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

H.J. Bouwmeester, T.E. Wallaart, M.H.A. Janssen, B. van Loo, B.J.M. Jansen, M.A. Posthumus, C.O. Schmidt, J.W. de Kraker, W.A. König, M.C.R. Franssen

Research output: Contribution to journalArticleAcademicpeer-review

206 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 Km 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
JournalPhytochemistry
Volume52
DOIs
Publication statusPublished - 1999

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