Improving fatty acids production by engineering dynamic pathway regulation and metabolic control

Significance One important synthetic chemistry reaction endowed by nature is the decarboxylative carbon condensation reaction using malonyl-CoA as carbon donor. Previous metabolic engineering efforts centered on the malonyl-CoA–dependent pathway have resulted in the production of many value-added compounds. Here we mimicked the native biological systems and used a dynamic regulatory network to optimize production titers and yield. The naturally existing transcriptional regulator FapR was rewired to dynamically control gene expressions involved in the supply and consumption of malonyl-CoA. Applying this metabolic control allowed the engineered cell to dynamically regulate pathway expression and compensated the metabolic activity of critical enzymes. The synthetic malonyl-CoA switch engineered in this study opens up new venues for dynamic pathway optimization and efficient production of malonyl-CoA–derived compounds.