athway alone, but transplant a similar pathway from yeast. This pathway takes in a common chemical in E. coli, acetyl co-enzyme A, and sends it down a cascade of reactions resulting in isoprenoid precursors, primarily isopentenyl pyrophospahate (IPP) and dimethylallyl pyrophospate (DMAPP). In initial experiments, these isoprenoids accumulated in the cells and threw then out of whack -- the cells either stopped growing or mutated to avoid the toxins -- so he stuck in a wormwood gene for an enzyme that converts them to amorphadiene, a chemical precursor of artemisinin that the cells can deal with.

Artemisinin has been known to the Chinese for 2,000 years as an herbal medicine, qinghaosu. Though highly effective at killing the malaria parasite, currently it is expensive to manufacture because of the costs of chemical extraction from wormwood (Artemisia annua, a relative of the herb used to make absinthe) or total laboratory synthesis. The expense stands in the way of its use in Africa, where resistance is rapidly spreading to the first-line antimalarial drugs-- chloroquine and sulfadoxine-pyrimethamine.

Since their first success, Keasling and his laboratory colleagues have improved yield from the bacteria 10,000 fold, nearly to the level at which industrial production of the antimalarial drug would be cost effective. Another order of magnitude is doable, he said.

Keasling noted, however, that it is feasible to insert another chemical step into the bacteria to produce a compound, artemisinic acid, that is even closer to artemisinin. And one possibility is to let the bacteria grow and evolve in a petri dish and see if they can produce derivatives of artemisinin that have similar or improved effects on the malaria parasite.

"With the ability to produce taxol or amorphadiene in E. coli, we can easily encourage the bacteria to evolve a molecule not found in nature that could be more effective in human disease," he said.

IPP and DMAPP
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Contact: Robert Sanders
rls@pa.urel.berkeley.edu
510-643-6998
University of California - Berkeley
1-Jun-2003

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