UDP-glycosyltransferases (UGTs) for the biocatalytic production of flavonoid di-glycosides

Plants synthesize a wide diversity of flavonoid compounds, the majority of which occur in glycosylated forms. Among these, flavonoid glycosides containing a single glycosyl moiety are particularly abundant. In recent years, increasing attention has been directed toward the di-glycosylation of flavonoids, driven by the recognized biological and pharmacological significance of flavonoid di-glycosides. To date, three major classes of UDP-dependent glycosyltransferases (UGTs) have been identified and characterized according to the nature of the glycosidic linkage they form in di-glycoside products: O -glycosyltransferases (OGTs), C -glycosyltransferases (CGTs), and promiscuous O / C -glycosyltransferases. These enzymes are responsible for the formation of di- O -, di- C -, and mixed di- O / C -glycosides, respectively. UGT comparison reveals marked differences in enzyme catalytic properties, including specific activity, regioselectivity, and preference for both the flavonoid acceptor and the UDP-sugar donor substrates. Several flavonoid UGTs have been utilized for the enzymatic synthesis of di-glycosides in vitro and introduced into microbial platform strains to enable whole cell bioconversion and de novo biosynthesis. In this review, we summarize recent advances in the characterization of flavonoid UGTs, and discuss their expanding applications in the enzymatic and whole-cell synthesis of flavonoid di-glycosides. Challenges in proceeding to higher technology readiness levels of processes, suitable for biocatalytic production, are critically considered.