Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study

Phytochemistry. 2010 Feb;71(2-3):179-87. doi: 10.1016/j.phytochem.2009.10.015. Epub 2009 Nov 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / isolation & purification
  • Antimalarials / metabolism*
  • Artemisia annua / chemistry
  • Artemisia annua / metabolism*
  • Artemisinins / chemistry
  • Artemisinins / isolation & purification
  • Artemisinins / metabolism*
  • Biosynthetic Pathways*
  • Carbon Dioxide / metabolism
  • Carbon Isotopes
  • Malaria / drug therapy
  • Mevalonic Acid / metabolism*
  • Molecular Structure
  • Phytotherapy
  • Polycyclic Sesquiterpenes
  • Polyisoprenyl Phosphates / chemistry
  • Polyisoprenyl Phosphates / metabolism*
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / metabolism*

Substances

  • Antimalarials
  • Artemisinins
  • Carbon Isotopes
  • Polycyclic Sesquiterpenes
  • Polyisoprenyl Phosphates
  • Sesquiterpenes
  • amorpha-4,11-diene
  • Carbon Dioxide
  • farnesyl pyrophosphate
  • artemisinine
  • Mevalonic Acid