Mechanisms of myeloperoxidase catalyzed oxidation of H2S by H2O2 or O2 to produce potent protein Cys-polysulfide-inducing species
Mechanisms of myeloperoxidase catalyzed oxidation of H2S by H2O2 or O2 to produce potent protein Cys-polysulfide-inducing species
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DOI：
10.1016/j.freeradbiomed.2017.10.384
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发表时间：
2017-12-01
影响因子：
7.4
通讯作者：
Nagy, Peter
中科院分区：
文献类型：
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作者：
Garai, Dorottya;Rios-Gonzalez, Bessie B.;Nagy, Peter
血红素蛋白与硫化氢的相互作用作为硫化物介导的抗氧化应激保护和氧化还原信号调节的重要元素而受到关注。在我们以前的研究中，我们报道了有效的可逆抑制髓过氧化物酶（MPO）活性的硫化物和硫化物与铁MPO，化合物I和化合物II的反应动力学。在这里，我们提供了几条线的证据表明，在营业额的MPO硫化物的中央中间物种是化合物III状态。化合物III在硫化物与铁或亚铁MPO在氧存在下的反应中形成，或通过硫化物还原化合物I或化合物II形成。活性铁MPO从化合物III的再生是缓慢的，代表周转期间的限速步骤-但由抗坏血酸盐或超氧化物歧化酶促进。这些催化循环产生无机硫烷硫物种，这被证明是促进蛋白质半胱氨酸过硫化。基于编译的实验数据，我们提出，在对比血红蛋白，肌红蛋白，过氧化氢酶或乳过氧化物酶的硫化物与MPO的氧化相互作用中的硫血红素衍生物的形成不是一个主要途径。使用Met 243 Val突变体，我们证明了Met 243硫与血红素吡咯环A的锍离子连接，这是MPO的独特特征，在硫化物通过化合物III的催化氧化中是关键的。所提出的新型MPO催化的硫化物氧化模型不需要过氧化氢的初始存在，仅需要氧气来提供硫烷硫物质产生的缓慢通量，这在硫化物介导的内源性信号传导中可能是重要的。此外，过氧化物诱导的MPO形成硫烷硫物质可能在（例如中性粒细胞诱导的）炎症氧化应激期间保护调节性或功能性Cys残基中起作用。
The interaction of heme proteins with hydrogen sulfide is gaining attention as an important element in sulfide-mediated protection against oxidative stress and in regulation of redox signaling. In our previous study we reported the efficient reversible inhibition of myeloperoxidase (MPO) activity by sulfide and the kinetics of the reactions of sulfide with ferric MPO, Compound I and Compound II. Here we provide several lines of evidence that a central intermediate species in the turnover of MPO by sulfide is the Compound III state. Compound III is formed in the reactions of sulfide with ferric or ferrous MPO in the presence of oxygen or via the reductions of Compound I or Compound II by sulfide. The regeneration of active ferric MPO from Compound III is slow representing the rate-limiting step during turnover - but facilitated by ascorbate or superoxide dismutase. These catalytic cycles produce inorganic sulfane sulfur species, which were shown to promote protein Cys persulfidation. Based on compiling experimental data we propose that in contrast to hemoglobin, myoglobin, catalase or lactoperoxidase the formation of a sulfheme derivative in the oxidative interactions of sulfide with MPO is not a major pathway. Using the Met243Val mutant we demonstrated that the sulfonium ion linkage of the Met243 sulfur to the heme pyrrole ring A, which is a unique feature of MPO, is pivotal in the catalytic oxidation of sulfide via Compound III. The proposed novel MPO-catalyzed sulfide oxidation model does not require the initial presence of hydrogen peroxide, only oxygen to provide a slow flux of sulfane sulfur species generation, which could be important in sulfide-mediated endogenous signaling. Furthermore, peroxide-induced formation of sulfane sulfur species by MPO may have a role in protection of regulatory or functional Cys residues during ( for example neutrophil induced) inflammatory oxidative stress.