Biotechnological advances in UDP-sugar based glycosylation of small molecules

• Systematic review about advances and perspectives for UGT mediated glycosylation
• Synthases and phosphorylases emerge as novel route for in vivo UDP-sugar generation.
• Glycorandomization fuels next generation glycosides.
• Metabolic engineering unlocks de novo production as replacement for extraction.

Glycosylation of small molecules like specialized (secondary) metabolites has a profound impact on their solubility, stability or bioactivity, making glycosides attractive compounds as food additives, therapeutics or nutraceuticals. The subsequently growing market demand has fuelled the development of various biotechnological processes, which can be divided in the in vitro (using enzymes) or in vivo (using whole cells) production of glycosides. In this context, uridine glycosyltransferases (UGTs) have emerged as promising catalysts for the regio- and stereoselective glycosylation of various small molecules, hereby using uridine diphosphate (UDP) sugars as activated glycosyldonors. This review gives an extensive overview of the recently developed in vivo production processes using UGTs and discusses the major routes towards UDP-sugar formation. Furthermore, the use of interconverting enzymes and glycorandomization is highlighted for the production of unusual or new-to-nature glycosides. Finally, the technological challenges and future trends in UDP-sugar based glycosylation are critically evaluated and summarized.