The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase
The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase
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DOI：
10.1016/j.fct.2019.03.049
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发表时间：
2019-06-01
影响因子：
4.3
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
--
作者：
Cuyas, Elisabet;Verdura, Sara;Menendez, Javier A.
咖啡和茶中存在的含儿茶酚的多酚，虽然是儿茶酚-O-甲基转移酶(COMT)催化的O-甲基化的优秀底物，但也可以作为COMT的抑制剂。然而，人们对COMT和特级初榨橄榄油(EVOO)中特有的酚类物质之间的关系知之甚少。在这里，我们选择了EVOO二羟基苯酚油酸乙酯，使用经典的分子对接/分子动力学模拟和混合量子力学/分子力学，对COMT驱动的甲基化进行了计算研究，这一研究得到了使用人类COMT的体外活性研究的支持。醇溶蛋白可以叠加在邻苯二酚结合部位，保持与S-腺苷-L-蛋氨酸辅因子参与甲基转移的原子位置的相互作用。预测了油酸苯二酚部分的O5位偏甲基化的过渡态结构优先发生。对儿茶酚到O-烷化愈创木酚转化率的酶分析证实了油酸乙酯对人COMT的抑制作用，当与COMT基因的功能性Val(158)Met多态编码的蛋白质版本进行比较时，这种抑制作用保持不变。我们的研究为EVOO二羟基酚如何通过COMT代谢提供了理论依据。油酸抑制COMT的能力为EVOO Secoiridoid的生理和治疗作用增加了一个新的维度。
Catechol-containing polyphenols present in coffee and tea, while serving as excellent substrates for catechol-O-methyltransferase (COMT)-catalyzed O-methylation, can also operate as COMT inhibitors. However, little is known about the relationship between COMT and the characteristic phenolics present in extra virgin olive oil (EVOO). We here selected the EVOO dihydroxy-phenol oleacein for a computational study of COMT-driven methylation using classic molecular docking/molecular dynamics simulations and hybrid quantum mechanical/molecular mechanics, which were supported by in vitro activity studies using human COMT. Oleacein could be superimposed onto the catechol-binding site of COMT, maintaining the interactions with the atomic positions involved in methyl transfer from the S-adenosyl-L-methionine cofactor. The transition state structure for the meta-methylation in the O5 position of the oleacein benzenediol moiety was predicted to occur preferentially. Enzyme analysis of the conversion ratio of catechol to O-alkylated guaiacol confirmed the inhibitory effect of oleacein on human COMT, which remained unaltered when tested against the protein version encoded by the functional Val(158)Met polymorphism of the COMT gene. Our study provides a theoretical determination of how EVOO dihydroxy-phenols can be metabolized via COMT. The ability of oleacein to inhibit COMT adds a new dimension to the physiological and therapeutic utility of EVOO secoiridoids.