Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid
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Background: Due to the global occurrence of multi-drug-resistant malarial parasites ( Plasmodium falciparum ), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood ( Artemisia annua ). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua . In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required. Results: Three plant genes coding for amorphadiene synthase, amorphadiene oxidase ( AMO or CYP71AV1 ), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL -1 in shake-flask cultures and 1 g L -1 in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance ( PDR ) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by yeast microarray further demonstrated that the induction of drug-resistant genes such as ABC transporters and major facilitator superfamily (MSF) genes is the primary cellular stress-response; in addition, oxidative and osmotic stress responses were observed in the engineered yeast. Conclusion: The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses. The use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisinic acid production in the engineered yeast.
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The approach outlined in Scheme 13 has succeeded in producing high levels of amorpha-4,11-diene from E. coli and artemisinic acid from S. cerevisiae in quantities exceeding those from A. annua itself (100 mg-1 g L-1).
“The approach outlined in Scheme 13 has succeded in producing high levels of amorpha-4,11-diene (451) from E. coli [384] and artemisinic acid (473) from S. cerevisiae in quantities which exceed those from A. annua itself (100 mg–1·g·L-1) [385,386].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [385]
Dodecane has been incorporated into culture medium to provide a separate hydrophobic layer in which volatile amorpha-4,11-diene produced by microbial fermentation can be trapped.
“Previously, dodecane has been incorporated into the culture medium, in order to provide a separate hydrophobic layer in which volatile amorpha-4,11-diene (451) produced by microbial fermentation can be trapped [382, 385].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [385]
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- Authors
- Ro, D.-K., Ouellet, M., Paradise, E. M., Burd, H., Eng, D., Paddon, C. J., Newman, J. D., & Keasling, J. D.
- Affiliations
- University of Calgary (CA)
- University of California, Berkeley (US)
- Amyris (United States) (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Keasling, Jay D
- Venue
- BMC Biotechnology
- Published
- 2008-11-04
- Volume
- 8
- Issue
- 1
- Pages
- 83-83
- ISSN
- 1472-6750 (ISSN-L)
- PMC
- PMC2588579
- OpenAlex
- W2112762465
- Cited by
- 197
- References
- 50
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 7 · 2017: 12 · 2016: 15 · 2015: 6 · 2014: 18 · 2013: 19 · 2012: 18
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Biotechnology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Bill and Melinda Gates Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- pleiotropic drug resistance, ABC transporters, NADPH-cytochrome P450 reductase, plasmid stability, oxidative stress response, osmotic stress response, gene expression regulation
- MeSH terms
- Polycyclic Sesquiterpenes, Animals, Antimalarials, Fermentation, Genetic Engineering, Plasmids, Prodrugs, RNA, Fungal, Saccharomyces cerevisiae, Sesquiterpenes, Gene Expression Regulation, Fungal, Genes, Plant, Point Mutation, Oxidative Stress, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Drug Resistance, Multiple, Fungal, Artemisia annua, Artemisinins
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