Lancaster Jack R
Department of Anesthesiology, Environmental Health Sciences, and Physiology & Biophysics, Center for Free Radical Biology, The University of Alabama Birmingham, 35294, USA.
Chem Res Toxicol. 2006 Sep;19(9):1160-74. doi: 10.1021/tx060061w.
A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with 1:1 fluxes of ()NO and O(2)()(-) does not occur under biological conditions. (2) By far, the quantitatively dominant (92-99.6%) process in vivo is oxidation, compared to nitrosation and nitration. (3) Only five of the many possible RNS reactions involving thiol (glutathione, GSH) and tyrosine are quantitatively important biologically. (4) Under inflammatory conditions, approximately 1% of O(2)()(-) reacts with ()NO to produce ONOO(-), with the remainder reacting with SOD. (5) The dominant reaction of tyrosyl radical is a radical swap with GSH, producing the glutathiyl radical and regenerating tyrosine. (6) Nitrosothiol is formed virtually exclusively via radical recombination (RS() + ()NO) as opposed to reaction with nitrous anhydride (N(2)O(3)). (7) Nitrosothiol is an intermediate, not an endproduct, and responds dynamically to changes in the immediate chemical environment. (8) The formation of a nitroso group on a particular thiol can be considered a marker of increased reactivity of that thiol, and it is likely that other modifications of that thiol (oxidation, glutathiolation) are more abundant than nitrosation and may be the functionally significant modification. (9) Specific chemical mechanisms are proposed for posttranslational protein modification via nitrosation, nitration, glutathiolation, and also dithiol/disulfide exchange, with important roles for the thiolate anion and O(2) (suggesting possible mechanisms for O(2) sensing) and variable degrees of exposure of cysteine thiol and tyrosine phenolate. (10) Patterns of reactivity are similar for low (20 nM) and high (500 nM) steady-state levels of NO. (11) The dominant reactions are those involving reactants at the highest concentrations (CO(2), thiol, O(2)). Because of the dominance of oxidative processes caused by RNS, the term nitroxidative stress is proposed, emphasizing the oxidative (as opposed to nitrosative or nitrative) stress that dominates RNS actions under biological conditions.
一个基于Windows的免费程序RNSim1A，用于预测模拟生物条件下与金属无关的活性氮物质（RNS）化学过程（氧化、亚硝化和硝化），并做出以下具体预测。（1）在体外，当（）NO和O（2）（）-的通量为1:1时发生的氧化反应峰值，在生物条件下不会出现。（2）到目前为止，与亚硝化和硝化相比，体内数量上占主导的（92 - 99.6%）过程是氧化。（3）在涉及硫醇（谷胱甘肽，GSH）和酪氨酸的众多可能的RNS反应中，只有五个在生物学上具有重要的定量意义。（4）在炎症条件下，约1%的O（2）（）-与（）NO反应生成过氧亚硝酸根（ONOO-），其余与超氧化物歧化酶（SOD）反应。（5）酪氨酸自由基的主要反应是与GSH进行自由基交换，生成谷胱甘肽基自由基并再生酪氨酸。（6）亚硝基硫醇几乎完全通过自由基重组（RS（）+（）NO）形成，而不是与亚硝酸酐（N（2）O（3））反应。（7）亚硝基硫醇是一种中间体，而非终产物，并且会对即时化学环境的变化做出动态响应。（8）特定硫醇上亚硝基的形成可被视为该硫醇反应性增加的标志，并且该硫醇的其他修饰（氧化、谷胱甘肽化）可能比亚硝化更为丰富，并且可能是功能上重要的修饰。（9）提出了通过亚硝化、硝化、谷胱甘肽化以及二硫醇/二硫化物交换进行翻译后蛋白质修饰的具体化学机制，硫醇阴离子和O（2）起重要作用（暗示了O（2）传感的可能机制）以及半胱氨酸硫醇和酪氨酸酚盐的不同程度暴露。（10）对于低（20 nM）和高（500 nM）稳态水平的NO，反应模式相似。（11）主要反应是那些涉及最高浓度反应物（CO（2）、硫醇、O（2））的反应。由于RNS引起的氧化过程占主导，提出了“硝氧化应激”这一术语，强调在生物条件下主导RNS作用的氧化（与亚硝化或硝化相对）应激。
