Oxetane Ring Formation in Taxol Biosynthesis Is Catalyzed by a Bifunctional Cytochrome P450 Enzyme,Journal of the American Chemical Society

当前位置： X-MOL 学术 › J. Am. Chem. Soc. › 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.)

Oxetane Ring Formation in Taxol Biosynthesis Is Catalyzed by a Bifunctional Cytochrome P450 Enzyme
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-12-21 , DOI: 10.1021/jacs.3c10864
Yong Zhao ₁ , Feiyan Liang ₁ , Yuman Xie ₁ , Yao-Tao Duan ₁ , Aggeliki Andeadelli _{2,

3} , Irini Pateraki ₁ , Antonios M Makris ₂ , Thomas G Pomorski ₄ , Dan Staerk ₅ , Sotirios C Kampranis ₁

Affiliation

Taxol is a potent drug used in various cancer treatments. Its complex structure has prompted extensive research into its biosynthesis. However, certain critical steps, such as the formation of the oxetane ring, which is essential for its activity, have remained unclear. Previous proposals suggested that oxetane formation follows the acetylation of taxadien-5α-ol. Here, we proposed that the oxetane ring is formed by cytochrome P450-mediated oxidation events that occur prior to C5 acetylation. To test this hypothesis, we analyzed the genomic and transcriptomic information for Taxus species to identify cytochrome P450 candidates and employed two independent systems, yeast (Saccharomyces cerevisiae) and plant (Nicotiana benthamiana), for their characterization. We revealed that a single enzyme, CYP725A4, catalyzes two successive epoxidation events, leading to the formation of the oxetane ring. We further showed that both taxa-4(5)-11(12)-diene (endotaxadiene) and taxa-4(20)-11(12)-diene (exotaxadiene) are precursors to the key intermediate, taxologenic oxetane, indicating the potential existence of multiple routes in the Taxol pathway. Thus, we unveiled a long-elusive step in Taxol biosynthesis.

中文翻译：

双功能细胞色素 P450 酶催化紫杉醇生物合成中氧杂环丁烷环的形成

紫杉醇是一种用于多种癌症治疗的强效药物。其复杂的结构促使人们对其生物合成进行广泛的研究。然而，某些关键步骤，例如对其活性至关重要的氧杂环丁烷环的形成，仍不清楚。先前的提议表明，氧杂环丁烷的形成是在紫杉二烯-5α-醇乙酰化之后形成的。在这里，我们提出氧杂环丁烷环是由细胞色素 P450 介导的氧化事件形成的，该氧化事件发生在 C5 乙酰化之前。为了检验这一假设，我们分析了红豆杉属物种的基因组和转录组信息，以确定细胞色素 P450 候选物，并采用两个独立的系统：酵母（酿酒酵母）和植物（烟草本塞姆氏）来进行表征。我们发现，单一酶 CYP725A4 催化两个连续的环氧化事件，导致氧杂环丁烷环的形成。我们进一步表明，taxa-4（5）-11（12）-二烯（内紫杉二烯）和taxa-4（20）-11（12）-二烯（外紫杉二烯）都是关键中间体，分类学氧杂环丁烷的前体，这表明紫杉醇途径中可能存在多条途径。因此，我们揭示了紫杉醇生物合成中一个长期难以捉摸的步骤。

更新日期：2023-12-21

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