Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay;
Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5839-5848. doi: 10.1073/pnas.1804932115. Epub 2018 May 25.
Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of NO are modulated by its fast reaction with superoxide radical ([Formula: see text]), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.
氧衍生自由基和相关氧化剂是无处不在的，也是在整个生命过程中需氧生物形成的短暂中间体。这些活性物质参与氧化还原反应，导致生物分子发生氧化修饰，其中蛋白质和脂质是优先的靶标。尽管哺乳动物细胞和微生物中有广泛的酶和非酶抗氧化系统，但过量的氧化剂形成会导致新产物的积累，从而损害细胞功能和结构，导致细胞退化和死亡。氧化事件与病理状况和正常衰老过程有关。值得注意的是，氧化剂的生理水平也通过稳态氧化还原敏感细胞信号级联来调节细胞功能。另一方面，一氧化氮（NO）是一种自由基和弱氧化剂，通过与血红素蛋白的可逆相互作用，代表一种主要的生理调节剂。NO 的生物利用度和作用受其与超氧自由基 ([Formula: see text]) 的快速反应调节，这产生了一种不寻常且反应性强的过氧自由基，过氧亚硝酸盐，代表了氧自由基和 NO 途径的融合。在这篇开篇文章中，我总结了自由基生物化学的早期和显著发展以及该领域后来向分子医学的发展；这种转变包括我们揭示 NO 与氧化还原中间体和代谢关系的贡献。过氧亚硝酸盐的生化特征、鉴定和定量及其在疾病过程中的作用引起了我们的高度关注。作为蛋白质氧化和硝化、脂质过氧化、线粒体功能障碍和细胞死亡的介质，过氧亚硝酸盐既是一种与病理生理学相关的内源性细胞毒素，也是一种针对入侵病原体的细胞毒性效应物。
