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

摘要

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 synthaseenonribosomal 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 sigmatropic 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.