title: Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study.
abstract: 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.
authors.affiliation: Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, D-85747 Garching, Germany.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schramek
authors.forename: Huahong
authors.initials: H
authors.lastname: Wang
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.forename: Birgit
authors.initials: B
authors.lastname: Keil
authors.forename: Tanja
authors.initials: T
authors.lastname: Radykewicz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Winzenhörlein
authors.forename: Ludger
authors.initials: L
authors.lastname: Beerhues
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: Felix
authors.initials: F
authors.lastname: Rohdich
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gershenzon
authors.forename: Benye
authors.initials: B
authors.lastname: Liu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisenreich
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D031172:Artemisia annua / Q000737:chemistry / Q000378:metabolism*; D037621:Artemisinins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D053898:Biosynthetic Pathways; D002245:Carbon Dioxide / Q000378:metabolism; D002247:Carbon Isotopes; D008288:Malaria / Q000188:drug therapy; D008798:Mevalonic Acid / Q000378:metabolism*; D015394:Molecular Structure; D008517:Phytotherapy; D000081223:Polycyclic Sesquiterpenes; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002247:Carbon Isotopes; D000081223:Polycyclic Sesquiterpenes; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C515348:amorpha-4,11-diene; D002245:Carbon Dioxide; C004808:farnesyl pyrophosphate; C031327:artemisinin; D008798:Mevalonic Acid