Computational Studies of the Regioselectivities of COMT-Catalyzed Meta-/Para-O Methylations of Luteolin and Quercetin
Computational Studies of the Regioselectivities of COMT-Catalyzed Meta-/Para-O Methylations of Luteolin and Quercetin
复制标题
COMT 催化的木犀草素和槲皮素间位/对位 O 甲基化区域选择性的计算研究
DOI：
10.1021/jp410296s
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发表时间：
2014-01-16
影响因子：
3.3
通讯作者：
Chen, Jian-Zhong
中科院分区：
文献类型：
--
作者：
Cao, Yang;Chen, Zhong-Jian;Chen, Jian-Zhong
儿茶酚-O-甲基转移酶（COMT，EC 2.1.1.6）通过转移来自β-Met的甲基，在共有儿茶酚基序的神经递质的失活中起核心作用。在许多COMT底物中，如多巴胺和去甲肾上腺素，间位羟基的甲基化比对位羟基的甲基化更常见。我们的实验数据表明，槲皮素倾向于位甲基化，而毛地黄黄酮倾向于对位甲基化。为了阐明槲皮素和木樨草素甲基化反应不同偏好的机理，我们采用分子动力学模拟、从头计算和QM/MM计算相结合的方法，对COMT催化槲皮素和木樨草素甲基化反应的不同区域选择性进行了理论研究.从头计算结果表明，槲皮素和木犀草素的甲基化反应中，间位O原子上的负电荷比对位O原子上的负电荷多，表明间位O优先进行S（N）2反应。我们的QM/MM计算还证实，这两种黄酮类化合物具有较低的反应能量障碍COMT催化的间-O-甲基化比对位-O-甲基化。另一方面，我们的结合自由能计算结果表明，槲皮素有一个更稳定的结合模式间-O-甲基化比对位-O-甲基化，但木犀草素有一个更稳定的结合模式对位-O-甲基化比间-O-甲基化。我们从热力学和反应动力学两方面对该反应进行了全面的解释，并讨论了蛋白质抑制剂的相互作用以及O-甲基化的机理。
Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the inactivation of neuro-transmitters sharing a catecholic motif by transferring a methyl group from AdoMet. Methylation of the meta-hydroxyl is much more common than that of the para-hydroxyl in many COMT substrates, such as dopamine and norepinephrine. Our experimental data showed that quercetin preferred meta-methylation but luteolin favored a para-methylation. To elucidate the mechanism for different preferences of methylations of quercetin and luteolin, we performed a theoretical investigation on the different regioseletivities of COMT-catalyzed methylations for quercetin and luteolin by a combined approach of MD simulations, ab initio calculations, and QM/MM computations. The ab initio calculation results showed that both quercetin and luteolin have more negative charge distributions on the meta-O atom than the para-O atom, which indicated that meta-O preferred S(N)2 reaction for their methylation. Our QM/MM computations also confirmed that these two flavonoids have lower reaction energetic barriers for COMT-catalyzed meta-O-methylation than para-O-methylation. On the other hand, our binding free energy computation results indicated that quercetin has a more stable binding mode for meta-O-methylation than para-O-methylation but luteolin has a more stable binding mode for para-O-methylation than meta-O-methylation. We gave a comprehensive explanation considering both thermodynamics and reaction kinetics aspects and discussed the protein inhibitor interactions as well as the O-methylation mechanism in our present work.