Glycosylated cannabinoids in Cannabis sativa and enzyme design to modulate their synthesis

Abstract Cannabinoids are the primary active compounds in Cannabis sativa and hold significant medical potential. However, their high lipophilicity limits bioavailability, an issue which can be resolved by promiscuous glycosylation. Here, we reveal glycosylation as a natural modification occurring in the Cannabis plant. We detected glycosylated cannabinoids and intermediates and identified native glycosyltransferases involved in this process. Using merely computational structure prediction tools, we engineered enzyme mutant variants with enhanced activity, altered isomer production, and selectivity toward cannabinoids, without relying