Production of the antimalarial drug precursor artemisinic acid in engineered yeast

  title={Production of the antimalarial drug precursor artemisinic acid in engineered yeast},
  author={Dae-Kyun Ro and Eric M. Paradise and Mario Ouellet and Karl Fisher and Karyn L. Newman and John M Ndungu and Kimberly A. Ho and Rachel Eachus and Timothy S. Ham and James E Kirby and Michelle C. Y. Chang and Sydnor T. Withers and Y Shiba and Richmond Sarpong and Jay D. Keasling},
Malaria is a global health problem that threatens 300–500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae… 

Continuous-flow synthesis of the anti-malaria drug artemisinin.

Combined with the production of artemisinic acid in engineered yeast, access to the muchneeded malaria drug is now possible by semi-synthesis rather than isolation from plants, ensuring a steady supply of art Artemisinin at greatly reduced cost.

Infectious diseases: New routes to antimalarials?

  • S. Barton
  • Biology, Chemistry
    Nature Reviews Drug Discovery
  • 2006
The genetic engineering of Saccharomyces cerevisiae is described to potentially provide a more facile, cheaper route to artemisinin from the precursor artemisinic acid, which has implications for the development of more affordable treatments for malaria.

High-level semi-synthetic production of the potent antimalarial artemisinin

The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of art Artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs.

Generation of the potent anti-malarial drug artemisinin in tobacco

The metabolic engineering of tobacco to produce artemisinin is reported, generating transgenic plants that express five plantand yeast-derived genes involved in the mevalonate and art Artemisinin pathways, all expressed from a single vector, demonstrating that artemis inin can be fully biosynthesized in a heterologous plant system, such as tobacco.

Building a golden triangle for the production and use of artemisinin derivatives against falciparum malaria in Africa

The key genes encoding for enzymes regulating the biosynthesis of artemisinin in planta are fully understood to enable metabolic engineering of the pathway, and results from pilot genetic engineering studies in microbial strains thus far are very inspiring.

Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid

The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses, and the use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisic acid production in the genetically engineered yeast.

Recent Advances to Enhance Yield of Artemisinin: A Novel Antimalarial Compound, in Artemisia annua L. Plants

Non-conventional approaches have to be developed to evolve novel strains of the plant to optimize and scale up the production of artemisinin in bulk and make it available to ACT manufacturers at a price much lower than their current cost in turn making an important contribution toward attaining the goals of global malaria eradication programs.

Malaria and artemisinin derivatives: an updated review.

In this review, drugs of choice about malaria i.e. artemisinin and its analogus/derivatives have been discussed in detail e.g. bioavailability, formulation development, stability, combination therapy, additional benefits, drug resistance and toxicity have been reviewed.

Enhancing artemisinin content in and delivery from Artemisia annua: a review of alternative, classical, and transgenic approaches

This review analyses the most recent scientific research conducted for the purpose of enhancing artemisinin production to develop better art Artemisinin enhancement strategies which lead to decreased price of ACTs and increased profit to farmers.

Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin

Progress is described toward the goal of developing a supply of semisynthetic artemisinin based on production of the art Artemisinin precursor amorpha-4,11-diene by fermentation from engineered Saccharomyces cerevisiae, and its chemical conversion to dihydroartemisinic acid, which can be subsequently converted to artemis inin.



Identification of an antimalarial synthetic trioxolane drug development candidate

Here it is described how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Engineering a mevalonate pathway in Escherichia coli for production of terpenoids

The strains developed in this study can serve as platform hosts for the production of any terpenoid compound for which a terpene synthase gene is available, and are the universal precursors to all isoprenoids.

Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua.

It is hypothesised that the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation toArtemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinicAldehyde and oxidation to diHydroart Artemisinic acid.

Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L.

A cDNA clone is isolated encoding a putative key enzyme of artemisinin biosynthesis, amorpha-4,11-diene synthase, which has a broad pH optimum between 7.5 and 9.0 and the Km values for farnesyl diphosphate, Mg2+, and Mn2+ are 0.9, 70, and 13 microM, respectively, at pH7.5.

Suppression of a P450 hydroxylase gene in plant trichome glands enhances natural-product-based aphid resistance

The results demonstrate the feasibility of significantly modifying the natural-product chemical composition and aphid-interactive properties of gland exudates using metabolic engineering and have implications for molecular farming.

Malaria disaster in Africa

Cloning, heterologous expression, and functional characterization of 5-epi-aristolochene-1,3-dihydroxylase from tobacco (Nicotiana tabacum).

An in vivo assay for 5-epi-aristolochene hydroxylase activity was developed and used to demonstrate a dose-dependent inhibition of activity by ancymidol and ketoconazole, two well characterized inhibitors of cytochrome P450 enzymes.

Sesquiterpene lactones as taxonomic characters in the asteraceae

The tribal, subtribal and generic distribution of sesquiterpene lactones is examined, the compounds’ utility as taxonomic characters discussed and the biogenetically based methodology shows the efficacy of this analytical methodology.

The CYP88A cytochrome P450, ent-kaurenoic acid oxidase, catalyzes three steps of the gibberellin biosynthesis pathway.

Yeast strains expressing cDNAs encoding each of the two Arabidopsis and the barley CYP88A enzymes catalyze the three steps of the GA biosynthesis pathway from ent-kaurenoic acid to GA(12).