Department of Chemical Engineering, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Molecules. 2023 Oct 6;28(19):6961. doi: 10.3390/molecules28196961.
Cytochrome P450 enzymes in the human body play a pivotal role in both the biosynthesis and the degradation of the hormone melatonin. Melatonin plays a key role in circadian rhythms in the body, but its concentration is also linked to mood fluctuations as well as emotional well-being. In the present study, we present a computational analysis of the binding and activation of melatonin by various P450 isozymes that are known to yield different products and product distributions. In particular, the P450 isozymes 1A1, 1A2, and 1B1 generally react with melatonin to provide dominant aromatic hydroxylation at the C-position, whereas the P450 2C19 isozyme mostly provides -demethylation products. To gain insight into the origin of these product distributions of the P450 isozymes, we performed a comprehensive computational study of P450 2C19 isozymes and compared our work with previous studies on alternative isozymes. The work covers molecular mechanics, molecular dynamics and quantum mechanics approaches. Our work highlights major differences in the size and shape of the substrate binding pocket amongst the different P450 isozymes. Consequently, substrate binding and positioning in the active site varies substantially within the P450 isozymes. Thus, in P450 2C19, the substrate is oriented with its methoxy group pointing towards the heme, and therefore reacts favorably through hydrogen atom abstraction, leading to the production of -demethylation products. On the other hand, the substrate-binding pockets in P450 1A1, 1A2, and 1B1 are tighter, direct the methoxy group away from the heme, and consequently activate an alternative site and lead to aromatic hydroxylation instead.
人体内的细胞色素 P450 酶在激素褪黑素的生物合成和降解中起着关键作用。褪黑素在体内的昼夜节律中起着关键作用，但它的浓度也与情绪波动以及情绪健康有关。在本研究中，我们对已知产生不同产物和产物分布的各种 P450 同工酶进行了褪黑素结合和激活的计算分析。特别是 P450 同工酶 1A1、1A2 和 1B1 通常与褪黑素反应，在 C 位提供主要的芳香羟化，而 P450 2C19 同工酶主要提供 -去甲基化产物。为了深入了解 P450 同工酶产物分布的起源，我们对 P450 2C19 同工酶进行了全面的计算研究，并将我们的工作与替代同工酶的先前研究进行了比较。这项工作涵盖了分子力学、分子动力学和量子力学方法。我们的工作强调了不同 P450 同工酶之间底物结合口袋大小和形状的主要差异。因此，底物在 P450 同工酶中的结合和定位在活性位点有很大的不同。因此，在 P450 2C19 中，底物的甲氧基基团指向血红素，因此通过氢原子的提取有利地反应，导致 -去甲基化产物的产生。另一方面，P450 1A1、1A2 和 1B1 中的底物结合口袋更紧，将甲氧基基团从血红素上推开，因此激活了替代位点，并导致芳香羟化而不是。
