Genome Mining of the Marine-Derived Fungus <i>Trichoderma erinaceum</i> F1-1 Unearths Bergamotene-Type Sesquiterpenoids

Terpenoids are a vast group of natural products known for their remarkable biological properties and structural diversity. UbiA terpene synthases are increasingly recognized for producing various terpenoids. In this study, we identified a biosynthetic gene cluster (<i>bgt</i>) encoding a UbiA terpene synthase BgtA in the genome of the marine-derived fungus <i>Trichoderma erinaceum</i> F1-1. The gene <i>bgtA</i> was validated to encode the biosynthesis of (-)-α-<i>trans</i>-bergamotene (<b>1</b>). Heterologous expression of the <i>bgt</i> gene cluster in the characterized host <i>Aspergillus nidulans</i> LO8030 activated the biosynthetic pathway, leading to the isolation of eight previously undocumented bergamotene-derived sesquiterpenoids (<b>2</b>-<b>9</b>). Their structures, including the absolute configurations, were elucidated by a combination of spectroscopic analysis, ECD spectra, chemical hydrolysis, single-crystal X-ray diffraction, and biosynthetic considerations. We further demonstrated that the production of these structurally intricate sesquiterpenoids in heterologous expression is attributable to the concerted action of the UbiA terpene synthase BgtA, the cytochrome P450 BgtC, and endogenous enzymes. This study underscores the immense biosynthetic potential of fungal UbiA terpene synthase gene clusters and shows genome mining is a promising strategy for the discovery of novel terpenoids from fungi.