Thursday, August 2, 2007 - 4:00 PM
S183

Platform Technology to Produce Chiral Sesquiterpenoids Using Metabolically-Engineered Saccharomyces cerevisiae

Bryan Julien1, Joseph P. Noel2, Carolyn J. Fritz1, and Richard P. Burlingame1. (1) Allylix, Inc., A165 ASTeCC Building, University of Kentucky, Lexington, KY 40506, (2) The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037

Terpenes are a large and diverse family of natural products, assembled from branched five-carbon isoprene units and comprising many thousands of compounds.  Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are the five carbon biosynthetic precursors of all terpenes.  Successive condensation of these C5 units leads to the formation of geranyl pyrophosphate (C10), farnesyl pyrophosphate (C15), geranyl geranylpyrophosphate (C20), and higher order terpene precursors.  The extreme diversity in this chemical class presents many opportunities for the production of compounds of commercial utility.  However, terpenes are generally difficult and expensive to isolate due to their low level of production and are similarly difficult to synthesize chemically due to their chiral complexity.  To overcome these difficulties, a technology platform for the biosynthetic production of a wide variety of sesquiterpenes (C15) by fermentation of Saccharomyces cerevisiae is under development.  Exogenous sesquiterpene cyclases are introduced into proprietary yeast host strains engineered to overproduce farnesyl pyrophosphate.  When necessary, the sesquiterpene hydrocarbon products of the cyclases can be further modified, either chemically or by the introduction of additional genes to the yeast strains.  Further robustness and versatility is afforded to this platform through protein engineering, using both rational and random approaches.  Replacing active site and other amino acid residues in terpene cyclases results in enzymes with improved catalytic efficiency and modified product specificity.


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