Nickel superoxide dismutase reaction mechanism studied by hybrid density functional methods
Nickel superoxide dismutase reaction mechanism studied by hybrid density functional methods
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DOI：
10.1021/ja053665f
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发表时间：
2006-06-14
影响因子：
15
通讯作者：
Siegbahn, Per E. M.
中科院分区：
文献类型：
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作者：
Pelmenschikov, Vladimir;Siegbahn, Per E. M.
采用B3LYP杂化密度泛函（DFT）方法研究了镍依赖超氧化物歧化酶（NiSOD）催化超氧自由基生成分子氧和过氧化氢的反应机理.基于最近的X-射线结构的酶在休息氧化镍（III）和X-射线还原镍（II）的状态，研究模型包括6个残基（序列号1 - 6）作为结构框架的骨干间隔。残基His1，Cys2和Cys6，这是必不可少的镍结合和催化的侧链，明确建模。催化循环由两个半反应组成，每个半反应由连续的基底接近金属中心引发。歧化所需的两个质子被假定为与超氧阴离子自由基协同传递。第一（还原）阶段涉及Ni（III）还原成Ni（II），第二（氧化）阶段涉及金属再氧化回到其静止状态。Cys2硫醇盐硫在两个半反应之间的过渡中充当瞬时质子化位点，允许分别在还原和氧化阶段释放分子氧和过氧化氢分子。His1侧链氮和骨架酰胺的活性位点通道被证明是不太有利的瞬态质子的位置，相比Cys2硫。比较Cu和Zn依赖的SOD，以前使用类似的模型研究。
The reaction mechanism for the disproportionation of the toxic superoxide radical to molecular oxygen and hydrogen peroxide by the nickel-dependent superoxide dismutase ( NiSOD) has been studied using the B3LYP hybrid DFT method. Based on the recent X-ray structures of the enzyme in the resting oxidized Ni( III) and X-ray-reduced Ni( II) states, the model investigated includes the backbone spacer of six residues ( sequence numbers 1-6) as a structural framework. The side chains of residues His1, Cys2, and Cys6, which are essential for nickel binding and catalysis, were modeled explicitly. The catalytic cycle consists of two half-reactions, each initiated by the successive substrate approach to the metal center. The two protons necessary for the dismutation are postulated to be delivered concertedly with the superoxide radical anions. The first ( reductive) phase involves Ni( III) reduction to Ni( II), and the second ( oxidative) phase involves the metal reoxidation back to its resting state. The Cys2 thiolate sulfur serves as a transient protonation site in the interim between the two half-reactions, allowing for the dioxygen and hydrogen peroxide molecules to be released in the reductive and oxidative phases, respectively. The His1 side chain nitrogen and backbone amides of the active site channel are shown to be less favorable transient proton locations, as compared to the Cys2 sulfur. Comparisons are made to the Cu- and Zn-dependent SOD, studied previously using similar models.