Flavonoids, terpenoids, and polyketide antibiotics: Role of glycosylation and biocatalytic tactics in engineering glycosylation

Flavonoids, terpenoids, and polyketides are structurally diverse secondary metabolites used widely as pharmaceuticals and nutraceuticals. Most of these molecules exist in nature as glycosides, in which sugar residues act as a decisive factor in their architectural complexity and bioactivity. Engineering glycosylation through selective trimming or extension of the sugar residues in these molecules is a prerequisite to their commercial production as well to creating novel derivatives with specialized functions. Traditional chemical glycosylation methods are tedious and can offer only limited end-product diversity. New in vitro and in vivo biocatalytic tools have emerged as outstanding platforms for engineering glycosylation in these three classes of secondary metabolites to create a large repertoire of versatile glycoprofiles. As knowledge has increased about secondary metabolite–associated promiscuous glycosyltransferases and sugar biosynthetic machinery, along with phenomenal progress in combinatorial biosynthesis, reliable industrial production of unnatural secondary metabolites has gained momentum in recent years. This review highlights the significant role of sugar residues in naturally occurring flavonoids, terpenoids, and polyketide antibiotics. General biocatalytic tools used to alter the identity and pattern of sugar molecules are described, followed by a detailed illustration of diverse strategies used in the past decade to engineer glycosylation of these valuable metabolites, exemplified with commercialized products and patents. By addressing the challenges involved in current bio catalytic methods and considering the perspectives portrayed in this review, exceptional drugs, flavors, and aromas from these small molecules could come to dominate the natural-product industry.