Amorpha-4,11-diene synthase catalyses the first probable step in artemisinin biosynthesis

Harro J. Bouwmeester*, T. Eelco Wallaart, Michiel H.A. Janssen, Bert Van Loo, Ben J.M. Jansen, Maarten A. Posthumus, Claus O. Schmidt, Jan Willem De Kraker, Wilfried A. König, Maurice C.R. Franssen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

217 Citations (Scopus)

Abstract

The endoperoxide sesquiterpene lactone artemisinin and its derivatives are a promising new group of drugs against malaria. Artemisinin is a constituent of the annual herb Artemisia annua L. So far only the later steps in artemisinin biosynthesis - from artemisinic acid - have been elucidated and the expected olefinic sesquiterpene intermediate has never been demonstrated. In pentane extracts of A. annua leaves we detected a sesquiterpene with the mass spectrum of amorpha-4,11-diene. Synthesis of amorpha-4,11-diene from artemisinic acid confirmed the identity. In addition we identified several sesquiterpene synthases of which one of the major activities catalysed the formation of amorpha-4,11-diene from farnesyl diphosphate. This enzyme was partially purified and shows the typical characteristics of sesquiterpene synthases, such as a broad pH optimum around 6.5-7.0, a molecular mass of 56 kDa, and a K(m) of 0.6 μM. The structure and configuration of amorpha-4,11-diene, its low content in A. annua and the high activity of amorpha-4,11-diene synthase all support that amorpha-4,11-diene is the likely olefinic sesquiterpene intermediate in the biosynthesis of artemisinin.

Original languageEnglish
Pages (from-to)843-854
Number of pages12
JournalPhytochemistry
Volume52
Issue number5
DOIs
Publication statusPublished - 1 Nov 1999
Externally publishedYes

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