Genome Mining\nof the Marine-Derived Fungus <i>Trichoderma erinaceum</i> F1‑1 Unearths Bergamotene-Type\nSesquiterpenoids

Terpenoids\nare a vast group of natural products known\nfor their\nremarkable biological properties and structural diversity. UbiA terpene\nsynthases are increasingly recognized for producing various terpenoids.\nIn this study, we identified a biosynthetic gene cluster (<i>bgt</i>) encoding a UbiA terpene synthase BgtA in the genome\nof the marine-derived fungus <i>Trichoderma erinaceum</i> F1-1. The gene <i>bgtA</i> was validated to encode the\nbiosynthesis of (−)-α-<i>trans</i>-bergamotene\n(<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\nof eight previously undocumented bergamotene-derived sesquiterpenoids\n(<b>2</b>–<b>9</b>). Their structures, including\nthe absolute configurations, were elucidated by a combination of spectroscopic\nanalysis, ECD spectra, chemical hydrolysis, single-crystal X-ray diffraction,\nand biosynthetic considerations. We further demonstrated that the\nproduction of these structurally intricate sesquiterpenoids in heterologous\nexpression is attributable to the concerted action of the UbiA terpene\nsynthase BgtA, the cytochrome P450 BgtC, and endogenous enzymes. This\nstudy underscores the immense biosynthetic potential of fungal UbiA\nterpene synthase gene clusters and shows genome mining is a promising\nstrategy for the discovery of novel terpenoids from fungi.