Structural and Mechanistic Insight into Terpene Synthases that Catalyze the Irregular Non-Head-to-Tail Coupling of Prenyl Substrates

Terpenoids have diverse structures and thus represent an important class of biologically active natural products. The structural diversity of terpenoids originates from the coupling of prenyl diphosphate substrates, such as isopentenyl diphosphate and dimethylallyl diphosphate. These isoprenyl diphosphates undergo canonical and sequential head-to-tail coupling catalyzed by terpene synthases, followed by modifications such as cyclization, hydroxylation, and glycosylation. In recent years, several terpene synthases that catalyze irregular non-head-to-tail couplings to afford branched terpenoids have been identified. This minireview describes structural and mechanistic insights into these unusual coupling reactions that provide a new strategy for the structural diversification of natural products.