Yeast brew up anti-malarials

Bioengineers program the microbe to produce artemisinin precursor -- and at potentially lower cost, they argue

By | April 13, 2006

Bioengineers have programmed yeast to produce a precursor to the potent antimalarial drug artemisinin, they report in this week's Nature. They argue that the engineered cells, if scaled up to industrial-sized batches, could pump out the drug efficiently and for less than it costs to extract it from plants, currently the only source of the drug. Malaria is now resistant to the older and far cheaper drug chloroquine, making artemisinins "the most effective antimalarial drugs we have," Nick White, director of research in Southeast Asia for Wellcome Trust, told The Scientist. "Development of an inexpensive yeast source which could be scaled up for industrial production is very exciting." Artemisinins are currently produced using the Chinese herb wormwood (Artemisia annua), cultivated in Africa and its native China. However, the plant must grow for two years before harvest and then yields only 1% of its dry weight in artemisinins, according to White, who did not participate in the current study. During the study, the researchers, led by Jay Keasling at the University of California in Berkeley, boosted the activities of several genes and dampened the activity of another to bias a biosynthetic pathway in a strain of yeast. By manipulating regulatory elements that control the genes, they tweaked the pathway to maximize the output of one of its products, farnesyl pyrophosphate. Then they added a wormwood enzyme that converts the pyrophosphate to amorphadiene, which can be oxidized to their goal: artemisinic acid, a precursor to artemisinin. That's when they hit their first stroke of good luck. "We were assuming a worst case scenario: That we would need to clone out three enzymes" for the final three-step oxidation, Keasling told The Scientist. It turned out that a single plant enzyme did the trick. They found a cytochrome P450 enzyme that converts nearly all of the amorphadiene to artemisinic acid, with little remaining of the alcohol and aldehyde intermediates. Their final stroke of luck came when they discovered that the yeast secrete the artemisinic acid, which sticks to the outside of the cells and can be washed off with an alkaline rinse. "It essentially self-purified," Keasling said. Production costs should be even lower without the need to open the cells and sort the acid out from all the proteins and other metabolites, he added. Despite their good fortune, getting all the elements to work as a coordinated circuit was no easy feat, said synthetic biologist Chris Voigt of the University of California in San Francisco, who did not participate in the work. "They have developed new ways of controlling the expression of enzymes which required the beautiful combination of regulatory elements to really control every step of this pathway," Voigt told The Scientist. "It's a whole slew of advances." Although Keasling's group has previously reported preliminary progress toward their goal, "this is really the first time you can imagine the production of this molecule having a huge impact," Voigt said. Malaria kills more than a million people each year, mostly in the developing world. Previous efforts to wipe out the disease have failed. Still, artemisinins alone are no panacea, White warned -- for instance, the drugs must be used in combination with another to minimize the chance a second wave of drug resistance. But getting the drugs for cheaper is still crucial to controlling the disease, White said. "Current treatment depends on them." Susan Brown Links within this article D-K Ro, et al, "Production of the antimalarial drug precursor artemisinic acid in engineered yeast." Nature, April 12, 2006. P. Silver and J. Way, "Cells by design," The Scientist, September 27, 2004. Wellcome Trust South-East Asia Programme J. Parry, "Taking a new look at an ancient tradition," The Scientist, May 9, 2005. Jay Keasling J. Lucentini, "Is this life?" The Scientist, January, 2006. Chris Voigt B. Daviss, "Malaria, science, and social responsibility," The Scientist, March 28, 2005. World Health Organization Global Malaria Programme

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