IGEM:IMPERIAL/2009/JC1

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Journal Club 1

Charles & Dave

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Jay Keasling. Introduction of genes to produce artemisinin.

Concept of feedback important in metabolic engineering.

Artemesinin is an anti-malarial compound, extracted from the wormwood plant, but this process is not cheap or efficient. The biosynthetic pathway was copied into yeast.

  • Problem of cultivation of the plant to produce the product.


Metabolically engineer pathways to ultimately lead to artemisinin through a number of synthetic genes. This led to direct upregulation of certain pathways due to the increased flux through the metabolic pathways. They defined the topology of the metabolic network.
p450 was cloned and ADS was introduced, giving the alternate result required - this process was the engineering of a new function.

  • Upregulation of synthases to increase flux through pathway of interest and downregulating convertases. Push the reaction in favour of artemisinin production.


Needed to identify genes of interest. Looked for ancestral genes, using BLAST homology analyses - looking at homology between DNA sequences.

Results in increase in yield due to critical regulation at key steps. Increase yield throught the metabolic network.

Feedback inhibition - key step in regulation. Product often regulates the key steps leading to its own synthesis.

Increase the yield and decrease production costs.
Using a general theory to apply to further processes/synthesis of alternate compounds.

Criticisms:

  • Very laborious approach. Inhibition of one step can have drastic effects overall. Many factors to take into consideration.
  • Not easily reproducible - started off with a blank slate - this is not possible in all circumstances.
  • Industrial scale-up necessary to make it viable.


Relevance to SB:

  • Approach was not typical trial and error method usually applied to metabolic engineering. Used a logical approach for design.
  • Used computational modelling.