Three toxic gases meet in the mitochondria.
Three toxic gases meet in the mitochondria.
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DOI：
10.3389/fphys.2015.00210
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发表时间：
2015
影响因子：
4
通讯作者：
Collman JP
中科院分区：
文献类型：
--
作者：
Decréau RA;Collman JP
该研究的基本原理有两个：(i) 开发细胞色素 c 氧化酶 (CcO) 活性位点的功能合成模型，(ii) 将其用作理解或预测 CcO 与配体（生理相关气体和其他配体）反应结果的便捷工具。在生理 pH 值和电位下，该模型催化氧的 4 电子还原。该模型固定在自组装单层（SAM）修饰电极上。在催化氧还原过程中，通过 SAM 的电子传递受到速率限制，与 CcO 中的情况类似。该模型包含 CcO 活性位点中的所有三种氧化还原活性成分，这些成分是最大限度地减少部分还原氧物种 (PROS) 的产生所必需的：肌红蛋白样模型中的铁血红素（“血红素 a3”），配有近端咪唑配体，以及远端三咪唑铜（“CuB”）复合物，其中一个咪唑与一个咪唑交联。 苯酚（模仿“Tyr244”）。该功能性 CcO 模型展示了 CcO 本身如何耐受激素 NO（通过线粒体扩散）。据推测，CuB 将超氧化物传递给与 Fe-血红素结合的 NO，形成过氧亚硝酸盐，然后扩散走的硝酸盐。另一种有毒气体 H2S 具有特殊的生物效应：浓度约为 80 ppm 时，H2S 会导致小鼠进入类似于冬眠的状态，从而降低动物的体温并减慢呼吸。使用我们的功能性 CcO 模型，我们证明了在相同浓度范围内 H2S 可以可逆地抑制催化氧还原。模型上的这种可逆催化过程也通过有机化合物四唑（TZ）得到了证明。以下研究表明，TZ 可逆地抑制分离线粒体的呼吸，并诱导血小板失活，血小板是血液凝固的富含线粒体的关键成分。因此，该程序是一个罕见的例子，说明了使用功能模型来理解和预测 CcO 活性位点的重要生理反应。
The rationale of the study was two-fold: (i) develop a functional synthetic model of the Cytochrome c oxidase (CcO) active site, (ii) use it as a convenient tool to understand or predict the outcome of the reaction of CcO with ligands (physiologically relevant gases and other ligands). At physiological pH and potential, the model catalyzes the 4-electron reduction of oxygen. This model was immobilized on self-assembled-monolayer (SAM) modified electrode. During catalytic oxygen reduction, electron delivery through SAMs is rate limiting, similar to the situation in CcO. This model contains all three redox-active components in CcO's active site, which are required to minimize the production of partially-reduced-oxygen-species (PROS): Fe-heme (“heme a3”) in a myoglobin-like model fitted with a proximal imidazole ligand, and a distal tris-imidazole Copper (“CuB”) complex, where one imidazole is cross-linked to a phenol (mimicking “Tyr244”). This functional CcO model demonstrates how CcO itself might tolerate the hormone NO (which diffuses through the mitochondria). It is proposed that CuB delivers superoxide to NO bound to Fe-heme forming peroxynitrite, then nitrate that diffuses away. Another toxic gas, H2S, has exceptional biological effects: at ~80 ppm, H2S induces a state similar to hibernation in mice, lowering the animal's temperature and slowing respiration. Using our functional CcO model, we have demonstrated that at the same concentration range H2S can reversibly inhibit catalytic oxygen reduction. Such a reversible catalytic process on the model was also demonstrated with an organic compound, tetrazole (TZ). Following studies showed that TZ reversibly inhibits respiration in isolated mitochondria, and induces deactivation of platelets, a mitochondria-rich key component of blood coagulation. Hence, this program is a rare example illustrating the use of a functional model to understand and predict physiologically important reactions at the active site of CcO.