Hemoglobin as a nitrite anhydrase: modeling methemoglobin-mediated N2O3 formation.
Hemoglobin as a nitrite anhydrase: modeling methemoglobin-mediated N2O3 formation.
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DOI：
10.1002/chem.201003578
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发表时间：
2011-05-27
影响因子：
4.3
通讯作者：
Ghosh, Abhik
中科院分区：
文献类型：
--
作者：
Hopmann, Kathrin H.;Cardey, Bruno;Gladwin, Mark T.;Kim-Shapiro, Daniel B.;Ghosh, Abhik
亚硝酸盐最近被认为是一氧化氮在血液中的一种储存形式，在缺氧血管舒张中起着关键作用。这种离子很容易被红细胞中的血红蛋白还原为NO，然而，这也提出了一个难题。考虑到一氧化氮对亚铁血红素的巨大亲和力，一个关键问题是，当一氧化氮从红细胞扩散到血管舒张发生的内皮细胞时，它是如何逃脱血红蛋白的捕获的。三氧化二氮（N2O3）被认为是一种将NO运输到内皮细胞的载体，在内皮细胞中它解离成NO和NO2。虽然通过反应可以很容易地解释N2O3的形成，但高铁血红蛋白（Hb-Fe3+）、亚硝酸盐和NO相互作用的确切方式尚不清楚。提出了“Hb-Fe3+-NO2−+ NO”途径和“Hb-Fe3+-NO + NO2−”途径。这两种途径都没有得到实验证实。到目前为止，也没有任何尝试从理论上模拟N2O3的形成，即所谓的亚硝酸盐酸酐酶反应。这两种路径都在密度泛函理论（DFT, B3LYP/TZP）的详细研究中进行了检验，并且都发现基于能量学标准是可行的。“Hb-Fe3+-NO2 - + NO”途径的建模证明是复杂的。高铁血红蛋白-亚硝酸盐不仅有多重连接异构体（N-和O-配位）结构，N2O3也有多重异构体形式（最低能态是N-N-键的硝基结构，O2N-NO）。我们考虑了高铁血红蛋白-亚硝酸盐的多个自旋态以及Fe（III）和NO自旋的铁磁和反铁磁耦合。同分异构体和自旋变量共同导致了一个极其复杂的反应路径组合空间。幸运的是，对于绝大多数反应通道，无论是MS = 0还是MS = 1，都可以成功地计算出过渡态。对于六坐标Fe3+- o -亚硝酸盐起始几何结构，我们发现N2O3的形成需要约17-20 kcal/mol的势垒，这对于生理相关反应是合理的。对于“Hb-Fe3+-NO + NO2 -”途径，我们的计算表明了一个两步机制，这也被发现是能量上合理的。第一步是将一个电子从NO2 -转移到Fe3+-血红素- no （{FeNO}6）中心，形成二氧化氮和Fe2+-血红素- no （{FeNO}7）中心。随后形成的N2O3的势垒仅为8.1 kcal mol−1。因此，从能量学的观点来看，亚硝酸盐酸酐酶反应是一个合理的命题。虽然我们很容易将我们的结果解释为偏向于“{FeNO}6 + NO2 -”途径而不是“feiii -亚硝酸盐+ NO”途径，但对于生物反应来说，这两种途径都应该被认为是能量上合理的，并且似乎不建议只支持基于量子化学模型的独特反应通道。
Nitrite has recently been recognized as a storage form of NO in blood and as playing a key role in hypoxic vasodilation. The ion is readily reduced to NO by hemoglobin in red blood cells, which, however, also presents a conundrum. Given NO’s enormous affinity of ferrous heme, a key question concerns how it escapes capture by hemoglobin as it diffuses out of the red cells and to the endothelium, where vasodilation takes place. Dinitrogen trioxide (N2O3) has been proposed as a vehicle that transports NO to the endothelium, where it dissociates to NO and NO2. Although N2O3 formation might be readily explained via the reaction the exact manner in which methemoglobin (Hb-Fe3+), nitrite and NO interact with one another is unclear. Both an ‘Hb-Fe3+-NO2− + NO’ pathway and an ‘Hb-Fe3+-NO + NO2−’ pathway have been proposed. Neither pathway has been established experimentally. Nor has there been any attempt until now to theoretically model N2O3 formation, the so-called nitrite anhydrase reaction. Both pathways have been examined here in a detailed density functional theory (DFT, B3LYP/TZP) study and both have been found to be feasible based on energetics criteria. Modeling the ‘Hb-Fe3+-NO2− + NO’ pathway proved complex. Not only are multiple linkage-isomeric (N- and O- coordinated) structures conceivable for methemoglobin-nitrite, multiple isomeric forms are also possible for N2O3 (the lowest-energy state has an N-N-bonded nitro-nitrosyl structure, O2N-NO). We considered multiple spin states of methemoglobin-nitrite as well as ferromagnetic and antiferromagnetic coupling of the Fe(III) and NO spins. Together, the isomerism and spin variables result in a diabolically complex combinatorial space of reaction pathways. Fortunately, transition states could be successfully calculated for the vast majority of these reaction channels, both MS = 0 and MS = 1. For a six-coordinate Fe3+-O-nitrito starting geometry, which is plausible for methemoglobin-nitrite, we found that N2O3 formation entails barriers of about 17–20 kcal/mol, which is reasonable for a physiologically relevant reaction. For the ‘Hb-Fe3+-NO + NO2−’ pathway, which was also found to be energetically reasonable, our calculations indicate a two-step mechanism. The first step involves transfer of an electron from NO2− to the Fe3+-heme-NO ({FeNO}6) center, resulting in formation of nitrogen dioxide and an Fe2+-heme-NO ({FeNO}7) center. Subsequent formation of N2O3 entails a barrier of only 8.1 kcal mol−1. From an energetics point of view, the nitrite anhydrase reaction thus is a reasonable proposition. Although it is tempting to interpret our results as favoring the ‘{FeNO}6 + NO2−’ pathway over the ‘FeIII-nitrite + NO’ pathway, both pathways should be considered energetically reasonable for a biological reaction and it seems inadvisable to favor a unique reaction channel based solely on quantum chemical modeling.
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