Artemisinin: Controlling its production in artemisia annua

Abstract

Artemisinin, a potent antimalarial sesquiterpene lactone, is produced in low quantities by the plant Artemisia annua L. We used inhibitors of both the mevalonate and nonmevalonate terpenoid pathways to study in both seedlings and hairy root cultures the source of isopentenyl diphosphate (IPP), the channeling of carbon from sterols to sesquiterpenes, and the role that sugars may play in controlling artemisinin biosynthesis. Together, our results indicated that artemisinin is likely biosynthesized from IPP pools originating in both the plastid and the cytosol and that channeling of carbon can be directed away from competing sterol pathways and toward sesquiterpenes. Although glucose stimulated artemisinin production, the response is very complex with ratios of glucose to fructose involved; artemisinin levels increased proportionate to increasing amounts of glucose. Disaccharides mainly inhibited artemisinin production, but the response was less definitive. Glucose also increased expression of some of the genes in the artemisinin biosynthetic pathway, thereby suggesting that this sugar is acting not only as a carbon source but also as a signal. As we develop a better understanding of the regulation of the artemisinin biosynthetic pathway, results suggest that many factors can possibly be harnessed to increase artemisinin production in A. annua.