Synthetic Biology of Prenylated Stilbenoids: Biosynthetic Pathway, Prenyltransferases, and Biomanufacturing Strategies.

Abstract

Prenylated stilbenoids are valuable nutraceutical candidates found in dietary plants. Compared to their nonprenylated counterparts, they often exhibit enhanced bioactivities, which are attributed to the increased lipophilicity conferred by the prenyl groups, facilitating their partitioning into cell membranes and interaction with lipid-associated targets. This review systematically examines prenylated stilbenoid biosynthesis via three core aspects: the structural diversity and structure-activity relationships of prenylated stilbenoids, focusing on how prenyl chain length, linkage, and substitution position modulate bioactivities; catalytic mechanisms and regioselectivity of prenyltransferases that transfer from prenyl donors to stilbenoid backbones; and metabolic engineering strategies for microbial heterologous production, emphasizing precursor flux optimization, enzyme and host engineering such as peroxisomal compartmentalization, and strain mating. Finally, we outline key challenges─poor prenyltransferase expression, precursor competition, and product cytotoxicity─and discuss future AI-guided enzyme engineering and autonomous dynamic control systems, providing a roadmap for the sustainable industrial production of these high-value nutraceuticals.