Commercial production of microbially-derived complex anabolic compounds has previously been confined to the pharmaceutical or specialty chemical industries, in part because the energetic costs of biosynthesis translate to high production costs. Here, we design and implement an alternative carbon metabolism in Saccharomyces cerevisiae that reduces the metabolic cost of converting glucose to farnesyl pyrophosphate (FPP), the universal precursor for all sesquiterpene isoprenoids. By partitioning glucose catabolism through parallel heterologous routes and by altering the cofactor requirements of FPP biosynthesis, we dramatically improve internal pathway balance, reducing reliance on CO2-emitting and oxygen-consuming side-reactions required to maintain redox homeostasis and energy charge. The result is a 20% improvement in the maximum theoretical g/g yield of farnesene (an FPP derivative) from glucose, and a 170% improvement in the maximum theoretical molar yield of farnesene from oxygen. We transplant this synthetic metabolic network into a strain of S. cerevisiae that was previously engineered for commercial-scale production of farnesene, a commercially important molecule whose derivatives can be used in a wide variety of applications ranging from biofuels to novel performance materials. In this strain background, we observe an 80% increase in the molar yield of farnesene from oxygen, which translates directly to an 80% increase in the volume of farnesene that can be produced per unit time under industrial oxygen-limited conditions.

Reinventing central carbon metabolism in Saccharomyces cerevisiae for high-volume biofuel production

249th National Meeting (2015)

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