Reprogramming flavonoid glycosylation by bridging advanced biocatalysis and systems synthetic biology.

Abstract

Flavonoid glycosides exhibit profound pharmacological and nutritional value, yet their industrial-scale acquisition is severely hampered by low abundance in plant extracts and the stereochemical complexity of chemical synthesis. Synthetic biology offers a sustainable alternative, while the deployment of natural plant uridine diphosphate-dependent glycosyltransferases (UGTs) is intrinsically bottlenecked by low catalytic efficiency, poor stability, and severe intracellular metabolic competition. This review systematically explores the paradigm shifts in the biomanufacturing of these complex molecules, highlighting how the methodological evolution in UGT discovery has evolved from traditional sequence homology to multi-omics and AI-driven predictive models. Multidimensional engineering of UGTs spanning from active-site remodeling to distal allosteric regulation and computational-design is elucidated to precisely manipulate catalytic efficacy, enzyme stability, substrate promiscuity, and catalytic regioselectivity. Bridging the gap between optimized biocatalysts and robust microbial cell factories requires critical systems metabolic engineering strategies, including the rewiring of intracellular UDP-sugar flux, the elimination of catabolic sinks, and the deployment of spatiotemporally decoupled microbial consortia. Cell-free synthesis cascades offer a highly controllable alternative to circumvent in vivo physiological constraints. A strategic roadmap for future research emphasizes AI-driven de novo enzyme design, autonomous single-cell dynamic regulation, and the valorization of lignocellulosic biomass to achieve unprecedented atom economy. Ultimately, this integrated framework provides a scalable, multidimensional blueprint for the sustainable and green biomanufacturing of high-value flavonoid glycosides.

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