The unique reactivity of EKODE lipid peroxidation products allows in vivo detection of inflammation

• 成果类型: Article
• 署名作者: Shi, Chuan; Eskandari, Roozbeh; Zhang, Jianye; Zhang, Guofang; Li, Li; Hawkins, Deandrea; Zhu, Xiongwei; Tochtrop, Gregory P.
• 署名单位: University System of Ohio; Case Western Reserve University; Duke University; University System of Ohio; Case Western Reserve University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10162
• DOI: 10.1073/pnas.241503912
• 发表日期: 2025-02-11
• 关键词: mass-spectrometric characterization; human serum-albumin; linoleic-acid; covalent modification; oxidative stress; end-products; nonenzymatic oxidation; protein modification; oxidized metabolite; reperfusion

摘要

Lipid peroxidation is a complex biochemical process associated with oxidative stress, and its products play crucial roles in cellular signaling and the pathophysiology of many diseases. Among the diverse array of lipid peroxidation (LPO) products, epoxyketoocta-decenoic acids (EKODEs) have emerged as intriguing molecules with potential impacts on inflammatory diseases. EKODEs arise from linoleic acid reacting with reactive oxygen and nitrogen species present during inflammation. A hallmark of many LPO products is an electrophilic chemical functionality that can react with different biological nucleo-philes to form adducts that impact a broad swath of physiologic processes. Here, we present the identification of reactivity patterns exhibited by the EKODE class of LPO products that arise due to the unique chemistry of the EKODE electrophiles, namely alpha, beta- unsaturated epoxyketones of variable regiochemistry. Our initial investigations with models of the EKODE reactive core showed that surrogates of lysine did not react, and histidine nucleophiles formed reversible Michael adducts. However, when models of cysteine nucleophiles were tested, a unique reactivity profile emerged where rapid Michael addition was followed by slow rearrangement and epoxide opening at an unpredicted electrophilic site, affording what we postulated to be an advanced lipoxi-dation end product (ALE). After confirming the EKODE reactivity in model systems, we produced polyclonal antibodies of a stable epitope of the EKODE- based ALE and used these antibodies to investigate an approach for in vivo monitoring of inflammatory disease progression