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.

Quercetin and Rutin as Modifiers of Aphid Probing Behavior

“…Due to flavonoid nutritional importance, breeding attempts, conventional and involving genetic engineering, have been made to increase flavonoid levels in plants [54,56], which might influence different aspects of insect-plant interactions [26]. It is often expected that the elevated levels of secondary plant compounds in plant tissues may protect these plants against pathogens and herbivores [57].…”

Recent trends in biocatalysis

“…156 Although DBDs and linker sequences connecting them to the LBDs as well as chimeric TFs were constructed previously, 101,105,157,158 the combination of both strategies certainly points towards the expansion of the repertoire of (chimeric) biosensors for the detection of flavonoids and other natural products. 159 Thus, biosensors are a powerful tool not only for the engineering of enzymes and the set-up of HTS by monitoring the presence of metabolites in real-time; biosensor systems can time and precisely control the expression levels of pathway enzymes. 71 Most of the selected examples of biosensor applications in living cells sensed target molecules in the cytosol.…”

“… 156 Although DBDs and linker sequences connecting them to the LBDs as well as chimeric TFs were constructed previously, 101,105,157,158 the combination of both strategies certainly points towards the expansion of the repertoire of (chimeric) biosensors for the detection of flavonoids and other natural products. 159 …”

Native and non-native host assessment towards metabolic pathway reconstructions of plant natural products

“…Plant system has the upper hand over other systems in this regard, as several proteins are used in unprocessed or partially processed forms ( e.g ., recombinant vaccines in the form of edible fruits and vegetables). The transgenic plants can also be developed by introducing a set of genes or gene cluster as in the case of metabolic engineering, to increase the yield of desirable products [ 87 ]. The first report of flavonoid metabolic reconstruction in the plant was, introduction of the gene encoding dihydroquercetin 4-reductase of Maize origin into Petunia.…”