Biotechnological production of flavonoids: an update on plant metabolic engineering, microbial host selection and genetically encoded biosensors

Abstract

Flavonoids represent a diversified family of phenylpropanoid-derived plant secondary metabolites. They are widely found in fruits, vegetables and medicinal herbs and plants. There has been increasing interest on flavonoids because of their proven bioactivity associated with anti-obesity, anti-cancer, anti-inflammatory, anti-diabetic activity and the prevention of aging-related chronic conditions, such as nervous and cardiovascular disease. Low bioavailability of flavonoids is a major challenge restricting their wide applications. Due to safety and economic issues, traditional plant extraction or chemical synthesis could not provide a scalable route for large-scale production of flavonoids. 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. We summarized the recent advances on plant metabolic engineering, microbial host and genetically encoded biosensors. 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 and robust 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.