The polyketides are a diverse group of natural products with great clinical importance. A major barrier to the high level production of both natural and genetically engineered polyketides has been the lack of a generic heterologous system that (a) functionally expresses the polyketide synthase and accessory enzymes and (b) contains adequate levels of acyl-Coenzyme A substrates. The long term goal of this project is to construct strains of Saccharomyces cerevisiae optimized for polyketide overproduction. In Phase I, we showed that a fungal polyketide could be produced at extremely high levels in S. cerevisiae. We also demonstrated that the three genes for the polyketide precursor of erythromycin could be functionally expressed from separate plasmids in a heterologous Streptomyces host. In Phase II of the project we will: (a) Develop yeast host strains that (i) produce substrates and post-translational enzymes necessary to produce modular polyketides; (ii) have necessary nutritional deficiencies to allow positive selection of at least three compatible plasmids; and (iii) will permit radioactive labeling of -CoA pools and polyketide synthases. (b) Demonstrate that such a strain can express a modular polyketide synthase and produce a complex polyketide at levels suitable for commercial development.

Proposed Commercial Applications

A generic overproducing yeast strain will enable production of commercially valuable polyketides with significant cost and time savings over existing native host organisms and production methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44GM056575-02
Application #
6338171
Study Section
Special Emphasis Panel (ZRG1-SSS-K (10))
Program Officer
Jones, Warren
Project Start
1998-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$375,000
Indirect Cost
Name
Kosan Biosciences, Inc.
Department
Type
DUNS #
932981319
City
Hayward
State
CA
Country
United States
Zip Code
94545