Systems metabolic engineering of microorganisms to achieve large-scale production of flavonoid scaffolds

Flavonoids possess pharmaceutical potential due to their health-promoting activities. The complex structures of these products make extraction from plants difficult, and chemical synthesis is limited because of the use of many toxic solvents. Microbial production offers an alternate way to produce these compounds on an industrial scale in a more economical and environment-friendly manner. However, at present microbial production has been achieved only on a laboratory scale and improvements and scale-up of these processes remain challenging. Naringenin and pinocembrin, which are flavonoid scaffolds and precursors for most of the flavonoids, are the model molecules that are key to solving the current issues restricting industrial production of these chemicals. The emergence of systems metabolic engineering, which combines systems biology with synthetic biology and evolutionary engineering at the systems level, offers new perspectives on strain and process optimization. In this review, current challenges in large-scale fermentation processes involving flavonoid scaffolds and the strategies and tools of systems metabolic engineering used to overcome these challenges are summarized. This will offer insights into overcoming the limitations and challenges of large-scale microbial production of these important pharmaceutical compounds.