Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite.
Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite.
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DOI：
10.1016/j.bbagen.2013.07.005
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发表时间：
2014-02
影响因子：
3
通讯作者：
Radi, Rafael
中科院分区：
文献类型：
--
作者：
Carballal, Sebastian;Bartesaghi, Silvina;Radi, Rafael
过氧亚硝酸盐是超氧自由基和一氧化氮反应的产物，是生物系统中半衰期短、稳态浓度低的一种难以捉摸的氧化剂;它促进氮氧化损伤。我们将考虑动力学和机械方面，允许合理化的过氧亚硝酸盐的生物命运的方法，包括快速动力学技术，电子顺磁共振和动力学模拟的组合获得的数据。此外，我们提供了一个定量分析的过氧亚硝酸盐的生产率和可能的状态-状态水平在生活系统中。过氧亚硝酸盐在体内的优先反应包括与二氧化碳、硫醇和金属蛋白的反应;其均裂仅占其命运的<1%。值得注意的是，二氧化碳占过氧亚硝酸盐消耗的很大一部分，导致形成强的单电子氧化剂，碳酸根和二氧化氮。另一方面，过氧亚硝酸盐被过氧化物还原酶迅速还原，这代表了有效的基于硫醇的过氧亚硝酸盐解毒系统。谷胱甘肽在细胞中以mM浓度存在，经常被认为是过氧亚硝酸盐的直接清除剂，在体内与其反应速度不够快;谷胱甘肽主要通过与次级自由基反应来抑制过氧亚硝酸盐依赖性过程。蛋白质3-硝基酪氨酸（分子足迹）的检测可以证明体内过亚硝酸盐的形成。细胞中过氧亚硝酸根的基础形成速率可以估计为0.1至0.5 μM s−1，其稳态浓度约为1 nM。分析提供了一个手柄，以预测生活系统中的过氧亚硝酸盐的优先命运和稳态水平。这是有用的，以了解病理生理方面和药理学前景连接到过氧亚硝酸盐。
Peroxynitrite, the product of the reaction between superoxide radicals and nitric oxide, is an elusive oxidant of short half-life and low steady-state concentration in biological systems; it promotes nitroxidative damage. We will consider kinetic and mechanistic aspects that allow rationalizing the biological fate of peroxynitrite from data obtained by a combination of methods that include fast kinetic techniques, electron paramagnetic resonance and kinetic simulations. In addition, we provide a quantitative analysis of peroxynitrite production rates and conceivable state-state levels in living systems. The preferential reactions of peroxynitrite in vivo include those with carbon dioxide, thiols and metalloproteins; its homolysis represents only < 1 % of its fate. To note, carbon dioxide accounts for a significant fraction of peroxynitrite consumption leading to the formation of strong one-electron oxidants, carbonate radicals and nitrogen dioxide. On the other hand, peroxynitrite is rapidly reduced by peroxiredoxins, which represent efficient thiol-based peroxynitrite detoxification systems. Glutathione, present at mM concentration in cells and frequently considered a direct scavenger of peroxynitrite, does not react sufficiently fast with it in vivo; glutathione mainly inhibits peroxynitrite-dependent processes by reactions with secondary radicals. The detection of protein 3-nitrotyrosine, a molecular footprint, can demonstrate peroxynitrite formation in vivo. Basal peroxynitrite formation rates in cells can be estimated in the order of 0.1 to 0.5 μM s−1 and its steady-state concentration ~ 1 nM. The analysis provides a handle to predict the preferential fate and steady-state levels of peroxynitrite in living systems. This is useful to understand pathophysiological aspects and pharmacological prospects connected to peroxynitrite.
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