Cellular targets and mechanisms of nitros(yl)ation:: An insight into their nature and kinetics in vivo
Cellular targets and mechanisms of nitros(yl)ation:: An insight into their nature and kinetics in vivo
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DOI：
10.1073/pnas.0306706101
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发表时间：
2004-03-23
影响因子：
11.1
通讯作者：
Feelisch, M
中科院分区：
文献类型：
--
作者：
Bryan, NS;Rassaf, T;Feelisch, M
越来越多的证据表明，一氧化氮(NO)生物化学的既定范例，从通过NO合成酶的形成，通过与可溶性鸟苷酸环酶的过度相互作用，到最终以亚硝酸盐/硝酸盐的形式处理，仅代表了NO通过其引发生物信号的更丰富化学的一部分。已提出的其他途径包括NO衍生的代谢物与硫醇和金属相互作用，形成S亚硝硫醇(RSNO)和金属亚硝基。尽管在这方面对RSNOS给予了极大的关注，但人们对这些物种的稳定性、它们在流通之外的意义以及其他亚硝化产物是否具有同样的重要性知之甚少。我们在这里证明了N-亚硝化和血红素亚硝化在体内确实和S亚硝化一样普遍存在，并且这些反应的产物结构性地存在于整个器官系统中。我们的研究进一步揭示，所有NO衍生产物都是高度动态的，寿命相当短，并与组织氧合和氧化还原状态有关。实验证据进一步表明，亚硝基的形成实质上是通过氧化亚硝化而不是无自氧化发生的，这解释了为什么S亚硝化可以有效地与亚硝化竞争。此外，在短暂的低氧状态下，组织亚硝酸盐可以作为重要的血管外NO池，组织硝酸盐/亚硝酸盐比率可以作为局部氧化和亚硝化应激之间平衡的指标。这些发现极大地扩展了我们对NO在体内的命运的理解，并为进一步探索亚硝化事件在氧化还原感知和信号转导中的意义提供了一个框架。这些发现还提出了一种有趣的可能性，即N-亚硝化直接参与了蛋白质功能的调节。
There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOS, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.