

  • To identify novel activators of the Nrf2 pathway.
  • To investigate the mechanism of action of a newly discovered class of ARE activators, termed AI-1.

Main Methods:

  • High-throughput cellular screening to identify ARE activators.
  • Biochemical assays to elucidate the molecular mechanism of AI-1 action.
  • Investigation of Keap1 modification and its effect on Nrf2 stabilization.

Main Results:

  • A new class of ARE activators, AI-1, was discovered.
  • AI-1 activates Nrf2 by covalently modifying Keap1 at Cys151.
  • Modification of Keap1 by AI-1 disrupts its function as a Cul3-Keap1 ubiquitin ligase adaptor.
  • This disruption leads to Nrf2 stabilization and transcriptional activation.

Conclusions:

  • AI-1 represents a novel mechanism for Nrf2 activation.
  • AI-1's ability to modify Keap1 offers a new strategy for modulating cellular antioxidant responses.
  • AI-1 and its derivatives serve as valuable tools for studying the Nrf2 pathway.

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