Abstract

Three novel dimeric xanthones, cryptosporioptides A-C were isolated from Cryptosporiopsis sp. 8999 and their structures elucidated. Methylation of cryptosporioptide A gave a methyl ester with identical NMR data to cryptosporioptide, a compound previously reported to have been isolated from the same fungus. However, HRMS analysis revealed that cryptosporioptide is a symmetrical dimer, not a monomer as previously proposed, and the revised structure was elucidated by extensive NMR analysis. The genome of Cryptosporiopsis sp. 8999 was sequenced and the dimeric xanthone (dmx) biosynthetic gene cluster responsible for the production of the cryptosporioptides was identified. Gene disruption experiments identified a gene (dmxR5) encoding a cytochrome P450 oxygenase as being responsible for the dimerisation step late in the biosynthetic pathway. Disruption of dmxR5 led to the isolation of novel monomeric xanthones. Cryptosporioptide B and C feature an unusual ethylmalonate subunit: a hrPKS and acyl CoA carboxylase are responsible for its formation. Bioinformatic analysis of the genomes of several fungi producing related xanthones, e.g. the widely occurring ergochromes, and related metabolites allows detailed annotation of the biosynthetic genes, and a rational overall biosynthetic scheme for the production of fungal dimeric xanthones to be proposed.

Highlights

  • Anthraquinones and xanthones are among the most common and earliest discovered fungal secondary metabolites,[1] and they o en have interesting and useful bioactivities

  • The major metabolite (900 mg kgÀ1) had almost identical IR, UV and 1H and 13C NMR data apart from the lack of a methoxy group when compared to that reported for cryptosporioptide A 13.17 When esteri ed using TMS-diazomethane, the resulting methyl ester had identical NMR data to those reported for cryptosporioptide 12 by Saleem et al.,[17] for which the reported FAB-HRMS data was 444.0781 [M + Na]+ (C19H19NO10Na).[17]

  • All analysed clusters encode proteins with high homologies (41–76% orf for orf) to proteins known to be involved in the biosynthesis of emodin hydroquinone 26, and all BGCs except that for geodin contain genes which advance the pathway to chrysophanol 2 (Table 1)

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Summary

Introduction

Anthraquinones and xanthones are among the most common and earliest discovered fungal secondary metabolites,[1] and they o en have interesting and useful bioactivities. 8999, which produces the unusual octadride, viburspiran.[16] This strain was reported[17] to produce a metabolite named cryptosporioptide, which was assigned the monomeric xanthone methyl ester structure 12 (Fig. 2). This structure contains an unusual ring-contracted xanthone which is difficult to rationalise biosynthetically, and an unprecedented N-malonyl aminal bridge. Further studies[18] of this strain led to the isolation of the corresponding free acid, named cryptosporioptide A 13, and cryptosporioptide B 14, which lacks the malonic acid ester amide bridge

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