Uncovering a miltiradiene biosynthetic gene cluster in the Lamiaceae reveals a dynamic evolutionary trajectory

Abstract The spatial organization of genes within plant genomes can drive evolution of specialized metabolic pathways. In this study we investigated the origin and subsequent evolution of a diterpenoid biosynthetic gene cluster (BGC) present throughout the Lamiaceae (mint) family. Terpenoids are important specialized metabolites in plants with diverse adaptive functions that enable environmental interactions, such as chemical defense. Based on core genes found in the BGCs of all species examined across the Lamiaceae, we predict a simplified version of this cluster evolved in an early Lamiaceae ancestor. The current composition of the extant BGCs highlights the dynamic nature of its evolution. We elucidate the terpene backbones generated by the Callicarpa americana BGC enzymes, including miltiradiene and the novel terpene (+)-kaurene, and show oxidization activities of BGC cytochrome P450s. Our work reveals the fluid nature of BGC assembly and the importance of genome structure in contributing to the origin of novel metabolites.