Tricarbocyclic core formation of tyrosine-decahydrofluorenes implies a three-enzyme cascade with XenF-mediated sigmatropic rearrangement as a prerequisite

Tyrosine-decahydrofluorene derivatives feature a fused [6.5.6] tricarbocyclic core and a 13 membered para-cyclophane ether. Herein, we identified new xenoacremones A, B, and C (1-3) from the fungal strain Xenoacremonium sinensis ML-31 and elucidated their biosynthetic pathway using gene deletion in the native strain and heterologous expression in Aspergillus nidulans. The hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) XenE together with enoyl reductase XenG were confirmed to be responsible for the formation of the tyrosine-nonaketide skeleton. This skeleton was subsequently dehydrated by XenA to afford a pyrrolidinone moiety. XenF catalyzed a novel sigma tropic rearrangement to yield a key cyclohexane intermediate as a prerequisite for the formation of the multi-ring system. Subsequent oxidation catalyzed by XenD supplied the substrate for XenC to link the para-cyclophane ether, which underwent subsequent spontaneous Diels-Alder reaction to give the end products. Thus, the results indicated that three novel enzymes XenF, XenD, and XenC coordinate to assemble the [6.5.6] tricarbocyclic ring and para-cyclophane ether during biosynthesis of complex tyrosine-decahydrofluorene derivatives. 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Three new xenoacremones, A, B, and C, were identified from the fungal strain Xenoacremonium sinensis ML-31, with their biosynthetic pathway elucidated through gene deletion and heterologous expression. Three novel enzymes, XenF, XenD, and XenC, were found to coordinate in assembling the [6.5.6] tricarbocyclic ring and para-cyclophane ether in the biosynthesis of complex tyrosine-decahydrofluorene derivatives.