Abstract
As a result of the discovery that flavonoids are directly or indirectly connected to health, flavonoid metabolism and its fascinating molecules that are natural products in plants, have attracted the attention of both the industry and researchers involved in plant science, nutrition, bio/chemistry, chemical bioengineering, pharmacy, medicine, etc. Subsequently, in the past few years, flavonoids became a top story in the pharmaceutical industry, which is continually seeking novel ways to produce safe and efficient drugs. Microbial cell cultures can act as workhorse bio-factories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a selective flavonoid. Furthermore, metabolic engineering methodology is used to reinforce what nature does best by correcting the inadequacies and dead-ends of a metabolic pathway. Combinatorial biosynthesis techniques led to the discovery of novel ways of producing natural and even unnatural plant flavonoids, while, in addition, metabolic engineering provided the industry with the opportunity to invest in synthetic biology in order to overcome the currently existing restricted diversification and productivity issues in synthetic chemistry protocols. In this review, is presented an update on the rationalized approaches to the production of natural or unnatural flavonoids through biotechnology, analyzing the significance of combinatorial biosynthesis of agricultural/pharmaceutical compounds produced in heterologous organisms. Also mentioned are strategies and achievements that have so far thrived in the area of synthetic biology, with an emphasis on metabolic engineering targeting the cellular optimization of microorganisms and plants that produce flavonoids, while stressing the advances in flux dynamic control and optimization. Finally, the involvement of the rapidly increasing numbers of assembled genomes that contribute to the gene- or pathway-mining in order to identify the gene(s) responsible for producing species-specific secondary metabolites is also considered herein.
Highlights
Flavonoids are known to be produced by all terrestrial plants
We review the current metabolic engineering approaches to achieving exploitable concentrations of natural flavonoid compounds in microorganisms, with potential application in the industry
We introduce several research efforts that aim to produce unnatural flavonoid analogs using in vivo approaches
Summary
Flavonoids are known to be produced by all terrestrial plants. They comprise a large group of natural compounds deriving from the phenylpropanoid metabolism, which has evolved in plants to produce a large number of inter-related flavonoid structures (Figure 1). The addition of a coenzyme A group to those hydroxycinnamic acids activates those molecules for the subsequent enzymatic decarboxylation and condensation with three activated malonyl-CoA molecules. This reaction is catalyzed by a polyketide III synthase (Chalcone Synthase, CHS) to create chalcones, the actual precursor molecules of the flavonoid backbone.These are converted to flavanones through the use of a Chalcone Isomerase (CHI) (Andersen and Markham, 2006). Flavonoids seemed to function as internal regulatory agents (Stafford, 1991), while in later evolutionary stages, they functioned as filters against ultraviolet irradiation (Stapleton and Walbot, 1994) Such flavonoid producing organisms, with either www.frontiersin.org
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