Abstract
Flavonoids are a structurally diverse class of natural products that have been found to have a range of beneficial activities in humans. However, the clinical utilisation of these molecules has been limited due to their low solubility, chemical stability, bioavailability and extensive intestinal metabolism in vivo. Recently, the view has been formed that site-specific modification of flavonoids by methylation and/or glycosylation, processes that occur in plants endogenously, can be used to improve and adapt their biophysical and pharmacokinetic properties. The traditional source of flavonoids and their modified forms is from plants and is limited due to the low amounts present in biomass, intrinsic to the nature of secondary metabolite biosynthesis. Access to greater amounts of flavonoids, and understanding of the impact of modifications, requires a rethink in terms of production, more specifically towards the adoption of plant biosynthetic pathways into ex planta synthesis approaches. Advances in synthetic biology and metabolic engineering, aided by protein engineering and machine learning methods, offer attractive and exciting avenues for ex planta flavonoid synthesis. This review seeks to explore the applications of synthetic biology towards the ex planta biosynthesis of flavonoids, and how the natural plant methylation and glycosylation pathways can be harnessed to produce modified flavonoids with more favourable biophysical and pharmacokinetic properties for clinical use. It is envisaged that the development of viable alternative production systems for the synthesis of flavonoids and their methylated and glycosylated forms will help facilitate their greater clinical application.
Highlights
Flavonoids are one the most abundant and broadly distributed families of biologically active plant natural products (PNP)
Flavonoids are an important natural repository for drug discovery, but ready access is limited from the low yields in plants, and their use has been further constrained by stability, bioavailability, and pharmacokinetics in vivo
Synthetic biology and metabolic engineering offer solutions to both the low availability of flavonoids in plants, and their challenging in vivo pharmacokinetic properties
Summary
Flavonoids are one the most abundant and broadly distributed families of biologically active plant natural products (PNP). These compounds are active against prostate, colorectal, breast, thyroid, lung and ovarian cancer, including others [9]. Flavonoids mediate their function in multiple ways:. It is well known that post-synthesis modifications, such as methylation, glycosylation, phosphorylation and alkylation, all impact pharmacokinetics (PK) and pharmacodynamics (PD) Plants already utilise this chemical space and these modified compounds may be the answer to the challenges facing the clinical usage of flavonoids. These modifications, which are otherwise difficult to access from traditional synthetic chemistry, can be accessed by applying synthetic biology methodologies and metabolic engineering to produce flavonoids in microorganisms
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