Parallel evolution of UbiA superfamily proteins into aromatic O-prenyltransferases in plants

Significance Plants produce approximately 300 O-prenylated aromatics, with their O-prenyl moieties often being crucial to their bioactivities. This study identified a gene from grapefruit encoding an aromatic O-prenyltransferase (O-PT) belonging to the UbiA superfamily. The O-PT was shown responsible for the biosynthesis of pharmaceutically active O-prenylated coumarins that cause grapefruit–drug interactions, an adverse effect disturbing the pharmacokinetics of more than 85 medications. Another UbiA O-PT for coumarins was isolated from Angelica keiskei, an apiaceous medicinal plant. Phylogenetic analysis of the rutaceous and apiaceous O-PTs suggested that aromatic O-prenylation activity emerged in parallel in these distant plant taxa. The molecular evolution of aromatic O-PTs from plant UbiA proteins may aid citrus breeding and a synthetic biology approach to bioactive O-prenylated coumarins. Plants produce ∼300 aromatic compounds enzymatically linked to prenyl side chains via C–O bonds. These O-prenylated aromatic compounds have been found in taxonomically distant plant taxa, with some of them being beneficial or detrimental to human health. Although their O-prenyl moieties often play crucial roles in the biological activities of these compounds, no plant gene encoding an aromatic O-prenyltransferase (O-PT) has been isolated to date. This study describes the isolation of an aromatic O-PT gene, CpPT1, belonging to the UbiA superfamily, from grapefruit (Citrus × paradisi, Rutaceae). This gene was shown responsible for the biosynthesis of O-prenylated coumarin derivatives that alter drug pharmacokinetics in the human body. Another coumarin O-PT gene encoding a protein of the same family was identified in Angelica keiskei, an apiaceous medicinal plant containing pharmaceutically active O-prenylated coumarins. Phylogenetic analysis of these O-PTs suggested that aromatic O-prenylation activity evolved independently from the same ancestral gene in these distant plant taxa. These findings shed light on understanding the evolution of plant secondary (specialized) metabolites via the UbiA superfamily.