细胞色素 P450 对双酚类药物代谢的计算研究：哪些因素有利于分子内苯酚偶联,Chemical Research in Toxicology

当前位置： X-MOL 学术 › Chem. Res. Toxicol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

细胞色素 P450 对双酚类药物代谢的计算研究：哪些因素有利于分子内苯酚偶联
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2022-03-01 , DOI: 10.1021/acs.chemrestox.1c00350
Lihong Chai _{1,

2,

3} , Huanni Zhang ₂ , Fangjie Guo ₄ , Runqian Song ₂ , Haiying Yu ₅ , Li Ji _{1,

2,

6}

Affiliation

生物碱的分子内酚偶联反应可产生由哺乳动物细胞色素P450酶（P450）催化的活性代谢物；然而，缺乏对这种“不寻常”过程的机械知识。这项工作进行密度泛函理论计算，通过探索涉及双自由基偶联、自由基加成和电子转移的可能的分子内苯酚偶联机制，揭示 P450 介导的从R -reticuline 到吗啡前体 salutaridine 的代谢途径。计算结果表明，具有高势垒（> 20.0 kcal / mol）的外球电子转移不太可能发生。然而，对于球间分子内酚偶联，它揭示了R的分子内酚偶联-reticuline 通过 P450 的化合物 I 和质子化化合物 II 连续通过双自由基机制而不是自由基加成机制进行。在四重态高自旋态中存在比 H-抽象更高的自由基反弹势垒可以赋予R-网状苯氧基自由基足够的寿命以实现分子内苯酚偶联，而 H-抽象/自由基反弹模式具有导致苯酚羟基化的可忽略不计的回弹屏障只能在双线低自旋状态下发生。因此，[偶联]/[羟基化]的比率可以通过 P450 的高自旋和低自旋 H 提取的相对产率来近似反映，因此可以为R提供 16:1 的理论比率-reticuline，这与之前的实验结果一致。特别是，苯氧基自由基的弱给电子能力导致的苯氧基自由基的高回弹势垒被揭示为固有性质。因此，揭示的分子内苯酚偶联机制可以潜在地扩展到其他几种双酚类药物，以推断生物体中意想不到的代谢物组。

"点击查看英文标题和摘要"

Computational Investigation of the Bisphenolic Drug Metabolism by Cytochrome P450: What Factors Favor Intramolecular Phenol Coupling

Intramolecular phenol coupling reactions of alkaloids can lead to active metabolites catalyzed by the mammalian cytochrome P450 enzyme (P450); however, the mechanistic knowledge of such an “unusual” process is lacking. This work performs density functional theory computations to reveal the P450-mediated metabolic pathway leading from R-reticuline to the morphine precursor salutaridine by exploring possible intramolecular phenol coupling mechanisms involving diradical coupling, radical addition, and electron transfer. The computed results show that the outer-sphere electron transfer with a high barrier (>20.0 kcal/mol) is unlikely to happen. However, for inter-sphere intramolecular phenol coupling, it reveals that intramolecular phenol coupling of R-reticuline proceeds via the diradical mechanism consecutively by compound I and protonated compound II of P450 rather than the radical addition mechanism. The existence of a much higher radical rebound barrier than that of H-abstraction in the quartet high-spin state can endow the R-reticuline phenoxy radical with a sufficient lifetime to enable intramolecular phenol coupling, while the H-abstraction/radical rebound mode with a negligible rebound barrier leading to phenol hydroxylation can only happen in the doublet low-spin state. Therefore, the ratio [coupling]/[hydroxylation] can be approximately reflected by the relative yield of the high-spin and low-spin H-abstraction by P450, which thus can provide a theoretical ratio of 16:1 for R-reticuline, which is in accordance with previous experimental results. Especially, the high rebound barrier of the phenoxy radical derived from the weak electron-donating ability of the phenoxy radical is revealed as an intrinsic nature. Therefore, the revealed intramolecular phenol coupling mechanism can be potentially extended to several other bisphenolic drugs to infer groups of unexpected metabolites in organisms.

更新日期：2022-03-01

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南