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Relative Propensities of Cytochrome c Oxidase and Cobalt Corrins for Reaction with Cyanide and Oxygen: Implications for Amelioration of Cyanide Toxicity
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-11-21 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00275
Quan Yuan 1 , Linda L. Pearce 1 , Jim Peterson 1
Affiliation  

In aqueous media at neutral pH, the binding of two cyanide molecules per cobinamide can be described by two formation constants, Kf1 = 1.1 (±0.6) × 105 M–1 and Kf2 = 8.5 (±0.1) × 104 M–1, or an overall cyanide binding constant of ∼1 × 1010 M–2. In comparison, the cyanide binding constants for cobalamin and a fully oxidized form of cytochrome c oxidase, each binding a single cyanide anion, were found to be 7.9 (±0.5) × 104 M–1 and 1.6 (±0.2) × 107 M–1, respectively. An examination of the cyanide-binding properties of cobinamide at neutral pH by stopped-flow spectrophotometry revealed two kinetic phases, rapid and slow, with apparent second-order rate constants of 3.2 (±0.5) × 103 M–1 s–1 and 45 (±1) M–1 s–1, respectively. Under the same conditions, cobalamin exhibited a single slow cyanide-binding kinetic phase with a second-order rate constant of 35 (±1) M–1 s–1. All three of these processes are significantly slower than the rate at which cyanide is bound by complex IV during enzyme turnover (>106 M–1 s–1). Overall, it can be understood from these findings why cobinamide is a measurably better cyanide scavenger than cobalamin, but it is unclear how either cobalt corrin can be antidotal toward cyanide intoxication as neither compound, by itself, appears able to out-compete cytochrome c oxidase for available cyanide. Furthermore, it has also been possible to unequivocally show in head-to-head comparison assays that the enzyme does indeed have greater affinity for cyanide than both cobalamin and cobinamide. A plausible resolution of the paradox that both cobalamin and cobinamide clearly are antidotal toward cyanide intoxication, involving the endogenous auxiliary agent nitric oxide, is suggested. Additionally, the catalytic consumption of oxygen by the cobalt corrins is demonstrated and, in the case of cobinamide, the involvement of cytochrome c when present. Particularly in the case of cobinamide, these oxygen-dependent reactions could potentially lead to erroneous assessment of the ability of the cyanide scavenger to restore the activity of cyanide-inhibited cytochrome c oxidase.

中文翻译:

细胞色素c氧化酶和钴柯林与氰化物和氧气反应的相对倾向:改善氰化物毒性的意义

在中性pH的水性介质中,每个共酰胺中两个氰化物分子的结合可以通过两个形成常数来描述,K f1 = 1.1(±0.6)×10 5 M –1K f2 = 8.5(±0.1)×10 4 M –1,或氰化物的总结合常数为〜1×10 10 M –2。相比之下,钴胺素和完全氧化形式的细胞色素C氧化酶的氰化物结合常数分别为7.9(±0.5)×10 4 M –1和1.6(±0.2)×10 7 M –1, 分别。通过停止流动分光光度法在中性pH下对cobinamide氰化物结合特性的检查显示出两个动力学相,快速和慢速,其表观二阶速率常数为3.2(±0.5)×10 3 M –1 s –1和分别为45(±1)M –1 s –1。在相同条件下,钴胺素表现出单一的慢速氰化物结合动力学相,其二级速率常数为35(±1)M –1 s –1。所有这三个过程均显着慢于酶转换期间(> 10 6 M –1 s –1)。总体而言,从这些发现中可以理解,为什么cobinamide是比钴胺素更好的氰化物清除剂,但尚不清楚钴钴蛋白如何对氰化物中毒具有解毒作用,因为这两种化合物本身都不能胜过细胞色素c的竞争。氧化酶为可用的氰化物。此外,也有可能在头对头比较试验中明确表明,该酶的确对氰化物的亲和力确实比钴胺素和钴胺都高。有人提出了一个合理的悖论解决方案,即钴胺素和钴胺都明显对氰化物中毒具有解毒作用,涉及内源性辅助剂一氧化氮。另外,证明了钴柯林对氧的催化消耗,并且对于cobinamide,当存在时涉及细胞色素c。特别是在cobinamide的情况下,这些依赖氧的反应可能会导致错误评估氰化物清除剂恢复氰化物抑制的细胞色素c活性的能力。 氧化酶。
更新日期:2017-11-22
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