Abstract

Microbial cell factories offer an economic and environmentally friendly method for the biosynthesis of acetyl-CoA-derived chemicals. However, the static control of carbon flux can cause direct and indirect competition for acetyl-CoA between cell growth and chemical biosynthesis, limiting the efficiency of microbial cell factories. Herein, recombinase-based genetic circuits were developed to achieve the optimal distribution of acetyl-CoA between cell growth and butyrate biosynthesis. First, three dynamic devices-a turn-on switch, a turn-off switch, and a recombinase-based inverter (RBI)-were constructed based on Bxb1 recombinase. Then, the turn-on switch was used to dynamically control the butyrate biosynthetic pathway, which directly improved the consumption of acetyl-CoA. Next, the turn-off switch was applied to dynamically control cell growth, which indirectly enhanced the supply of acetyl-CoA. Finally, an RBI was adopted for the dynamic dual control of the distribution of acetyl-CoA between cell growth and butyrate biosynthesis. The final butyrate production rate was increased to 34 g/L, with a productivity of 0.405 g/L/h. The strategy described herein will pave the way for the development of high-performance microbial cell factories for the production of other desirable chemicals. KEY POINTS: • Competition for acetyl-CoA between cell growth and synthesis limits productivity. • Recombinase-based genetic circuits were developed to dynamic control of acetyl-CoA. • Optimal distribution of acetyl-CoA between cell growth and synthesis was achieved.

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