硫化水化合物抑制脂质过氧化,保护细胞免受铁
Zijun Wu1, Vinayak S Khodade2, Jean-Philippe R Chauvin1
1Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ONK1N 6N5, Canada.
Journal of the American Chemical Society
|August 17, 2022
概括
硫化 (RSSH) 通过清除有害基来有效抑制铁,与强大的抑制剂相匹配. 它们的*in situ*生成提高了效率,这表明它们在细胞防御系统中起着关键作用.
科学领域:
- 生物化学
- 细胞生物学
- 氧化应激研究
背景情况:
- 硫化 (RSSH) 是关键的内源分子,参与清除有害氧化剂和电友.
- 与硫醇 (RSH) 相比,α效应增强了RSSH的核友性和H原子转移 (HAT) 能力.
- HAT是脂过氧化和铁的强大小分子抑制剂的已确定的机制.
研究的目的:
- 研究水硫化物 (RSSH) 作为脂过氧化和铁的抑制剂的反应性.
- 探索RSSH的现场生成策略,以提高它们的基因捕获效率.
- 评估RSSH作为生理性铁灭抑制系统的潜力.
主要方法:
- 使用光激活抑制自氧化 (FENIX) 方法量化RSSH反应性.
- 在生理条件下研究RSSH和相关 (多) 硫化物的反应性.
- 使用设计的前体生成RSSH并评估其在细胞培养中的有效性.
主要成果:
- RSSH对脂衍生的过氧基具有较高的反应性 (kinh = 2 × 105 M-1 s-1),与主要的铁灭抑制剂相当.
- 通过最大限度地减少自身反应,提高了基因捕获效率.
- 当GPX4被禁用或其基因被删除时,RSSH及其前体有效地抑制了小鼠胚胎纤维细胞的铁.
结论:
- 通过H原子转移中和有害基,RSSH是铁灭的强有力的抑制剂.
- 能够在现场生成RSSH的设计前体提供了一种克服自我反应限制和增强治疗潜力的策略.
- 这些发现突出显示RSSH及其生物合成途径是抑制铁的重要内源系统,与已知的途径如FSP1/ubiquinone和GCH1/BH4/DHFR一起.
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