Institute of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91940 Jerusalem, Israel.
J Phys Chem B. 2010 May 27;114(20):7078-89. doi: 10.1021/jp1008994.
Density functional theory has been applied to elucidate the mechanism of the O-demethylation reaction that generates serotonin from 5-methoxytryptamine (5-MT); a process that is efficiently catalyzed by P450 CYP2D6. Two substrates, the neutral 5-MT and the protonated 5-MTH(+), were used to probe the reactivity of CYP2D6 compound I. Notably, the H-abstraction process is found to be slightly more facile for 5-MT. However, our DFT augmented by docking results show that the amino acid Glu216 in the active site holds the NH(3)(+) tail of the 5-MTH(+) substrate in an upright conformation and thereby controls the regioselectivity of the bond activation. Thus, the substrate protonation serves an important function in maximizing the yield of serotonin. This finding is in accord with experimental conclusions that 5-MTH(+) serves as the substrate for the CYP2D6 enzyme. The study further shows that the H-abstraction follows two-state reactivity (TSR), whereas the rebound path may involve more states due to the appearance of both Fe(IV) and Fe(III) electromers during the reaction of 5-MTH(+).
密度泛函理论已被应用于阐明生成血清素的 5-甲氧基色胺（5-MT）的 O-去甲基化反应机制；该过程由 P450 CYP2D6 高效催化。两种底物，中性 5-MT 和质子化的 5-MTH(+)，被用于探测 CYP2D6 化合物 I 的反应性。值得注意的是，对于 5-MT，H 提取过程略为容易。然而，我们的 DFT 加上对接结果表明，活性位点中的氨基酸 Glu216 将 5-MTH(+)底物的 NH(3)(+)尾巴保持在直立构象，从而控制键活化的区域选择性。因此，底物质子化在最大程度地提高血清素产量方面发挥了重要作用。这一发现与实验结论一致，即 5-MTH(+) 是 CYP2D6 酶的底物。该研究进一步表明，H 提取遵循双态反应性（TSR），而由于在 5-MTH(+)的反应过程中出现 Fe(IV)和 Fe(III)电偶极子，回弹路径可能涉及更多状态。
