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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Quantum Chemical Modeling of Reaction Mechanism for 2-Oxoglutarate Dependent Enzymes:Effect of Substitution of Iron by Nickel and Cobalt
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Quantum Chemical Modeling of Reaction Mechanism for 2-Oxoglutarate Dependent Enzymes:Effect of Substitution of Iron by Nickel and Cobalt

机译：2-氧戊二酸依赖性酶反应机理的量子化学建模：镍和钴取代铁的作用

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摘要

Enzymatic hydroxylation reactions carried out by 2-oxoglutarate(2OG)dependent iron-containing oxygenases were recently implicated in oxygen sensing.In addition to oxygen depletion,two metals,cobalt and nickel,are capable of inducing hypoxic stress in cells by inhibiting oxygenase activity.Two possible scenarios have been proposed for the explanation of the hypoxic effects of cobalt and nickel:oxidation of enzyme-bound iron following cobalt or nickel exposure,and substitution of iron by cobalt or nickel.Here,by using density functional theory calculations,we modeled the reaction route from the reaction components to the high-spin metal-oxide intermediate in the activation of oxygen molecule by 2OG-dependent enzymes for three metal ions Fe(II),Ni(II),and Co(II)in the active site.An initial molecular model was constructed based on the crystal structure of iron-containing asparaginyl hydroxylase(FIH-1).Nickel-and cobalt-containing enzymes were modeled by a consequent replacement of the iron in the active center.The energy profiles connecting stationary points on the potential surfaces were computed by using the intrinsic reaction coordinate(IRC)technique from the located transition states.The results of calculations show that the substitution of iron by nickel or cobalt modifies the reaction energy profile;however,qualitatively,the reaction mechanism remains essentially the same.Thus,we would postulate that if the iron ion in the active site were substitutable by nickel and/or cobalt ions enzyme activity would be considerably altered due to high activation barriers.
机译：最近，由2-氧代戊二酸酯（2OG）依赖性含铁氧化酶进行的酶促羟基化反应涉及氧传感。除氧耗竭外，钴和镍这两种金属还能够通过抑制氧化酶活性来诱导细胞缺氧应激。为了解释钴和镍的低氧效应，提出了两种可能的情况：暴露于钴或镍后酶结合的铁的氧化，以及用钴或镍替代铁。在此，我们使用密度泛函理论计算进行了建模。活性位点上三种金属离子Fe（II），Ni（II）和Co（II）的2OG依赖性酶激活氧分子活化过程中反应组分到高自旋金属氧化物中间体的反应路线根据铁的天冬酰胺基羟化酶（FIH-1）的晶体结构构建了一个初始分子模型，随后替换了iro来模拟了含镍和钴的酶在活动中心的n处。通过使用固有的反应坐标（IRC）技术，根据所定位的过渡态来计算连接势能表面上的固定点的能量分布图。计算结果表明，铁被镍或钴取代会改变铁的结构。反应能谱;但是，定性地，反应机理基本相同。因此，我们假设，如果活性位点中的铁离子被镍和/或钴离子取代，则由于高的活化势垒，酶的活性将发生很大变化。 。

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