Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae

Area of Science:

• Biotechnology
• Synthetic Biology
• Metabolic Engineering

Background:

• Polyketides are vital natural products with significant medicinal applications.
• Saccharomyces cerevisiae is a promising host for producing simple polyketides but lacks pathways for complex ones.
• Heterologous production of complex polyketides requires specific precursor molecules like methylmalonyl-coenzyme A (CoA).

Purpose of the Study:

• To engineer Saccharomyces cerevisiae for the production of methylmalonyl-CoA, a precursor for complex polyketides.
• To establish a generic heterologous host system for high-level polyketide production.
• To demonstrate the in vivo utilization of produced methylmalonyl-CoA for polyketide synthesis.

Main Methods:

• Introduction of propionyl-CoA-dependent and propionyl-CoA-independent pathways into S. cerevisiae.
• Metabolic engineering of yeast strains to enable methylmalonyl-CoA biosynthesis.
• Fermentation and analysis of polyketide production in engineered yeast.

Main Results:

• Successfully engineered S. cerevisiae strains capable of producing methylmalonyl-CoA via two distinct routes.
• Demonstrated that the engineered yeast utilizes the produced methylmalonyl-CoA for synthesizing a polyketide product.
• Achieved in vivo production of a triketide lactone using the engineered precursor pathways.

Conclusions:

• Engineered S. cerevisiae can be a viable host for producing essential polyketide precursors.
• This work overcomes a significant barrier to heterologous production of complex polyketides.
• The developed system holds potential for efficient and scalable biosynthesis of valuable natural products.