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O'Connor and chemistry graduate student Elizabeth McCoy decided to
explore the periwinkle plant in part because it is the only plant that
produces vinblastine, a drug widely used to treat cancers such as
Hodgkin's lymphoma.
The biochemical pathway that produces vinblastine and other alkaloid
compounds is long and complicated, usually requiring at least 10
enzymatic steps, which occur in different parts of the periwinkle
plant (also known as Catharanthus roseus).
O'Connor and McCoy essentially tricked the plants into producing new
compounds by feeding them slightly altered versions of the normal
starting materials (tryptamines) for alkaloid synthesis.
"You can make a great number of modifications of simple starting
materials, and the plants incorporate those starting materials into
the biosynthetic pathway," said O'Connor.
Alkaloids are believed to have a protective function for plants
because they are toxic to bacteria and herbivores who try to eat the
plants. This theory is bolstered by the fact that the reaction
products move closer to the plant surface as they move through the
biosynthetic pathway, said McCoy.
Vinblastine, which has been used as a cancer drug since the 1960s, is
very difficult to isolate from the periwinkle plant because it is
produced in minute quantities (the yield is about 0.002 percent of the
plant's weight). However, it would be even more difficult (and
expensive) to synthesize vinblastine in the laboratory.
"It's a beautiful and elegant synthesis, but it's not cost-effective,
so industry does not currently use synthesis to make vinblastine,"
said O'Connor.
Other researchers are now running clinical trials for artificial
analogues of vinblastine, so it could be beneficial if periwinkle
plants could be induced to synthesize those same compounds or new
compounds that might be even more effective.
Because it is easier to make modifications to the starting materials
than the end product, the researchers' method could produce a diverse
array of alkaloids to test for potential drug activity. "You can only
make a limited number of modifications to natural products that are
already synthesized," O'Connor said.
In their recent paper, the researchers describe 18 new products, but
there are many more possibilities. "There's no end to what you could
do to modify the starting materials," said McCoy.
Scientists often engineer bacteria and yeast to produce desired
compounds, such as antibiotics, but few have tried it with plants,
because their biochemistry is so complex.
"Plants are the hardest to work with, so people have avoided looking
at plant biosynthetic pathways," O'Connor said.
The research is funded by the Smith Family Medical Foundation, 3M, the
Beckman Foundation, the American Cancer Society and the American
Chemical Society.
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