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| Grant Number: | 5R44GM056575-03 |
| PI Name: | KEALEY, JAMES T. |
| PI Email: | kealey@kosan.com |
| PI Title: | |
| Project Title: | Metabolic Engineering of Yeast for Polyketide Production |
Abstract: DESCRIPTION (provided by applicant): 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 APPLICATION: 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.
Thesaurus Terms:
Saccharomyces cerevisiae, biosynthesis, biotherapeutic agent, fungal genetics, microorganism metabolism, polyketide synthase, protein engineering
gene expression, genetic regulation, genetic regulatory element, isomerase, methylmalonyl coA epimerase, microorganism population study, posttranslational modification, propionyl coA carboxylase, protein sequence
biotechnology, liquid chromatography mass spectrometry, molecular cloning, radiotracer, scintillation counter, transfection /expression vector, tritium
| Institution: | KOSAN BIOSCIENCES |
| 3832 BAY CENTER PL | |
| HAYWARD, CA 94545 | |
| Fiscal Year: | 2002 |
| Department: | |
| Project Start: | 01-MAY-1998 |
| Project End: | 30-APR-2004 |
| ICD: | NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES |
| IRG: | ZRG1 |