Radi Rafael
Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Avda. General Flores 2125, 11800 Montevideo, Uruguay.
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4003-8. doi: 10.1073/pnas.0307446101. Epub 2004 Mar 12.
The occurrence of protein tyrosine nitration under disease conditions is now firmly established and represents a shift from the signal transducing physiological actions of (.)NO to oxidative and potentially pathogenic pathways. Tyrosine nitration is mediated by reactive nitrogen species such as peroxynitrite anion (ONOO(-)) and nitrogen dioxide ((.)NO2), formed as secondary products of (.)NO metabolism in the presence of oxidants including superoxide radicals (O2(.-)), hydrogen peroxide (H2O2), and transition metal centers. The precise interplay between (.)NO and oxidants and the identification of the proximal intermediate(s) responsible for nitration in vivo have been under controversy. Despite the capacity of peroxynitrite to mediate tyrosine nitration in vitro, its role on nitration in vivo has been questioned, and alternative pathways, including the nitrite/H2O2/hemeperoxidase and transition metal-dependent mechanisms, have been proposed. A balanced analysis of existing evidence indicates that (i) different nitration pathways can contribute to tyrosine nitration in vivo, and (ii) most, if not all, nitration pathways involve free radical biochemistry with carbonate radicals (CO3(.-)) and/or oxo-metal complexes oxidizing tyrosine to tyrosyl radical followed by the diffusion-controlled reaction with (.)NO2 to yield 3-nitrotyrosine. Although protein tyrosine nitration is a low-yield process in vivo, 3-nitrotyrosine has been revealed as a relevant biomarker of (.)NO-dependent oxidative stress; additionally, site-specific nitration focused on particular protein tyrosines may result in modification of function and promote a biological effect. Tissue distribution and quantitation of protein 3-nitrotyrosine, recognition of the predominant nitration pathways and individual identification of nitrated proteins in disease states open new avenues for the understanding and treatment of human pathologies.
疾病状态下蛋白质酪氨酸硝化作用的发生现已得到确凿证实，它代表了从（·）NO的信号转导生理作用向氧化及潜在致病途径的转变。酪氨酸硝化作用由活性氮物质介导，如过氧亚硝酸根阴离子（ONOO⁻）和二氧化氮（·NO₂），它们是在包括超氧阴离子自由基（O₂⁻·）、过氧化氢（H₂O₂）和过渡金属中心在内的氧化剂存在下（·）NO代谢的次级产物。（·）NO与氧化剂之间的确切相互作用以及体内负责硝化作用的近端中间体的鉴定一直存在争议。尽管过氧亚硝酸根在体外具有介导酪氨酸硝化的能力，但其在体内硝化作用中的作用受到质疑，并且已经提出了替代途径，包括亚硝酸盐/H₂O₂/血红素过氧化物酶和过渡金属依赖性机制。对现有证据的综合分析表明：（i）不同的硝化途径可促成体内酪氨酸硝化；（ii）大多数（如果不是全部）硝化途径涉及自由基生物化学，碳酸根自由基（CO₃⁻·）和/或氧代金属配合物将酪氨酸氧化为酪氨酰自由基，随后通过扩散控制反应与·NO₂反应生成3-硝基酪氨酸。尽管蛋白质酪氨酸硝化在体内是一个低产率过程，但3-硝基酪氨酸已被揭示为（·）NO依赖性氧化应激的相关生物标志物；此外，针对特定蛋白质酪氨酸的位点特异性硝化可能导致功能改变并促进生物学效应。蛋白质3-硝基酪氨酸的组织分布和定量、对主要硝化途径的识别以及疾病状态下硝化蛋白质的个体鉴定为理解和治疗人类疾病开辟了新途径。
