Notch another victory for synthetic biology. Researchers report today that they have designed a common laboratory plant to produce the starting material for a powerful chemotherapy drug initially harvested from a Himalayan plant endangered. The new work could provide an abundant supply of the anticancer drug and make it easier for chemists to twist the compound to come up with safer and more efficient versions.
Throughout history, people have relied on plants for medicines. Even modern drug companies get about half of their new drugs from plants. But it is harder to do when the plants are slow growing and disappearing, like the Himalayan mayapple ( Podophyllum hexandrum ). The plant short leaves was the original source of podophyllotoxin, a cytotoxic compound that is the starting point of an anticancer drug called etoposide. The drug has been on the US market since 1983 and is used to treat dozens of different cancers, lymphoma lung cancer. Today, podophyllotoxin is mainly harvested from the more common American mayapple. But this plant is slow growing, that producing only small amounts of the compound.
Mayapples churn podophyllotoxine to defend against would-be munchers. To do this, plants use a step by step approach to synthesize their chemical defense. But because the synthetic pathway of the compound has not been developed, it was not clear which genes were involved in the seam of the molecule. What the researchers knew was that podophyllotoxin is not always present in the plant. "It is only when the sheet is hurt that the molecule is made," said Elizabeth Sattely, a chemical engineer at Stanford University in Palo Alto, California, who led the current research effort.
Sattely and his graduate student Warren Lau held that the podophyllotoxin-building proteins themselves were probably not made by the plant in response to injury. Thus, the pair made tiny holes in the leaves of the Himalayas healthy mayapples provided to them by a commercial nursery, to test the before and after to see what new proteins appeared around the damaged tissue. they found 31, which they classified probable function.
the couple then shrunk likely candidates for the enzymes in the production of podophyllotoxin focusing on the members of four classes known to carry out the right types of chemical reactions. They then spliced genes for each of these enzymes in bacteria known to infect Nicotiana benthamiana , a fast growing Parent tobacco used as a sort of plant biologists laboratory rat. Bacteria easily infect tobacco and insert their genes into the plant tissue. Sattely Lau and inserted many combinations of genes for the enzymes they thought they could produce the desired compound. As they report online today in Science , they finally hit on a group of 10 enzymes that allowed the plant to make a molecule called (-) - 4'-desmethyl epipodophyllotoxin, a direct precursor to etoposide and a powerful anticancer drug in its own right.
"It is a great piece of work," said Sarah O'Connor, a biological chemist at the John Innes Center, a research institute on plants in Norwich, UK Finally, new job can give pharmaceutical companies a stable, abundant supply of their drug fight against cancer, and it can result in similar compounds that might work even better.
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