Optimization of mevalonate production using acetate by precursor balancing and flux redistribution in Escherichia coli

Abstract

Mevalonate is an important organic acid that can be used to synthesize bioplastics and is utilized as a key precursor for the synthesis of terpenoids and biofuels. To develop economically feasible microbial fermentation, the use of acetate, which is an inexpensive and non-edible feedstock, as the substrate is advantageous. However, a previous study that used acetate as a carbon source reported low levels of mevalonate production, which was caused by a precursor imbalance and insufficient acetyl-CoA. Mevalonate production was substantially improved by simultaneously regulating the expression levels of mvaE and mvaS to balance the precursors. Then, the excess carbon flux for cell growth was redirected to mevalonate by repressing gltA, which encodes citrate synthase, resulting in efficient production. The optimized strain produced a yield of 0.41 g mevalonate/g acetate (72% of the theoretical maximum yield). Finally, repeated feeding resulted in the highest reported mevalonate titer (7.9 g/L) among all reported studies using acetate. These results show that precise regulation of the expression levels of mvaE, mvaS, and gltA is a powerful strategy for mevalonate production. Moreover, this strategy can be widely applied to the production of mevalonate using other substrates.