合成生物学 ›› 2024, Vol. 5 ›› Issue (3): 527-547.DOI: 10.12211/2096-8280.2023-085

• 特约评述 • 上一篇    下一篇

紫杉醇生物合成机制研究进展

刘晓楠1,2(), 李静1,2,3, 祝晓熙1,2, 徐子硕1,2,4,5, 齐健1,2, 江会锋1,2   

  1. 1.中国科学院天津工业生物技术研究所,低碳合成工程生物学重点实验室,天津 300308
    2.国家合成生物技术创新中心,天津 300308
    3.南开大学化学学院,天津 300071
    4.东北林业大学,东北盐碱植被恢复与重建教育部重点实验室,黑龙江 哈尔滨 150040
    5.东北林业大学,黑龙江省植物天然活性物质的合成与利用重点实验室,黑龙江 哈尔滨 150040
  • 收稿日期:2023-11-17 修回日期:2024-04-12 出版日期:2024-06-30 发布日期:2024-07-12
  • 通讯作者: 刘晓楠,江会锋
  • 作者简介:刘晓楠(1990—),女,博士,副研究员,硕士生导师。研究方向为植物天然产物合成、酵母基因组工程。E-mail:liu_xn@tib.cas.cn
    江会锋(1981—),男,博士,研究员,博士生导师。研究方向为新酶设计与酵母基因组工程。E-mail:jiang_hf@tib.cas.cn
  • 基金资助:
    国家自然科学基金(32371499);中国博士后科学基金(2019M661032);北京生命科技研究院有限公司重点项目(2023200CB0090)

Research advances on paclitaxel biosynthesis

Xiaonan LIU1,2(), Jing LI1,2,3, Xiaoxi ZHU1,2, Zishuo XU1,2,4,5, Jian QI1,2, Huifeng JIANG1,2   

  1. 1.Key Laboratory of Engineering Biology for Low-Carbon Manufacturing,Tianjin Institute of Industrial Biotechnology,Chinese Academy of Sciences,Tianjin 300308,China
    2.National Center of Technology Innovation for Synthetic Biology,Tianjin 300308,China
    3.College of Chemistry,Nankai University,Tianjin 300071,China
    4.Key Laboratory of Saline-Alkali Vegetation Ecology Restoration,Northeast Forestry University,Harbin 150040,Heilongjiang,China
    5.Heilongjiang Key Laboratory of Plant Bioactive Substance Biosynthesis and Utilization,Northeast Forestry University,Harbin 150040,Heilongjiang,China
  • Received:2023-11-17 Revised:2024-04-12 Online:2024-06-30 Published:2024-07-12
  • Contact: Xiaonan LIU, Huifeng JIANG

摘要:

紫杉醇是目前已发现的最具抗癌活性的天然广谱抗癌药物之一,其生产方式主要依赖于从珍稀植物红豆杉中进行分离提取以及化学半合成,因其含量稀少,生产能力受到严重的限制。随着红豆杉基因组的全解析和合成生物学的迅速发展,通过合成生物技术,构建重组工程细胞合成紫杉醇及其关键前体成为解决当前供需不平衡和资源有限的有效方法。本文针对紫杉醇生物合成途径解析、红豆杉组学分析、底盘细胞构建、关键前体合成、紫杉醇合成途径关键酶的改造及催化机理解析等相关研究进展开展系统性的综述,尤其对近期发表的关于氧杂环丁烷环形成的相关突破性研究进行了详细介绍,并基于相关进展探讨当前紫杉醇合成生物学研究面临的关键酶催化效率低下、产物杂泛性严重、具体反应顺序未知等技术挑战及生物合成紫杉醇关键中间体的未来前景。助力加强对紫杉醇合成通路和催化过程的理解,进一步实现紫杉醇的绿色、高效生物合成。

关键词: 紫杉醇, 途径解析, P450酶, 酶改造, 合成生物学

Abstract:

Paclitaxel (Taxol) is a natural broad-spectrum anticancer drug, which is well-known for its potent anticancer activity. Its production mainly relies on the extraction and purification from the rare Taxus plant, followed by chemical semi-synthesis. The limited natural resource for paclitaxel imposes a significant constraint on its production capacity. In recent years, with the complete decoding of the Taxus genome and the rapid development of synthetic biology, constructing recombinant cells through synthetic biology techniques has emerged as an effective method to address this challenge. Since paclitaxel biosynthesis involves more than 20 steps of complicated enzymatic reactions and about half of them are P450 enzyme-mediated hydroxylation reactions, the complete elucidation of its biosynthetic pathway remains elusive. Meanwhile, the production of paclitaxel by engineered microbes is still at the initial stage, and there are numerous by-products, which seriously compromise the efficient synthesis of paclitaxel. Therefore, this article reviews research progress related to paclitaxel synthesis pathways, Taxus omics analyses, construction of chassis cells, synthesis of key precursors, modifications of crucial enzymes, and catalytic mechanisms underlying paclitaxel biosynthesis. Special attention is given to the recent breakthrough in elucidating the formation of oxetane ring and the discovery of Taxane 1-β- and 9-α-hydroxylases. Recent advances in the study of the catalytic mechanism of Taxadiene-5-α-hydroxylase and significant progress in engineering tobacco and yeast chassis will also be commented. Furthermore, challenges and future prospects involved in the paclitaxel synthetic biology research are discussed, such as the issues of low enzyme catalytic efficiency, significant product promiscuity, unknown specific reaction sequences, and the biosynthesis of critical paclitaxel intermediates, aiming to enhance the understandings of paclitaxel biosynthetic pathways and catalytic mechanisms for greener and more efficient production of paclitaxel.

Key words: paclitaxel, pathway analysis, P450 enzymes, enzyme modifications, synthetic biology

中图分类号: