Metabolic engineering and fermentation optimization strategies for producing organic acids of the tricarboxylic acid cycle by microbial cell factories

The organic acids of the tricarboxylic acid (TCA) pathway are important platform compounds and are widely used in many areas. The high-productivity strains and high-efficient and low-cost fermentation are required to satisfy a huge market size. The high metabolic flux of the TCA pathway endows microorganisms potential to produce high titers of these organic acids. Coupled with metabolic engineering and fermentation optimization, the titer of the organic acids has been significantly improved in recent years. Herein, we discuss and compare the recent advances in synthetic pathway engineering, cofactor engineering, transporter engineering, and fermentation optimization strategies to maximize the biosynthesis of organic acids. Such engineering strategies were mainly based on the TCA pathway and glyoxylate pathway. Furthermore, organic-acid-secretion enhancement and renewable-substrate-based fermentation are often performed to assist the biosynthesis of organic acids. Further strategies are also discussed to construct high-productivity and acid-resistant strains for industrial large-scale production.