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The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin.

ABSTRACT: Background:Viriditoxin is one of the 'classical' secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown. Results:Here, a gene cluster (vdt) responsible for viriditoxin synthesis was identified, via a bioinformatics analysis of the genomes of Paecilomyces variotii and Aspergillus viridinutans that both are viriditoxin producers. The function of the eight-membered gene cluster of P. variotii was characterized by targeted gene disruptions, revealing the roles of each gene in the synthesis of this molecule and establishing its biosynthetic pathway, which includes a Baeyer-Villiger monooxygenase catalyzed reaction. Additionally, a predicted catalytically-inactive hydrolase was identified as being required for the stereoselective biosynthesis of (M)-viriditoxin. The subcellular localizations of two proteins (VdtA and VdtG) were determined by fusing these proteins to green fluorescent protein, to establish that at least two intracellular structures are involved in the compartmentalization of the synthesis steps of this metabolite. Conclusions:The predicted pathway for the synthesis of viriditoxin was established by a combination of genomics, bioinformatics, gene disruption and chemical analysis processes. Hence, this work reveals the basis for the synthesis of an understudied class of fungal secondary metabolites and provides a new model species for understanding the synthesis of biaryl compounds with a chiral axis.

SUBMITTER: Urquhart AS

PROVIDER: S-EPMC6600887 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin.

Urquhart Andrew S AS Hu Jinyu J Chooi Yit-Heng YH Idnurm Alexander A

Fungal biology and biotechnology 20190701

<h4>Background</h4>Viriditoxin is one of the 'classical' secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown.<h4>Results</h4>Here, a gene cluster (<i>vdt</i>) responsible for viriditoxin synthesis was identified, via a bioinformatics analysis of the genomes of <i>Paecilomyces variotii</i> and <i>Aspergillus viridinutans</i> that both are viriditoxin producers. The function of the eight-membered g ...[more]

PMID: 31304040

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Project description:Filamentous fungi produce numerous natural products that constitute a consistent source of potential drug leads, yet it seems that the majority of natural products are overlooked since most biosynthesis gene clusters are silent under standard cultivation conditions. Screening secondary metabolite genes of the model fungus Aspergillus nidulans, we noted a silent gene cluster on chromosome II comprising two nonribosomal peptide synthetase (NRPS) genes, inpA and inpB, flanked by a regulatory gene that we named scpR for secondary metabolism cross-pathway regulator. The induced expression of the scpR gene using the promoter of the alcohol dehydrogenase AlcA led to the transcriptional activation of both the endogenous scpR gene and the NRPS genes. Surprisingly, metabolic profiling of the supernatant of mycelia overexpressing scpR revealed the production of the polyketide asperfuranone. Through transcriptome analysis we found that another silent secondary metabolite gene cluster located on chromosome VIII coding for asperfuranone biosynthesis was specifically induced. Quantitative reverse transcription-PCR proved the transcription not only of the corresponding polyketide synthase (PKS) biosynthesis genes, afoE and afoG, but also of their activator, afoA, under alcAp-scpR-inducing conditions. To exclude the possibility that the product of the inp cluster induced the asperfuranone gene cluster, a strain carrying a deletion of the NRPS gene inpB and, in addition, the alcAp-scpR overexpression cassette was generated. In this strain, under inducing conditions, transcripts of the biosynthesis genes of both the NRPS-containing gene cluster inp and the asperfuranone gene cluster except gene inpB were detected. Moreover, the existence of the polyketide product asperfuranone indicates that the transcription factor ScpR controls the expression of the asperfuranone biosynthesis gene cluster. This expression as well as the biosynthesis of asperfuranone was abolished after the deletion of the asperfuranone activator gene afoA, indicating that ScpR binds to the afoA promoter. To the best of our knowledge, this is the first report of regulatory cross talk between two biosynthesis gene clusters located on different chromosomes.

Dataset Information

The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin.

Publications

The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin.

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