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

TLDR

Malonyl‑CoA is a key donor in natural decarboxylative carbon condensation reactions, and prior metabolic engineering of malonyl‑CoA pathways has produced many value‑added compounds. The study aims to mimic native systems with a dynamic regulatory network to optimize malonyl‑CoA pathway 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, allowing the engineered cell to regulate pathway expression and compensate 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.

Abstract

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.