Metabolic Engineering of TCA Cycle for Production of Chemicals

The tricarboxylic acid (TCA) cycle has been used for decades in the microbial production of chemicals such as citrate, L-glutamate, and succinate. Maximizing yield is key for cost-competitive production. However, for most TCA cycle products, the maximum pathway yield is lower than the theoretical maximum yield (Y^E). For succinate, this was solved by creating two pathways to the product, using both branches of the TCA cycle, connected by the glyoxylate shunt (GS). A similar solution cannot be applied directly for production of compounds from the oxidative branch of the TCA cycle because irreversible reactions are involved. Here, we describe how this can be overcome and what the impact is on the yield. The TCA cycle is a source of industrially important chemicals. Current pathway yields of chemicals from the TCA cycle are below their theoretical maximum (Y^E).Y^E becomes achievable by combining the oxidative and reductive part of the TCA cycle.Metabolic engineering is required to reverse some of the thermodynamically unfeasible steps.