ArticleFree radical biology & medicine2011
Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal.
Article in Free radical biology & medicine, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 63 citations in OpenAlex.
- GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.Cell death and differentiation · 2025Article
- Arsenite-Mediated Transcriptional Regulation of Glutathione Synthesis in Mammalian Primary Cortical Astrocytes.International journal of molecular sciences · 2025Article
- Lipid Quality Control and Ferroptosis: From Concept to Mechanism.Annual review of biochemistry · 2024Review
- Lipid Peroxidation-Related Redox Signaling in Osteosarcoma.International journal of molecular sciences · 2024Review
- Click chemistry-based thiol redox proteomics reveals significant cysteine reduction induced by chronic ethanol consumption.Redox biology · 2023Article
- Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy.Antioxidants (Basel, Switzerland) · 2023Review
- The 4-Hydroxynonenal-Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?Antioxidants (Basel, Switzerland) · 2023Review
- Ubiquitination as a key regulatory mechanism for ORedox biology · 2022Article
- Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.International journal of molecular sciences · 2022Article
- The Role of Non-Coding RNAs in the Neuroprotective Effects of Glutathione.International journal of molecular sciences · 2021Review
- Response of Cytoprotective and Detoxifying Proteins to Vanadate and/or Magnesium in the Rat Liver: The Nrf2-Keap1 System.Oxidative medicine and cellular longevity · 2021Article
- S1P and plasmalogen derived fatty aldehydes in cellular signaling and functions.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2020Review
- Lipoxidation and cancer immunity.Redox biology · 2019Review
- NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis.Redox biology · 2019Review
- 4-Hydroxy-Trans-2-Nonenal in the Regulation of Anti-Oxidative and Pro-Inflammatory Signaling Pathways.Oxidative medicine and cellular longevity · 2019Review
- Post-translational Activation of Glutamate Cysteine Ligase with Dimercaprol: A NOVEL MECHANISM OF INHIBITING NEUROINFLAMMATIONThe Journal of biological chemistry · 2017Article
- Signaling by 4-hydroxy-2-nonenal: Exposure protocols, target selectivity and degradation.Archives of biochemistry and biophysics · 2017Review
- Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment.Toxicological sciences : an official journal of the Society of Toxicology · 2015Review
- The cysteine proteome.Free radical biology & medicine · 2015Review
- Quantitative chemoproteomics for site-specific analysis of protein alkylation by 4-hydroxy-2-nonenal in cells.Analytical chemistry · 2015Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
4-Hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product formed during oxidative stress that can alter protein function via adduction of nucleophilic amino acid residues. 4-HNE detoxification occurs mainly via glutathione (GSH) conjugation and transporter-mediated efflux. This results in a net loss of cellular GSH, and restoration of GSH homeostasis requires de novo GSH biosynthesis. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate-cysteine ligase (GCL), a heterodimeric holoenzyme composed of a catalytic (GCLC) and a modulatory (GCLM) subunit. The relative levels of the GCL subunits are a major determinant of cellular GSH biosynthetic capacity and 4-HNE induces the expression of both GCL subunits. In this study, we demonstrate that 4-HNE can alter GCL holoenzyme formation and activity via direct posttranslational modification of the GCL subunits in vitro. 4-HNE directly modified Cys553 of GCLC and Cys35 of GCLM in vitro, which significantly increased monomeric GCLC enzymatic activity, but reduced GCL holoenzyme activity and formation of the GCL holoenzyme complex. In silico molecular modeling studies also indicate these residues are likely to be functionally relevant. Within a cellular context, this novel posttranslational regulation of GCL activity could significantly affect cellular GSH homeostasis and GSH-dependent detoxification during periods of oxidative stress.
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