Advancing Precision UDP-Glycosyltransferase Engineering: A Multilevel Strategy from Mechanism to Design

Abstract Natural glycosides are widely used in food, pharmaceutical, and cosmetic sectors. This is because glycosides exhibit crucially enhanced solubility, bioavailability, and application potential compared to their aglycones. This reaction is primarily catalyzed by uridine-diphosphate-dependent glycosyltransferases (UGTs). However, native UGTs are mainly limited by insufficient activity, narrow substrate scope, poor regioselectivity, and poor stability. Therefore, engineering efficient and robust UGT biocatalysts is essential to advancing the sustainable production of valuable glycosides. This review elaborates a systematic multilevel strategy for UGT engineering from discovery to precision design. It critically assesses these diverse engineering strategies and emerging trends while discussing their applicability and limitations for the development of advanced UGT biocatalysts.