Oxidative Stress Research Laboratory, MIGAL-Galilee Research Institute, PO Box 831, Kiryat Shmona 11016, Israel.
Bioorg Med Chem. 2013 Jun 1;21(11):3348-55. doi: 10.1016/j.bmc.2013.02.055. Epub 2013 Mar 30.
Flavonoids are plant phenolic secondary metabolites that are widely distributed in the human diet. These antioxidants have received much attention because of their neuroprotective, cardioprotective, and chemopreventive actions. While a major focus has been on the flavonoids' antioxidant properties, there is an emerging view that many of the potential health benefits of flavonoids and their in vivo metabolites are due to modulatory actions in cells through direct interactions with proteins, and not necessarily due to their antioxidant function. This view relies on the observations that flavonoids are present in the circulation at very low concentrations, which are not sufficient to exert effective antioxidant effects. The enzyme paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL), and is responsible for many of HDLs' antiatherogenic properties. We previously showed that the flavonoid glabridin binds to rePON1 and affects the enzyme's 3D structure. This interaction protects the enzyme from inhibition by an atherogenic component of the human carotid plaque. Here, we broadened our study to an investigation of the structure-activity relationships (SARs) of 12 flavonoids from different subclasses with rePON1 using Trp-fluorescence quenching, modeling calculations and Cu(2+)-induced low-density lipoprotein (LDL) oxidation methods. Our findings emphasize the 'protein-binding' mechanism by which flavonoids exert their beneficial biological role toward rePON1. Flavonoids' capacity to interact with the enzyme's rePON1 hydrophobic groove mostly dictates their pro/antioxidant behavior.
类黄酮是植物酚类次生代谢物，广泛存在于人类饮食中。由于其具有神经保护、心脏保护和化学预防作用，这些抗氧化剂受到了广泛关注。虽然人们主要关注的是类黄酮的抗氧化特性，但有一种新观点认为，类黄酮及其体内代谢物的许多潜在健康益处是由于它们通过与蛋白质的直接相互作用在细胞中发挥调节作用，而不一定是由于其抗氧化功能。这一观点依赖于以下观察结果：类黄酮在循环中的浓度非常低，不足以发挥有效的抗氧化作用。对氧磷酶 1（PON1）与高密度脂蛋白（HDL）相关，负责 HDL 的许多抗动脉粥样硬化特性。我们之前曾表明，类黄酮甘草素与 rePON1 结合，并影响酶的 3D 结构。这种相互作用保护酶免受人类颈动脉斑块中动脉粥样硬化成分的抑制。在这里，我们将研究范围扩大到使用色氨酸荧光猝灭、建模计算和 Cu(2+)-诱导的低密度脂蛋白（LDL）氧化方法研究 12 种来自不同亚类的 rePON1 与 rePON1 的结构-活性关系（SAR）。我们的研究结果强调了类黄酮通过与酶的 rePON1 疏水性凹槽相互作用发挥其对 rePON1 的有益生物学作用的“蛋白结合”机制。类黄酮与酶的 rePON1 疏水性凹槽相互作用的能力在很大程度上决定了它们的促/抗氧化行为。
