Advanced metabolic engineering strategies for increasing artemisinin yield in Artemisia annua L

Abstract

Artemisinin, also known as 'Qinghaosu', is a chemically sesquiterpene lactone containing an endoperoxide bridge. Due to the high activity to kill Plasmodium parasites, artemisinin and its derivatives have continuously served as the foundation for antimalarial therapies. Natural artemisinin is unique to the traditional Chinese medicinal plant Artemisia annua L., and its content in this plant is low. This has motivated the synthesis of this bioactive compound using yeast, tobacco, and Physcomitrium patens systems. However, the artemisinin production in these heterologous hosts is low and cannot fulfil its increasing clinical demand. Therefore, A. annua plants remain the major source of this bioactive component. Recently, the transcriptional regulatory networks related to artemisinin biosynthesis and glandular trichome formation have been extensively studied in A. annua. Various strategies including (i) enhancing the metabolic flux in artemisinin biosynthetic pathway; (ii) blocking competition branch pathways; (iii) using transcription factors (TFs); (iv) increasing peltate glandular secretory trichome (GST) density; (v) applying exogenous factors; and (vi) phytohormones have been used to improve artemisinin yields. Here we summarize recent scientific advances and achievements in artemisinin metabolic engineering, and discuss prospects in the development of high-artemisinin yielding A. annua varieties. This review provides new insights into revealing the transcriptional regulatory networks of other high-value plant-derived natural compounds (e.g., taxol, vinblastine, and camptothecin), as well as glandular trichome formation. It is also helpful for the researchers who intend to promote natural compounds production in other plants species.

Figure 1

Metabolic engineering strategies for artemisinin biosynthesis in Artemisia annua

Figure 2

Artemisinin biosynthetic pathway in Artemisia annua. ADH1, alcohol dehydrogenase 1; ADS, amorpha-4,11-diene synthase; ALDH1, aldehyde dehydrogenase 1; BFS, β-farnesene synthase; CPR, cytochrome P450 oxidoreductase; CPS, β-caryophyllene synthase; CYP71AV1, cytochrome P450 monooxygenase; DBR2, artemisinic aldehyde Δ11(13)-reductase (double bond reductase 2); FPS, farnesyl pyrophosphate synthase; GAS, germacrene A; SQS, squalene synthase.

Figure 3

Transcriptional regulatory network of GST formation in Artemisia annua.

Figure 4

Transcriptional regulatory networks that are related to environmental factors and phytohormones-promoted artemisinin biosynthesis in Artemisia annua.