Concerted nitric oxide formation and release from the simultaneous reactions of nitrite with deoxy- and oxyhemoglobin
Concerted nitric oxide formation and release from the simultaneous reactions of nitrite with deoxy- and oxyhemoglobin
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DOI：
10.1074/jbc.m700546200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Gladwin, Mark T.
中科院分区：
文献类型：
--
作者：
Grubina, Rozalina;Huang, Zhi;Gladwin, Mark T.
最近的研究揭示了血红蛋白作为一种变构调节的亚硝酸盐还原酶的新作用，其可以沿着生理氧梯度介导一氧化氮（NO）依赖性信号传导。亚硝酸盐在变构反应中与脱氧血红蛋白反应，生成NO并将脱氧血红蛋白氧化为高铁血红蛋白。然后，NO以接近扩散限制的速率与脱氧血红蛋白反应，形成铁-亚硝酰-血红蛋白，迄今为止，铁-亚硝酰-血红蛋白被认为是高度稳定的加合物，因此不是生物可利用的NO的来源。然而，在部分氧饱和的生理条件下，亚硝酸盐也将与氧合血红蛋白反应，尽管这种复杂的自催化反应已经研究了世纪，氧和脱氧反应的相互作用以及对NO处置的影响从未被探索过。我们现在已经表征了在一定范围的氧分压下血红蛋白氧化和NO生成的动力学，并发现脱氧反应与氧反应平行运行并部分抑制氧反应。事实上，氧化反应中的中间体会氧化亚硝酰铁血红蛋白中的血红素铁（脱氧反应的产物），从而从亚硝酰铁中释放出NO。在亚硝酸盐存在的情况下，这种氧化性脱亚硝基化在血红蛋白脱氧和氧化的循环期间特别引人注目。这些化学物质可能通过限制氧合血红蛋白对亚硝酸盐的氧化失活，促进脱氧血红蛋白将亚硝酸盐还原为NO，以及从铁-亚硝基血红蛋白中释放游离NO，从而促进红细胞中亚硝酸盐的氧依赖性处置。
Recent studies reveal a novel role for hemoglobin as an allosterically regulated nitrite reductase that may mediate nitric oxide (NO)-dependent signaling along the physiological oxygen gradient. Nitrite reacts with deoxyhemoglobin in an allosteric reaction that generates NO and oxidizes deoxyhemoglobin to methemoglobin. NO then reacts at a nearly diffusion-limited rate with deoxyhemoglobin to form iron-nitrosyl-hemoglobin, which to date has been considered a highly stable adduct and, thus, not a source of bioavailable NO. However, under physiological conditions of partial oxygen saturation, nitrite will also react with oxyhemoglobin, and although this complex autocatalytic reaction has been studied for a century, the interaction of the oxy- and deoxy-reactions and the effects on NO disposition have never been explored. We have now characterized the kinetics of hemoglobin oxidation and NO generation at a range of oxygen partial pressures and found that the deoxy-reaction runs in parallel with and partially inhibits the oxy-reaction. In fact, intermediates in the oxy-reaction oxidize the heme iron of iron nitrosyl hemoglobin, a product of the deoxy-reaction, which releases NO from the iron-nitrosyl. This oxidative denitrosylation is particularly striking during cycles of hemoglobin deoxygenation and oxygenation in the presence of nitrite. These chemistries may contribute to the oxygen-dependent disposition of nitrite in red cells by limiting oxidative inactivation of nitrite by oxyhemoglobin, promoting nitrite reduction to NO by deoxyhemoglobin, and releasing free NO from iron-nitrosyl-hemoglobin.