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Metab Eng. 2007 Mar;9(2):160-8. Epub 2006 Nov 17.

Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids.

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Berkeley Center for Synthetic Biology, Department of Chemical Engineering, University of California, 717 Potter Street, Building 977, Mail code 3224, Berkeley, CA 94720-3224, USA.


Amorphadiene, a sesquiterpene precursor to the anti-malarial drug artemisinin, is synthesized by the cyclization of farnesyl pyrophosphate (FPP). Saccharomyces cerevisiae produces FPP through the mevalonate pathway using acetyl-CoA as a starting compound. In order to enhance the supply of acetyl-CoA to the mevalonate pathway and achieve high-level production of amorphadiene, we engineered the pyruvate dehydrogenase bypass in S. cerevisiae. Overproduction of acetaldehyde dehydrogenase and introduction of a Salmonella enterica acetyl-CoA synthetase variant increased the carbon flux into the mevalonate pathway resulting in increased amorphadiene production. This work will be generally applicable to the production of a broad range of isoprenoids in yeast.

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