SynBioLab Achieves Efficient Biosynthesis and Small-Scale Production of Key Taxol Intermediate
Recently, the Xinbeilai team successfully enhanced the synthesis efficiency of key intermediates of paclitaxel, a star anticancer drug, by optimizing gene editing systems for multiple modules in the metabolic pathway, and achieved small-scale mass production. This achievement is of great significance for accelerating the industrialization process of biosynthetic paclitaxel.
Plant-derived natural products typically exhibit diverse pharmacological activities and serve as a crucial source for drug discovery and development.Paclitaxel (Taxol)It is a diterpenoid compound with anticancer activity found in plants of the genus Taxus. Since its approval by the U.S. Food and Drug Administration (FDA) for cancer treatment in 1992, its broad-spectrum efficacy as an anticancer drug has been continuously validated, including but not limited to therapeutic applications for breast cancer, lung cancer, pancreatic cancer, and gastric cancer, and it has gradually grown into a prominent presence in the marketOne of the Most Effective Natural Anti-Cancer Drugs。
Figure 1. Structural formulas of Taxus and paclitaxel
With the intensifying aging of the population and the persistent impact of unhealthy lifestyles, cancer has become one of the major threats to global health. According to the latest data released in February 2024 by the International Agency for Research on Cancer (IARC) of the World Health Organization,By 2022, there were approximately 20 million cancer cases globally, and the number of new cancer cases is projected to exceed 35 million by 2050.
Currently, lung cancer and breast cancer are the leading types of cancer globally, among whichLung cancer is the most common type of cancer (2.5 million cases), followed by female breast cancer (2.3 million cases)., followed by colorectal cancer, prostate cancer, and gastric cancer (Figure 2). Against the backdrop of the severe global cancer burden, paclitaxel, as a first-line chemotherapeutic agent with broad-spectrum antitumor activity, has become a key component of treatment regimens for various cancers, with its market demand continuing to expand amidst the explosive growth in cancer incidence.
Figure 2. Global Cancer Incidence (IARC, Globocan 2022)
To meet the substantial market demand, research on paclitaxel production has been continuously iterated. Due to the limited availability of Taxus resources, natural extraction from tree bark was once halted; plant cell culture has been constrained by environmental factors and yield limitations; chemical synthesis has failed to achieve industrialization due to issues such as lengthy steps, high costs, and low efficiency; and the mainstream method of semi-synthesis using active ingredients extracted from Taxus branches and leaves has consistently fallen short of meeting robust market demand. With advancements in genomics, synthetic biology, and other technologies, the pursuit ofEfficient, Green, and Sustainable Biosynthetic Route for PaclitaxelBecome the focus.
As early as 2021, the Xinbeilai team collaborated with institutions such as the Institute of Industrial Technology, Chinese Academy of Sciences, Northwestern Polytechnical University, and BGI Research.Completed the first chromosome-level whole-genome sequencing of Himalayan yew (Taxus wallichiana) exceeding 10 Gb, and identified the key gene clusters responsible for paclitaxel biosynthesis in Taxus species.provides profound insights into the origin and evolution of the paclitaxel biosynthetic pathway (Figure 3).
Figure 3. Xinbeilai’s research on paclitaxel was published in the journal *Molecular Plant* (IF 27.5).
With the heterologous characterization of enzymes in the paclitaxel biosynthetic pathway and the public disclosure of related mechanisms,The Xinbeilai team discovered that multiple enzymes in this pathway exhibit broad substrate promiscuity, which has significantly hindered the elucidation of the primary pathway and the identification of key enzymes.
The biosynthetic pathway of paclitaxel involves multiple steps, including hydroxylation, acylation, and epoxidation, among other biochemical reactions, as well as the participation of several key synthetic enzymes. The acquisition of its key intermediates is crucial for pathway elucidation and enzyme characterization.
By the end of 2023, Xinbeilai Bio completed the iterative upgrade of its full-stack integrated R&D platform combining IT and BT (Information Technology and Biotechnology)—the “Syn+ Platform.” Through the continuous integration and innovation of biotechnology digitalization and informatization with artificial intelligence, the platform has achieved internationally leading levels in the breadth of key gene mining, the efficiency of multi-omics analysis, and the precision of quantum computing. Meanwhile, by integrating digital high-throughput screening with wet-lab validation, leveraging multidisciplinary strengths in purification, and innovating a combined strategy of precision fermentation and “one strain, one formula,” the company is driving an exponential increase in R&D efficiency. This has enabled the parallel development of multiple R&D pipelines and established a new development pattern in which multiple technologies have achieved industrialization.
Leveraging the advantages of the “Syn+ Platform,”Recently, the Xinbeilai team successfully enhanced the synthesis efficiency of key intermediates for paclitaxel, a star anticancer drug, by optimizing gene-editing systems across multiple modules in metabolic pathways, implementing metabolic engineering modifications, and strengthening key components. Small-scale production was achieved in a 5L fermentation system.. The efficient biosynthesis of this key intermediate,It is of great significance for accelerating the industrialization process of biosynthetic paclitaxel.
Green biosynthesis of paclitaxel, by mimicking natural biosynthetic mechanisms, has reshaped our approach to utilizing natural resources, offering multiple advantages such as conservation of plant resources, significant cost reduction, and improved drug accessibility.Its industrialization will not only optimize existing production methods and effectively replace traditional agricultural cultivation, thereby sustainably meeting the demand in the existing paclitaxel market, but also create opportunities for the development of novel drugs and the expansion of new incremental markets.
In the future, Xinbeilai Biotech will fully leverage its core strengths in intelligent biosynthesis, strengthen multi-party collaboration with industry partners, and further advance the green intelligent biosynthesis of paclitaxel and other high-value-added products.
References:
1.https://www.iarc.who.int/wp-content/uploads/2024/02/pr345_E.pdf
2. https://doi.org/10.1016/j.molp.2021.04.015
3. https://doi.org/10.1038/s41477-021-00963-5
4. https://www.science.org/doi/10.1126/science.adj3484