Contents lists available at ScienceDirect Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv Research review paper Flavonoids, terpenoids, and polyketide antibiotics: Role of glycosylation and biocatalytic tactics in engineering glycosylation Ushasree Mrudulakumari Vasudevan, Eun Yeol Lee ⁎ Department of Chemical Engineering, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Republic of Korea ARTICLEINFO Keywords: Biocatalysis Glycosyltransferase Glycosylation Glycodiversifcation Deglycosylation Flavonoid Terpenoid Polyketide antibiotic ABSTRACT Flavonoids, terpenoids, and polyketides are structurally diverse secondary metabolites used widely as phar- maceuticals 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 ofer 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 glycoprofles. As knowledge has increased about secondary metabolite–associated promiscuous glycosyltransferases and sugar biosynthetic machinery, along with phenomenal progress in com- binatorial biosynthesis, reliable industrial production of unnatural secondary metabolites has gained momentum in recent years. This review highlights the signifcant role of sugar residues in naturally occurring favonoids, 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, exemplifed 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, favors, and aromas from these small molecules could come to dominate the natural-product industry. 1. Introduction Secondary metabolic pathways in plants and microbes generate a plethora of small molecules with broad bioactivity. Flavonoids, terpe- noids, and polyketide antibiotics are important groups of secondary metabolites with multiple industrially desirable characteristics (Singh et al., 2018; Vickery et al., 2016). Flavonoids are polyphenolic phyto- nutrients with a common 15-carbon skeleton and are recognized for their health benefts (Kumar and Pandey, 2013; Panche et al., 2016). Terpenoids are the largest group of secondary metabolites and exist ubiquitously in plants. Members of this group are derived from fve carbon precursor isoprenoids and are indispensable components in food, drugs, and cosmetics (Lange et al., 2000). Polyketide-based an- tibiotics are predominant drug leads derived mainly from actinomycetes, in which they are synthesized by a specialized enzyme complex, the polyketide synthases. Interestingly, a high proportion of these three groups of secondary metabolites occur as glycosides, with a sugar attached to their core scafolds (Fig. 1). In some instances, the sugar moiety is crucial to their activity, and in other cases it improves their bioactivity, stability, and solubility. In secondary metabolites with clinical relevance, in addition to enabling efective drug targeting and improving pharmacokinetic properties, the distinctiveness of the sugar moiety can defne the precise mechanism of action (Xiao, 2017; Xiao et al., 2016). Natural-product discovery programs have already introduced nu- merous glycosylated favonoids, terpenoids and polyketides as ther- apeutics, fragrances, favors, nutrients, repellants, and colorants. Nevertheless, broad application of these natural glycosides is limited by https://doi.org/10.1016/j.biotechadv.2020.107550 Received 28 January 2020; Received in revised form 19 April 2020; Accepted 24 April 2020 Abbreviations: CAZy, Carbohydrate-Active enZymes; 6dEB, 6-deoxyerythronolide B; dTKDG, Thymidine diphosphate 4-keto-4, 6-dideoxy-D-glucose; dTDP, deox- ythymidine diphosphate; GH, Glycosyl hydrolases; GT, Glycosyltransferases; 8-OHDe, 8-Hydroxydaidzein; LC, Liquid chromatography; MS, Mass spectrometry; NDP- sugar, Nucleotide diphospho-sugar; NMR, Nuclear magnetic resonance spectroscopy; PKS, Polyketide synthases; UDP, Uridine-diphosphate; UGT, UDP-dependent glycosyltransferase ⁎ Corresponding author. E-mail address: eunylee@khu.ac.kr (E.Y. Lee). Biotechnology Advances 41 (2020) 107550 Available online 01 May 2020 0734-9750/ © 2020 Elsevier Inc. All rights reserved. T