Publication Date:
2016-09-29
Description:
Rewriting yeast central carbon metabolism for industrial isoprenoid production Nature 537, 7622 (2016). doi:10.1038/nature19769 Authors: Adam L. Meadows, Kristy M. Hawkins, Yoseph Tsegaye, Eugene Antipov, Youngnyun Kim, Lauren Raetz, Robert H. Dahl, Anna Tai, Tina Mahatdejkul-Meadows, Lan Xu, Lishan Zhao, Madhukar S. Dasika, Abhishek Murarka, Jacob Lenihan, Diana Eng, Joshua S. Leng, Chi-Li Liu, Jared W. Wenger, Hanxiao Jiang, Lily Chao, Patrick Westfall, Jefferson Lai, Savita Ganesan, Peter Jackson, Robert Mans, Darren Platt, Christopher D. Reeves, Poonam R. Saija, Gale Wichmann, Victor F. Holmes, Kirsten Benjamin, Paul W. Hill, Timothy S. Gardner & Annie E. Tsong A bio-based economy has the potential to provide sustainable substitutes for petroleum-based products and new chemical building blocks for advanced materials. We previously engineered Saccharomyces cerevisiae for industrial production of the isoprenoid artemisinic acid for use in antimalarial treatments. Adapting these strains for biosynthesis of other isoprenoids such as β-farnesene (C15H24), a plant sesquiterpene with versatile industrial applications, is straightforward. However, S. cerevisiae uses a chemically inefficient pathway for isoprenoid biosynthesis, resulting in yield and productivity limitations incompatible with commodity-scale production. Here we use four non-native metabolic reactions to rewire central carbon metabolism in S. cerevisiae, enabling biosynthesis of cytosolic acetyl coenzyme A (acetyl-CoA, the two-carbon isoprenoid precursor) with a reduced ATP requirement, reduced loss of carbon to CO2-emitting reactions, and improved pathway redox balance. We show that strains with rewired central metabolism can devote an identical quantity of sugar to farnesene production as control strains, yet produce 25% more farnesene with that sugar while requiring 75% less oxygen. These changes lower feedstock costs and dramatically increase productivity in industrial fermentations which are by necessity oxygen-constrained. Despite altering key regulatory nodes, engineered strains grow robustly under taxing industrial conditions, maintaining stable yield for two weeks in broth that reaches 〉15% farnesene by volume. This illustrates that rewiring yeast central metabolism is a viable strategy for cost-effective, large-scale production of acetyl-CoA-derived molecules.
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
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Chemistry and Pharmacology
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Medicine
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Natural Sciences in General
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Physics
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