Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis
Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis
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DOI：
10.1111/jpi.12196
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发表时间：
2015-01-01
影响因子：
10.3
通讯作者：
Reiter, Russel J.
中科院分区：
文献类型：
--
作者：
Galano, Annia;Medina, Manuel E.;Reiter, Russel J.
在密度泛函理论的框架下，研究了褪黑素及其代谢产物环3-羟基甲酰尿胺(3OHM)、N-1-乙酰基-N-2-甲酰基-5-甲氧基犬尿胺(AFMK)和N-1-乙酰基-5-甲氧基犬尿胺(AMK)对铜的吸附能力。结果表明，这些化合物能够络合铜离子，生成稳定的络合物。确定了最有可能的螯合部位。模拟了两种不同的机理，即直接络合机理(DCM)和耦合去质子络合机理(CDCM)。在生理条件下，CDCM可能是铜(II)的主要络合途径。结果发现，褪黑素及其代谢产物通过与铜(II)的络合作用，完全抑制了铜(II)-抗坏血酸混合物诱导的氧化应激。同样，褪黑素、AFMK和3OHM也阻止了Haber-Weiss反应的第一步，从而关闭了Fenton反应产生的OH。因此，有人提出，除了先前报道的清除自由基的级联反应外，褪黑素还参与了一个并发的螯合级联反应，从而有助于减少氧化应激。3OHM被确定为所研究的化合物中最有效的，支持这种代谢物在褪黑素对抗氧化应激的有益作用中的重要作用。
The copper sequestering ability of melatonin and its metabolites cyclic 3-hydroxymelatonin (3OHM), N-1-acetyl-N-2-formyl-5-methoxykynuramine (AFMK), and N-1-acetyl-5-methoxykynuramine (AMK) was investigated within the frame of the Density Functional Theory. It was demonstrated that these compounds are capable of chelating copper ions, yielding stable complexes. The most likely chelation sites were identified. Two different mechanisms were modeled, the direct-chelation mechanism (DCM) and the coupled-deprotonation-chelation mechanism (CDCM). It is proposed that, under physiological conditions, CDCM would be the main chelation route for Cu(II). It was found that melatonin and its metabolites fully inhibited the oxidative stress induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation. In the same way, melatonin, AFMK, and 3OHM also prevented the first step of the Haber-Weiss reaction, consequently turning off the OH production via the Fenton reaction. Therefore, it is proposed that, in addition to the previously reported free radical scavenging cascade, melatonin is also involved in a concurrent chelating cascade', thereby contributing to a reduction in oxidative stress. 3OHM was identified as the most efficient of the studied compounds for that purpose, supporting the important role of this metabolite in the beneficial effects of melatonin against oxidative stress.