Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jan 31:9:87.
doi: 10.3389/fpls.2018.00087. eCollection 2018.

Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin

Stephanie H Kung  1 , Sean Lund  1 , Abhishek Murarka  1 , Derek McPhee  1 , Chris J Paddon  1
Affiliations
Review

Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin

Stephanie H Kung et al. Front Plant Sci. .

Abstract

The antimalarial drug artemisinin is a natural product produced by the plant Artemisia annua. Extracts of A. annua have been used in Chinese herbal medicine for over two millennia. Following the re-discovery of A. annua extract as an effective antimalarial, and the isolation and structural elucidation of artemisinin as the active agent, it was recommended as the first-line treatment for uncomplicated malaria in combination with another effective antimalarial drug (Artemisinin Combination Therapy) by the World Health Organization (WHO) in 2002. Following the WHO recommendation, the availability and price of artemisinin fluctuated greatly, ranging from supply shortfalls in some years to oversupply in others. To alleviate these supply and price issues, a second source of artemisinin was sought, resulting in an effort to produce artemisinic acid, a late-stage chemical precursor of artemisinin, by yeast fermentation, followed by chemical conversion to artemisinin (i.e., semi-synthesis). Engineering to enable production of artemisinic acid in yeast relied on the discovery of A. annua genes encoding artemisinic acid biosynthetic enzymes, and synthetic biology to engineer yeast metabolism. The progress of this effort, which resulted in semi-synthetic artemisinin entering commercial production in 2013, is reviewed with an emphasis on recent publications and opportunities for further development. Aspects of both the biology of artemisinin production in A. annua, and yeast strain engineering are discussed, as are recent developments in the chemical conversion of artemisinic acid to artemisinin.

Keywords: Artemisia annua; Saccharomyces cerevisiae; artemisinic acid; artemisinin; semi-synthetic; synthetic biology.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Summary of yeast strain engineering underlying fermentative production of artemisinic acid and subsequent conversion to artemisinin. (A) Biosynthetic pathway engineered in yeast for production of amorphadiene, its oxidation to artemisinic acid, and subsequent chemical conversion to artemisinin. (B) A. annua enzymes expressed in yeast for oxidation of amorphadiene to artemisinic acid. MVA, mevalonate; FPP, farnesyl diphosphate; AaADH1, alcohol dehydrogenase; AaALDH1, aldehyde dehydrogenase.
FIGURE 2
FIGURE 2
Generic chemical synthesis of artemisinin from artemisinic acid.
See this image and copyright information in PMC

References

    1. Acton N., Roth R. J. (1992). On the conversion of dihydroartemisinic acid into artemisinin. J. Org. Chem. 57 3610–3614. 10.1021/jo00039a020 - DOI
    1. Arendt P., Miettinen K., Pollier J., De Rycke R., Callewaert N., Goossens A. (2017). An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids. Metab. Eng. 40 165–175. 10.1016/j.ymben.2017.02.007 - DOI - PubMed
    1. Benjamin K. R., Silva I. R., Cherubim J. P., McPhee D., Paddon C. J. (2016). Developing commercial production of semi-synthetic artemisinin, and of β-Farnesene, an isoprenoid produced by fermentation of Brazilian sugar. J. Braz. Chem. Soc. 27 1339–1345. 10.5935/0103-5053.20160119 - DOI
    1. Boehme K., Brauer H.-D. (1992). Generation of singlet oxygen from hydrogen peroxide disproportionation catalyzed by molybdate ions. Inorg. Chem. 31 3468–3471. 10.1021/ic00042a024 - DOI
    1. Burgard A., Gieshoff T., Peschl A., Hörstermann D., Keleschovsky C., Villa R., et al. (2016). Optimisation of the photochemical oxidation step in the industrial synthesis of artemisinin. Chem. Eng. J. 294 83–96. 10.1016/j.cej.2016.02.085 - DOI

LinkOut - more resources