Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae.
Polyketides are a diverse group of natural products with significance in human and veterinary medicine. Because polyketides are structurally complex molecules and fermentation is the most commercially viable route of production, a generic heterologous host system for high-level polyketide production is desirable. Saccharomyces cerevisiae has been shown to be an excellent production host for a simple polyketide, yielding 1.7 g of 6-methylsalicylic acid per liter of culture in un-optimized shake-flask fermentations. However, a barrier to the heterologous production of more complex 'modular' polyketides in S. cerevisiae is the lack of required polyketide precursor pathways. In this work, we describe the introduction into S. cerevisiae of pathways for the production of methylmalonyl-coenzyme A (CoA), a precursor for complex polyketides, by both propionyl-CoA-dependent and propionyl-CoA-independent routes. Furthermore, we demonstrate that the methylmalonyl-CoA produced in the engineered yeast strains is used in vivo for the production of a polyketide product, a triketide lactone.
Mutka
Sarah C
SC
Kosan Biosciences, Inc., Hayward, CA 94545, USA.
Bondi
Shana M
SM
Carney
John R
JR
Da Silva
Nancy A
NA
Kealey
James T
JT
D000214:Acyl Coenzyme A / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005818:Genetic Engineering / Q000379:methods*; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D043586:Methylmalonyl-CoA Decarboxylase / Q000235:genetics / Q000378:metabolism; D048630:Polyketide Synthases / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D012486:Salmonella typhimurium / Q000201:enzymology / Q000235:genetics; D048372:Streptomyces coelicolor / Q000201:enzymology / Q000235:genetics
D000214:Acyl Coenzyme A; D018942:Macrolides; C015357:methylmalonyl-coenzyme A; C009061:propionyl-coenzyme A; D048630:Polyketide Synthases; D043586:Methylmalonyl-CoA Decarboxylase