amorpha-4-11-diene and Malaria

Topics: Antimalarials; Artemisia annua; Artemisinins; Genetic Vectors; Humans; Malaria; Metabolic Networks and Pathways; Molecular Structure; NADPH-Ferrihemoprotein Reductase; Nicotiana; Oxidoreductases; Plant Proteins; Plants, Genetically Modified; Polycyclic Sesquiterpenes; Sesquiterpenes

Artemisinin from Artemisia annua has become one of the most important drugs for malaria therapy. Its biosynthesis proceeds via amorpha-4,11-diene, but it is still unknown whether the isoprenoid precursors units are obtained by the mevalonate pathway or the more recently discovered non-mevalonate pathway. In order to address that question, a plant of A. annua was grown in an atmosphere containing 700 ppm of 13CO2 for 100 min. Following a chase period of 10 days, artemisinin was isolated and analyzed by 13C NMR spectroscopy. The isotopologue pattern shows that artemisinin was predominantly biosynthesized from (E,E)-farnesyl diphosphate (FPP) whose central isoprenoid unit had been obtained via the non-mevalonate pathway. The isotopologue data confirm the previously proposed mechanisms for the cyclization of (E,E)-FPP to amorphadiene and its oxidative conversion to artemisinin. They also support deprotonation of a terminal allyl cation intermediate as the final step in the enzymatic conversion of FPP to amorphadiene and show that either of the two methyl groups can undergo deprotonation.

Topics: Antimalarials; Artemisia annua; Artemisinins; Biosynthetic Pathways; Carbon Dioxide; Carbon Isotopes; Malaria; Mevalonic Acid; Molecular Structure; Phytotherapy; Polycyclic Sesquiterpenes; Polyisoprenyl Phosphates; Sesquiterpenes