An international team, including researchers from the National Research Council (NRC), has published a new semi-synthetic method for producing the anti-malarial drug artemisinin. The system combines biotechnology and industrial chemistry to greatly reduce the cost of the drug and its associated therapies.
Artemisinin is currently extracted from sweet wormwood (Artemisia annua) at high cost. “The plant produces only about one per cent dry weight of artemisinin,” says Patrick Covello, a biochemist at NRC in Saskatoon. About 10 years ago, Covello and his team began studying the biochemical pathway by which the plant makes artemisinin. Replicating the same pathway in yeast would enable the use of industrial fermentation to produce large quantities of the chemical.
The team began by sequencing the messenger RNA (mRNA) from trichomes — gland-like structures on the plant — in order to determine which enzymes were being expressed during artemisinin biosynthesis. Candidate enzymes were then replicated in E. coli and tested for their activity against the various chemical intermediates that eventually lead to artemisinin. “We actually had to chemically synthesize most of those precursors,” says Covello, noting that the ability to do this is often the limiting factor in these studies.
Meanwhile, the American company Amyris was working on the same problem and in 2006 published a paper in Nature that outlined a biosynthetic route to artemisinic acid, which can be converted to artemsinin via industrial chemistry. Unfortunately, the yield turned out to be too low to be economically competitive, so in 2011 Amyris joined forces with the team from the NRC. Their latest joint paper, also published in Nature, describes how the identification of two additional dehydrogenase enzymes (ADH1 and ALDH1) by the NRC led to a doubling of yield. Other modifications to the process by Amyris, both enzymatic and industrial, eventually increased the yield to 10 times that achieved in 2006.
Covello says that the most gratifying part of the discovery was its quick uptake by industry. “The day after this paper was published, the pharmaceutical company Sanofi announced the opening of a production line in Italy,” he says. “There are photographs on the Internet of barrels of artemisinic acid — that’s what makes me the proudest.”