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.

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2023YFC3503900), National Natural Science Foundation of China (82003889, 82304651), Zhejiang Provincial Natural Science Foundation of China (LQ21H280004), National ‘Ten-thousand Talents Program’ for Leading Talents of Science and Technology Innovation in China, National Young Qihuang Scholars Training Program, Innovative Leading Talents Program for Zhejiang Provincial Universities, the Major Science and Technology Projects of Breeding New Varieties of Agriculture in Zhejiang Province (2021C02074), Key Project at Central Government Level: The Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources (2060302), Research Project of Zhejiang Chinese Medical University (2021JKZDZC06, 2022RCZXZK23, 2023JKZKTS08) and China Postdoctoral Science Foundation (2022M722851). We appreciate the experimental support from the Public Platform of Pharmaceutical Research Center, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University.

Author contributions

G.K., X.H,. and Y.L. conceived and designed the project. Y.L., X.H., and Y.Y. wrote the manuscript. X.H., L.L., K.T., and G.K. revised the manuscript. All authors read and approved the final manuscript.

Data availability statement

Data availability does not apply to this review article as no new data were created or analysed in this study.

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