鬼臼毒素及其衍生物生物合成研究进展

鬼臼毒素(Podophyllotoxin,PTOX)是来源于中药八角莲、山荷叶和桃儿七等鬼臼属植物的芳基四氢萘类木脂素。其化学半合成衍生物依托泊苷和替尼泊苷被用于多种癌症的临床治疗。作为天然产物来源新药创制的典型代表,鬼臼毒素目前依赖天然提取,供求矛盾日渐突出。生物合成具有不受资源限制、反应条件友好等优势,是鬼臼毒素及其衍生物生产的新方式。文中总结了鬼臼毒素在植物中的生物合成途径的研究进展,阐述了合成途径中关键酶的功能及其亚细胞定位,进而介绍了以模式植物烟草为底盘的鬼臼毒素合成生物学研究。最后总结了利用微生物对鬼臼毒素进行异源表达及生物转化的研究进展,以期为利用微生物细胞工厂高效合成鬼臼毒素及其衍生物提供参考。

Research progress in biosynthesis of podophyllotoxin and its derivatives

Podophyllotoxin (PTOX) is an aryl-tetralin lignan of plant origin found in some species of Podophyllum such as Dysosma versipellis, Diphylleia sinensis, and Sinopodophyllum hexandrum. Etoposide and teniposide are produced semisynthetically from PTOX and used clinically to treat several forms of cancer. As a typical representative of new drug discovery from natural products, the production of PTOX solely depends on extraction from plants, resulting in severe contradiction between supply and demand. With the advantages of unconstrained resources and eco-friendly reaction conditions, biosynthesis method has become a trend in the production of PTOX and its derivatives. In this review, we summarize the research progress of PTOX biosynthesis in plants and expound the functions of the key enzymes as well as their subcellular location. The synthetic biology for production of PTOX intermediates in a tobacco chassis is also introduced. Finally, the heterologous expression and biotransformation of PTOX in microorganisms is summarized, which sets the foundation for the efficient microbial production of PTOX using cell factories.