ArticleJournal of the American Society for Mass Spectrometry2007
Sites of alkylation of human Keap1 by natural chemoprevention agents.
Article in Journal of the American Society for Mass Spectrometry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 181 citations in OpenAlex.
- Cysteine-based molecular switches: a focus on KEAP1 and BACH1 in regulating the antioxidant response.Archives of toxicology · 2026Review
- Development of a high-throughput screening platform for identification of functional BACH1 inhibitors reveals compounds with anti-invasive potential.Redox biology · 2026Article
- Covalent Modification of Keap1 by the Key Metabolic Cofactor Coenzyme A Under Oxidative and Metabolic Stress.Antioxidants (Basel, Switzerland) · 2026Article
- Xanthohumol Alters Gut Microbiota Metabolism and Bile Acid Dynamics in Gastrointestinal Simulation Models of Eubiotic and Dysbiotic States.International journal of molecular sciences · 2025Article
- The Role of Reactive Oxygen Species in Lung Cancer Development: Nanomedicine as a Therapeutic Strategy.Biomolecules · 2025Review
- Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases.Antioxidants (Basel, Switzerland) · 2024Review
- Ginsenoside Rg5, a potent agonist of Nrf2, inhibits HSV-1 infection-induced neuroinflammation by inhibiting oxidative stress and NF-κB activation.Journal of ginseng research · 2024Article
- Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2.International journal of molecular sciences · 2024Review
- Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer.Frontiers in oncology · 2024Review
- Foodomics-Based Approaches Shed Light on the Potential Protective Effects of Polyphenols in Inflammatory Bowel Disease.International journal of molecular sciences · 2023Review
- A Point Mutation at C151 ofMolecular pharmacology · 2023Article
- Phytochemical Screening and Antioxidant Potential of Selected Extracts fromPlants (Basel, Switzerland) · 2023Article
- Dietary (poly)phenols mitigate inflammatory bowel disease: Therapeutic targets, mechanisms of action, and clinical observations.Current research in food science · 2023Review
- Post-translational modifications of Keap1: the state of the art.Frontiers in cell and developmental biology · 2023Review
- JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses IntracellularOxidative medicine and cellular longevity · 2023Article
- Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy.Molecules (Basel, Switzerland) · 2022Review
- Review
- Genetic Variations on Redox Control in Cardiometabolic Diseases: The Role of Nrf2.Antioxidants (Basel, Switzerland) · 2022Review
- The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity.Frontiers in nutrition · 2022Review
- The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications.Molecules (Basel, Switzerland) · 2021Review
18 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Under basal conditions, the interaction of the cytosolic protein Keap1 (Kelch-like ECH-associated protein 1) with the transcription factor nuclear factor-E(2)-related factor 2 (Nrf2) results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). Alkylation of one or more of the 27 cysteine sulfhydryl groups of human Keap1 is proposed to lead to Nrf2 nuclear accumulation, to upregulation of cytoprotective gene expression by the ARE, and to prevention of degenerative diseases, such as cancer. Therefore, identification of the most reactive of these cysteine residues toward specific electrophiles should help clarify this mechanism of cancer prevention, also known as chemoprevention. To address this issue, preliminary analyses of tryptic digests of Keap1 alkylated by the model electrophile 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido) butane were carried out using liquid chromatographic-tandem mass spectrometry (LC-MS/MS) with a cylindrical ion trap mass spectrometer and also using LC-MS/MS with a hybrid linear ion trap FT ICR mass spectrometer. Because the FT ICR instrument provided more complete peptide sequencing coverage and enabled the identification of more alkylated cysteine residues, only this instrument was used in subsequent studies of Keap1 alkylation by three electrophilic natural products that can upregulate the ARE, xanthohumol, isoliquiritigenin, and 10-shogaol. Among the various cysteine residues of Keap1, C151 was most reactive toward these three electrophiles. These in vitro results agree with evidence from in vivo experiments, and indicate that C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the ARE through Nrf2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.