Biotechnological Production of Flavonoids: An Update on Plant Metabolic Engineering, Microbial Host Selection, and Genetically Encoded Biosensors

Flavonoids represent a diversified family of phenylpropanoid‐derived plant secondary metabolites. They are widely found in fruits, vegetables, and medicinal herbs. There has been increasing interest on flavonoids because of their proven bioactivity associated with anti‐obesity and anti‐cancer, anti‐inflammatory and anti‐diabetic activity. Low bioavailability of flavonoids is a major challenge restricting their applications. Due to safety and economic issues, plant extraction or chemical synthesis could not provide a scalable route for large‐scale production. Alternatively, reconstruction of biosynthetic gene clusters in plants and industrially relevant microbes offer significant promise for discovery and scalable synthesis of flavonoids. This review provides an update on biotechnological production of flavonoids. The recent advances on plant metabolic engineering, microbial host, and genetically encoded biosensors are summarized. Plant metabolic engineering holds the promise to improve the yield of specific flavonoids and expand the chemical space of novel flavonoids. The choice of microbial host provides the cellular chassis that could be tailored for various stereo‐ or regio‐selective chemistries that are crucial for their bioactivities. When coupled with transcriptional biosensing, genetically encoded biosensors could be welded into cellular metabolism to achieve high throughput screening or dynamic carbon flux re‐allocation to deliver efficient microbial workhorse. The convergence of these technologies will translate the vast majority of plant genetic resources into valuable flavonoids with pharmaceutical/nutraceutical values in the foreseeable future. Plant culture suffers from scalability and economics issues that cannot afford low‐cost manufacturing of flavonoids. Microbial host could be tailored for regio‐ or stereo‐selective chemistry for valuable flavonoid production. Genetically encoded biosensors are efficient tools for high throughput phenotypic screening. The convergence of these technologies will deliver efficient flavonoid‐producing microbial cell factories with improved cost‐efficiency.