Assembly of Melleolide Antibiotics Involves a Polyketide Synthase with Cross-Coupling Activity

Lackner, Gerald; Bohnert, Markus; Wick, Jonas; Hoffmeister, Dirk

doi:10.1016/j.chembiol.2013.07.009

Cited by 70 publications

(77 citation statements)

References 31 publications

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“…The latter is further oxidized to terrein by monooxygenase and multicopper oxidase (23). The OA produced by PKS ArmB is esterified to a diverse class of sesquiterpene alcohols in the plant pathogen Armillaria mellea (32). It is noteworthy that the closely related PKSs containing an additional methyltransferase domain form 3-methyl or 3,5-dimethyl OA (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 99%

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

Peng

Shang

Cen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

194

176

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Quinones are widely distributed in nature and exhibit diverse biological or pharmacological activities; however, their biosynthetic machineries are largely unknown. The bibenzoquinone oosporein was first identified from the ascomycete insect pathogen Beauveria bassiana >50 y ago. The toxin can also be produced by different plant pathogenic and endophytic fungi with an array of biological activities. Here, we report the oosporein biosynthetic machinery in fungi, a polyketide synthase (PKS) pathway including seven genes for quinone biosynthesis. The PKS oosporein synthase 1 (OpS1) produces orsellinic acid that is hydroxylated to benzenetriol by the hydroxylase OpS4. The intermediate is oxidized either nonenzymatically to 5,5′-dideoxy-oosporein or enzymatically to benzenetetrol by the putative dioxygenase OpS7. The latter is further dimerized to oosporein by the catalase OpS5. The transcription factor OpS3 regulates intrapathway gene expression. Insect bioassays revealed that oosporein is required for fungal virulence and acts by evading host immunity to facilitate fungal multiplication in insects. These results contribute to the known mechanisms of quinone biosynthesis and the understanding of small molecules deployed by fungi that interact with their hosts.

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Section: Discussionmentioning

confidence: 99%

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

Peng

Shang

Cen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

194

176

View full text Add to dashboard Cite

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“…A similar convergent evolution of bacterial and fungal type I PKSs has previously been observed in orsellinic acid biosynthesis. While the fungal orsellinic acid synthases are typical fungal nonreducing PKSs (41)(42)(43), the bacterial orsellinic acid synthases are related to bacterial iterative type I PKSs (homologous to fungal PR-PKSs) and are likely to have evolved from ancestral bacterial 6MSASs via mutations in the KR domain (44)(45)(46). From a protein engineering perspective, the convergent evolution of MLNSs implies that there is more than one way in nature to modify the chain length specificity and ketoreduction regioselectivity of iterative PKSs.…”

Section: Discussionmentioning

confidence: 99%

An In Planta -Expressed Polyketide Synthase Produces ( R )-Mellein in the Wheat Pathogen Parastagonospora nodorum

Chooi

Krill

Barrow

et al. 2015

Appl Environ Microbiol

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dParastagonospora nodorum is a pathogen of wheat that affects yields globally. Previous transcriptional analysis identified a partially reducing polyketide synthase (PR-PKS) gene, SNOG_00477 (SN477), in P. nodorum that is highly upregulated during infection of wheat leaves. Disruption of the corresponding SN477 gene resulted in the loss of production of two compounds, which we identified as (R)-mellein and (R)-O-methylmellein. Using a Saccharomyces cerevisiae yeast heterologous expression system, we successfully demonstrated that SN477 is the only enzyme required for the production of (R)-mellein. This is the first identification of a fungal PKS that is responsible for the synthesis of (R)-mellein. The P. nodorum ⌬SN477 mutant did not show any significant difference from the wild-type strain in its virulence against wheat. However, (R)-mellein at 200 g/ml inhibited the germination of wheat (Triticum aestivum) and barrel medic (Medicago truncatula) seeds. Comparative sequence analysis identified the presence of mellein synthase (MLNS) homologues in several Dothideomycetes and two sodariomycete genera. Phylogenetic analysis suggests that the MLNSs in fungi and bacteria evolved convergently from fungal and bacterial 6-methylsalicylic acid synthases.

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“…In order to study the genetic basis underlying melleolide biosynthesis, we first searched the genomic sequence of A. mellea DSM3731 (13) using the primary sequences of the protoilludene cyclase Pro1 and the polyketide synthase ArmB (11,12). Notably, the query sequences hit loci that were separated by only nine genes.…”

Section: Resultsmentioning

confidence: 99%

“…AFL91703), and the halogenase ArmH1 (GenBank accession no. AEM76785) as queries (11,12,22) and using the BLASTP function integrated in the Joint Genome Institute's Genome Portal (23).…”

Section: Methodsmentioning

confidence: 99%

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

Wick

Heine

Lackner

et al. 2016

Appl Environ Microbiol

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The basidiomycetous tree pathogen Armillaria mellea (honey mushroom) produces a large variety of structurally related antibiotically active and phytotoxic natural products, referred to as the melleolides. During their biosynthesis, some members of the melleolide family of compounds undergo monochlorination of the aromatic moiety, whose biochemical and genetic basis was not known previously. This first study on basidiomycete halogenases presents the biochemical in vitro characterization of five flavin-dependent A. mellea enzymes (ArmH1 to ArmH5) that were heterologously produced in Escherichia coli. We demonstrate that all five enzymes transfer a single chlorine atom to the melleolide backbone. A 5-fold, secured biosynthetic step during natural product assembly is unprecedented. Typically, flavin-dependent halogenases are categorized into enzymes acting on free compounds as opposed to those requiring a carrier-protein-bound acceptor substrate. The enzymes characterized in this study clearly turned over free substrates. Phylogenetic clades of halogenases suggest that all fungal enzymes share an ancestor and reflect a clear divergence between ascomycetes and basidiomycetes.

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Assembly of Melleolide Antibiotics Involves a Polyketide Synthase with Cross-Coupling Activity

Cited by 70 publications

References 31 publications

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

An In Planta -Expressed Polyketide Synthase Produces ( R )-Mellein in the Wheat Pathogen Parastagonospora nodorum

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

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