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On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

机译：一氧化氮抑制细胞色素氧化酶的机理与生物学

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The detailed molecular mechanism for the reversible inhibition of mitochondrial respiration by NO has puzzled investigators: The rate constants for the binding of NO and O-2 to the reduced binuclear center Cu-B/a(3) of cytochrome oxidase (COX) are similar, and NO is able to dissociate slowly from this center whereas O-2 is kinetically trapped, which altogether seems to favor the complex of COX with O-2 over the complex of COX with NO. Paradoxically, the inhibition of COX by NO is observed at high ratios Of O-2 to NO (in the 40-500 range) and is very fast (seconds or faster). in this work, we used simple mathematical models to investigate this paradox and other important biological questions concerning the inhibition of COX by NO. The results showed that all known features of the inhibition of COX by NO can be accounted for by a direct competition between NO and O-2 for the reduced binuclear center Cu-B/a(3) of COX. Besides conciliating apparently contradictory data, this work provided an explanation for the so-called excess capacity of COX by showing that the COX activity found in tissues actually is optimized to avoid an excessive inhibition of mitochondrial respiration by NO, allowing a moderate, but not excessive, overlap between the roles of NO in COX inhibition and in cellular signaling. in pathological situations such as COX-deficiency diseases and chronic inflammation, an excessive inhibition of the mitochondrial respiration is predicted.
机译：NO可逆地抑制线粒体呼吸的详细分子机制使研究人员感到困惑：NO和O-2与细胞色素氧化酶（COX）的还原双核中心Cu-B / a（3）结合的速率常数相似，并且NO能够从该中心缓慢解离，而O-2被动力学捕获，这似乎完全支持了COX与O-2的络合物，而不是COX与NO的络合物。矛盾的是，在O-2与NO的比例高（在40-500范围内）时，观察到NO对COX的抑制作用非常快（秒或更快）。在这项工作中，我们使用简单的数学模型研究了这一悖论以及其他有关NO抑制COX的重要生物学问题。结果表明，NO抑制COX的所有已知特征都可以由NO和O-2直接竞争降低COX的双核中心Cu-B / a（3）来解释。除了调和明显矛盾的数据外，这项工作还通过证明组织中发现的COX活性实际上得到了优化，以避免NO过度抑制线粒体呼吸，从而提供了适度但不过度的作用，从而为所谓的COX过量提供了解释。 ，NO在COX抑制和细胞信号传导中的作用之间存在重叠。在诸如COX缺乏症和慢性炎症等病理情况下，线粒体呼吸作用被过度抑制。

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