Catalytic mechanism and engineering of aromatic prenyltransferase: A review

The prenylation of aromatic compounds significantly enhances their metabolic stability and bioactivity. Prenyltransferases, as essential biocatalysts, facilitate the regioselective transfer of prenyl groups from donors to aromatic substrates. This review systematically summarizes recent progress in the rational engineering of prenyltransferases through protein-based strategies, critically evaluates current challenges, and outlines future research priorities. Firstly, we delineate the biosynthetic pathways of prenylated phenolic compounds, emphasizing the pivotal roles of prenyltransferases, and classify these enzymes according to the structural diversity of their aromatic acceptor molecules. Secondly, the current state of prenyltransferase biosynthesis by comparing their heterologous expression levels across diverse microbial hosts is discussed, highlighting key factors influencing catalytic efficiency. Furthermore, we dissect the molecular mechanisms governing prenyltransferase activity and propose innovative engineering approaches integrating artificial intelligence and deep learning to develop high-performance biocatalysts for industrial applications. Finally, we address unresolved challenges in this field, including suboptimal catalytic activity, narrow substrate specificity, and limitations in multi-enzyme cascade systems and immobilization techniques. This review offers strategic insights to guide the engineering and scalable application of prenyltransferases in synthetic biology and pharmaceutical innovation.