Magnesium starvation improves production of malonyl-CoA-derived metabolites in Escherichia coli

Abstract

Starvation of essential nutrients, such as nitrogen, sulfur, magnesium, and phosphorus, leads cells into stationary phase and potentially enhances target metabolite production because cells do not consume carbon for the biomass synthesis. The overall metabolic behavior changes depend on the type of nutrient starvation in Escherichia coli. In the present study, we determined the optimum nutrient starvation type for producing malonyl-CoA-derived metabolites such as 3-hydroxypropionic acid (3HP) and naringenin in E. coli. For 3HP production, high production titer (2.3 or 2.0 mM) and high specific production rate (0.14 or 0.28 mmol gCDW−1 h−1) was observed under sulfur or magnesium starvation, whereas almost no 3HP production was detected under nitrogen or phosphorus starvation. Metabolic profiling analysis revealed that the intracellular malonyl-CoA concentration was significantly increased under the 3HP producing conditions. This accumulation should contribute to the 3HP production because malonyl-CoA is a precursor of 3HP. Strong positive correlation (r = 0.95) between intracellular concentrations of ATP and malonyl-CoA indicates that the ATP level is important for malonyl-CoA synthesis due to the ATP requirement by acetyl-CoA carboxylase. For naringenin production, magnesium starvation led to the highest production titer (144 ± 15 μM) and specific productivity (127 ± 21 μmol gCDW−1). These results demonstrated that magnesium starvation is a useful approach to improve the metabolic state of strains engineered for the production of malonyl-CoA derivatives.