Abstract
Chemical derivatives of artemisinin, a sesquiterpene lactone produced by Artemisia annua, are the active ingredient in the most effective treatment for malaria. Comprehensive phytochemical analysis of two contrasting chemotypes of A. annua resulted in the characterization of over 80 natural products by NMR, more than 20 of which are novel and described here for the first time. Analysis of high- and low-artemisinin producing (HAP and LAP) chemotypes of A. annua confirmed the latter to have a low level of DBR2 (artemisinic aldehyde Δ11(13) reductase) gene expression. Here we show that the LAP chemotype accumulates high levels of artemisinic acid, arteannuin B, epi-deoxyarteannuin B and other amorpha-4,11-diene derived sesquiterpenes which are unsaturated at the 11,13-position. By contrast, the HAP chemotype is rich in sesquiterpenes saturated at the 11,13-position (dihydroartemisinic acid, artemisinin and dihydro-epi-deoxyarteannunin B), which is consistent with higher expression levels of DBR2, and also with the presence of a HAP-chemotype version of CYP71AV1 (amorpha-4,11-diene C-12 oxidase). Our results indicate that the conversion steps from artemisinic acid to arteannuin B, epi-deoxyarteannuin B and artemisitene in the LAP chemotype are non-enzymatic and parallel the non-enzymatic conversion of DHAA to artemisinin and dihyro-epi-deoxyarteannuin B in the HAP chemotype. Interestingly, artemisinic acid in the LAP chemotype preferentially converts to arteannuin B rather than the endoperoxide bridge containing artemisitene. In contrast, in the HAP chemotype, DHAA preferentially converts to artemisinin. Broader metabolomic and transcriptomic profiling revealed significantly different terpenoid profiles and related terpenoid gene expression in these two morphologically distinct chemotypes.
Highlights
Chemical derivatives of the sesquiterpene lactone, artemisinin, such as: artesunate, artemether or dihydroartemisinin are one of several active ingredients in artemisinin-combination therapies (ACTs)—the most effective treatment for malaria currently available
Consistent with this, we have found that mature leaves of NCV contain high levels of epi-deoxyarteannuin B (EDB, 13) and arteannuin B (ArtB, 60) (Figures 3Av,vii), Supplemental Table 2), while Artemis accumulates dihydroepi-deoxyarteannuin B (DHEDB, 12) and artemisinin (22) (Figures 3Aiv,vi) Supplemental Table 2) at 20–30-fold higher levels than NCV
It would be interesting to establish if sequence variant forms of CYP71AV1 and differential expression of DBR2 are generally found between these other low-artemisinin production (LAP)- and highartemisinin production (HAP)-chemotypes
Summary
Chemical derivatives of the sesquiterpene lactone, artemisinin, such as: artesunate, artemether or dihydroartemisinin are one of several active ingredients in artemisinin-combination therapies (ACTs)—the most effective treatment for malaria currently available. The biosynthetic pathway from artemisinin precursors has been fully elucidated over the past decade (Figure 3C). It starts from the cyclization of farnesyl pyrophosphate (FPP) to amorpha-4,11-diene (A4,11-D) by amorph-4,11-diene synthase (AMS) (Bouwmeester et al, 1999; Mercke et al, 2000) followed by the three-step oxidation of A-4,11-D by amorpha-4,11-diene C-12 oxidase (CYP71AV1), to artemisinic alcohol (AAOH), artemisinic aldehyde (AAA), and artemisinic acid (AA) (Ro et al, 2006; Teoh et al, 2006). DHAAA is subsequently oxidized in the final enzymatic reaction to dihydroartemisinic acid (DHAA) by aldehyde dehydrogenase ALDH1 (Teoh et al, 2009). It has previously been proposed that AA is photochemically converted to arteannuin B (ArtB) via the tertiary allylic hydroperoxide of artemisinic acid (Brown and Sy, 2007)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
