Amorpha-4,11-diene synthase catalyses the first probable step in artemisinin biosynthesis |
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Authors: | Bouwmeester H J Wallaart T E Janssen M H van Loo B Jansen B J Posthumus M A Schmidt C O De Kraker J W König W A Franssen M C |
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Affiliation: | Research Institute for Agrobiology and Soil Fertility (AB-DLO), Wageningen, Netherlands. h.j.bouwmeester@ab.dlo.nl |
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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 microM. 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. |
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