Deciphering a Distinct Biosynthetic Pathway for Meroterpenoids in Bacteria

Meroterpenoids are hybrid natural products that arise from the integration of terpenoid and non-terpenoid biosynthetic pathways. While the biosynthesis of fungal meroterpenoids typically follows a well-established sequence of prenylation, epoxidation, and cyclization, the pathways for bacterial perhydrophenanthrene meroterpenoids remain poorly understood. In this study, we report the construction of an engineered metabolic pathway in Streptomyces for the production of the bacterial meroterpenoid, atolypene A (1). Our research reveals a novel pathway wherein the structure of atolypene A is assembled through a distinct sequence of epoxidation, prenylation, and cyclization, divergent from its fungal counterparts. We demonstrate that the noncanonical class II terpene cyclase (TC) AtoE, through the E314 residue within the characteristic E314TAE motif, functions as a Brønsted acid, initiating cyclization by protonating the epoxide. Additionally, bioinformatic analysis of biosynthetic gene clusters (BGCs) that contain AtoE-like TCs supports that bacteria have the potential to produce a wide array of meroterpenoids.