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Medicinal Plant Biotechnology
Project Goals:..............Elucidating the biosynthesis of taxol (anticancer diterpene) and production of taxanes in engineered microbes
Plants are a rich source of natural products, including 25% of natural product-derived drugs. Paclitaxel (trademarked as taxol® by Bristol-Myers Squibb) is a microtubule-stabilizing anticancer drug produced by all species of the genus Taxus (yew trees). It has been developed into one of the most successful drugs to treat certain types of cancer. The clinical development of taxol was an agonizingly slow progress due to supply shortages of the natural producer Taxus brevifolia in the 1980s and 1990s. 3 Production of taxol in the plant is very low (< 0.0001% in bark tissue), and harvesting of yew for extraction is not sustainable. As is the case for all complex plant terpenes, full chemical synthesis is also not currently a viable economic option as it requires many steps (eleven chiral centers in the case of taxol), gives low yield, and is not scalable for production. Taxol is currently manufactured either by semisynthesis from 10-deacetylbaccatin III, extracted from the needles of Taxus species, or by extraction from plant cell suspension cultures. All of these methods still rely on a plant source, resulting in low and unstable yield, high production costs, and unwanted byproducts. To reduce the time, cost and environmental impact of the, we are developing a platform to synthesize taxanes (biosynthetic precursors of taxol) in engineered microbes.
Selected Recent Publications
Srividya N., Lange I., Hartmann M., Li Qunrui, Mirzaei M., Lange B.M. (2020) Biochemical characterization of acyl activating enzymes for side chain moieties of taxol and its analogs. J. Biol. Chem. 289, 4963-4973.
Lange B.M. (2018) Commercial-Scale Tissue Culture for the Production of Plant Natural Products: Successes, Failures and Outlook. In Biotechnology of Natural Products, W. Schwab, B.M. Lange, M. Wuest, Eds., Nature Springer, pp. 189-218. Link
Lange, B.M. (2016) Online resources for gene discovery and biochemical research with aromatic and medicinal plants. Phytochem. Rev. 15, 489-510. Link
Fischedick J.T., Johnson S.R., Ketchum R.E.B., Croteau R.B., Lange B.M. (2015) NMR spectral search module for Spektraris, an online resource for plant natural product identification taxane diterpenoids from Taxus x media cell suspension cultures as a case study. Phytochemistry 113, 87-95.