The Saccharomyces cerevisiae pheromone-response is a metabolically active stationary phase for bio-production

• Separating metabolic productivity from growth is highly desirable for bioprocesses.
• The Saccharomyces cerevisiae mating phenotype involves a cell cycle arrest.
• This unique phenotype was investigated for potential as a production phase.
• Gene expression capacity and central metabolic fluxes were high.
• Metabolism was more respiratory even in the presence of excess glucose.

The growth characteristics and underlying metabolism of microbial production hosts are critical to the productivity of metabolically engineered pathways. Production in parallel with growth often leads to biomass/bio-product competition for carbon. The growth arrest phenotype associated with the Saccharomyces cerevisiae pheromone-response is potentially an attractive production phase because it offers the possibility of decoupling production from population growth. However, little is known about the metabolic phenotype associated with the pheromone-response, which has not been tested for suitability as a production phase. Analysis of extracellular metabolite fluxes, available transcriptomic data, and heterologous compound production (para-hydroxybenzoic acid) demonstrate that a highly active and distinct metabolism underlies the pheromone-response. These results indicate that the pheromone-response is a suitable production phase, and that it may be useful for informing synthetic biology design principles for engineering productive stationary phase phenotypes.