Rare plant reveals its recipe for potent chemotherapeutic agent

September 10, 2015

Inconveniently, the only current method to synthesize the chemotherapy agent etoposide is by using extracts from a plant, but researchers have successfully manipulated Nicotiana benthamiana (tobacco) to create a more immediate and potent precursor. Etoposide is a topoisomerase inhibitor used to treat a variety of malignancies, including lung cancer and leukemia. There is currently no way to produce etoposide without one of its precursors, podophyllotoxin, which is found in the slow-growing Himalayan Mayapple plant. Four partial pathways behind podophyllotoxin are known, but the full recipe for this mysterious compound has eluded researchers, in part because of the Mayapple's immense genome. To tap into the Mayapple's chemotherapeutic potential, Warren Lau and Elizabeth Sattely focused on the four genes that are known in the production of podophyllotoxin, and then analyzed RNA-sequencing data of the Mayapple to identify similar genes. They then manipulated tobacco to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry. In total, the authors identified six new pathway enzymes that, combined with the original four, produce the immediate etoposide precursor (-)-4?-desmethyl-epipodophyllotoxin, which outperforms podophyllotoxin as a chemotherapy ingredient. A Perspective by Sarah O'Connor discusses the benefits and complexities of deriving compounds from plants, including the Mayapple, in more detail.
Article #12: "Six enzymes from Mayapple that complete the biosynthetic pathway to the etoposide aglycone," by W. Lau; E.S. Sattely at Stanford University in Stanford, CA.

Article #4: "Fighting cancer while saving the mayapple," by S.E. O'Connor at The John Innes Centre in Norwich, UK.

American Association for the Advancement of Science

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