Driving force is an essential element in a successful metabolic pathway. The lack of driving force usually leads to a suboptimal performance and results in low productivities. However, excessive amounts of driving force sometimes cause accumulation of toxic intermediates, resulting in cellular growth retardation and reduction of overall titers. Therefore, a delicate balance of total flux between chemical biosynthesis and the biomass generation is necessary for constructing synthetic pathways. Photosynthetic production of 3-hydroxybutyrate (3HB) provides an efficient method for direct recycling of CO<sub>2</sub> into valuable chemicals.<br/>In this study, the introduction of an ATP driving force into the biosynthetic pathway for 3HB production in cyanobacteria successfully increased the 3HB productivity. Unexpectedly, this driving force caused excessive carbon flux entering the 3HB biosynthesis and resulted in significant growth inhibition. To solve this metabolic imbalance, we constructed a metabolic loop allowing a self-regulated flux control between 3HB biosynthesis and cellular growth. This self-regulated flux control was enabled by the co-expression of acetoacetyl-CoA synthase and thiolase. The resulting strain was able to achieve simultaneous photoautotrophic growth and 3HB biosynthesis with significant improvement in titer.

Expressing a metabolic loop enables the continuous synthesis of 3-hydroxybutyrate in cyanobacteria

253rd National Meeting (2017)

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