Metabolic rewiring of synthetic pyruvate dehydrogenase bypasses for acetone production in cyanobacteria

Designing synthetic pathways for efficient CO₂ fixation and conversion is essential for sustainable chemical production. Here we have designed a synthetic acetate-acetyl-CoA/malonyl-CoA (AAM) bypass to overcome an enzymatic activity of pyruvate dehydrogenase complex. This synthetic pathway utilizes acetate assimilation and carbon rearrangements using a methyl malonyl-CoA carboxyltransferase. We demonstrated direct conversion of CO₂ into acetyl-CoA-derived acetone as an example in photosynthetic Synechococcus elongatus PCC 7942 by increasing the acetyl-CoA pools. The engineered cyanobacterial strain with the AAM-bypass produced 0.41 g/L of acetone at 0.71 m/day of molar productivity. This work clearly shows that the synthetic pyruvate dehydrogenase bypass (AAM-bypass) is a key factor for the high-level production of an acetyl-CoA-derived chemical in photosynthetic organisms.