パクリタキセルの生合成が解明される(Biosynthesis of paclitaxel unravelled)

2023-12-12 マックス・プランク研究所

<関連情報>

• https://www.mpg.de/21255442/biosynthesis-of-paclitaxel-unravelled?c=2249
• https://www.cell.com/molecular-plant/fulltext/S1674-2052(23)00330-1

合成生物学により、パクリタキセルの生合成に必要な最小限の遺伝子セットを植物シャーシで同定 Synthetic biology identifies the minimal gene set required for paclitaxel biosynthesis in a plant chassis

Youjun Zhang,Lorenz Wiese,Hao Fang,Saleh Alseekh,Leonardo Perez de Souza,Federico Scossa,John J. Molloy,Mathias Christmann,Alisdair R. Fernie
Molecular Plant  Published:October 26, 2023
DOI:https://doi.org/10.1016/j.molp.2023.10.016

Abstract

The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel from natural sources is limited. However, missing knowledge about the genes involved in several specific metabolic steps of paclitaxel biosynthesis has rendered it difficult to engineer the full pathway. In this study, we used a combination of transcriptomics, cell biology, metabolomics, and pathway reconstitution to identify the complete gene set required for the heterologous production of paclitaxel. We identified the missing steps from the current model of paclitaxel biosynthesis and confirmed the activity of most of the missing enzymes via heterologous expression in Nicotiana benthamiana. Notably, we identified a new C4β-C20 epoxidase that could overcome the first bottleneck of metabolic engineering. We used both previously characterized and newly identified oxomutases/epoxidases, taxane 1β-hydroxylase, taxane 9α-hydroxylase, taxane 9α-dioxygenase, and phenylalanine-CoA ligase, to successfully biosynthesize the key intermediate baccatin III and to convert baccatin III into paclitaxel in N. benthamiana. In combination, these approaches establish a metabolic route to taxoid biosynthesis and provide insights into the unique chemistry that plants use to generate complex bioactive metabolites.