Molecular genetic analysis of the orsellinic acid/F9775 genecluster of Aspergillus nidulans

Sanchez, James F.; Chiang, Yi‐Ming; Szewczyk, Edyta; Davidson, Ashley D.; Ahuja, Manmeet; Oakley, C. Elizabeth; Bok, Jin Woo; Keller, Nancy P.; Oakley, Berl R.; Wang, Clay C. C.

doi:10.1039/b904541d

Cited by 130 publications

(110 citation statements)

References 36 publications

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“…However, the divergent tailoring-enzyme genes within the PKS gene clusters lead to the formation of structurally diverse metabolites. For example, the OA precursor biosynthesized by OrsA (AN7909) in A. nidulans is further catalyzed into lecanoric acid or the analogs F-9775A and F-9775B, presumably through the functions of amdohydrolase (OrsB; AN7911), tyrosinase (OrsC; AN7912), and dehydrogenase (OrsE; AN7914) (22,31). In A. terreus, the closely related PKS TerA (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.

206

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.

206

176

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“…See the text for details. (22,58) allowed the extension of the F-type folding paradigm to RALs and orsellinic acid (59,60). Thus, PT domain sequences have been shown to form clades according to their F-type folding modes, with the single aromatic ring-forming, C-2-C-7-specific PTs for RALs and orsellinic acid constituting group I (22,58).…”

Section: Isolation Of the Dehydrocurvularin Biosynthetic Locusmentioning

confidence: 99%

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Espinosa-Artiles

Schubert

et al. 2013

Appl Environ Microbiol

114

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d 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta-or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.

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“…However, through chromosomal remodeling of A. nidulans, an array of novel bioactive compounds can be retrieved. For example, deletion of cclA, which encodes a protein (CclA) that is involved in histone 3 lysine 4 (H3K4) methylation, results in the activation of the several gene clusters yielding emodin derivatives, including monodictyophenone and the antiosteoporosis polyketides F9775A and F9775B, which are derived from orsellinic acid (5,28).…”

mentioning

confidence: 99%

Cryptic Aspergillus nidulans Antimicrobials

Giles

Soukup

Lauer

et al. 2011

Appl Environ Microbiol

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Secondary metabolite (SM) production by fungi is hypothesized to provide some fitness attribute for the producing organisms. However, most SM clusters are "silent" when fungi are grown in traditional laboratory settings, and it is difficult to ascertain any function or activity of these SM cluster products. Recently, the creation of a chromatin remodeling mutant in Aspergillus nidulans induced activation of several cryptic SM gene clusters. Systematic testing of nine purified metabolites from this mutant identified an emodin derivate with efficacy against both human fungal pathogens (inhibiting both spore germination and hyphal growth) and several bacteria. The ability of catalase to diminish this antimicrobial activity implicates reactive oxygen species generation, specifically, the generation of hydrogen peroxide, as the mechanism of emodin hydroxyl activity.

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Molecular genetic analysis of the orsellinic acid/F9775 genecluster of Aspergillus nidulans

Cited by 130 publications

References 36 publications

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

Fungal biosynthesis of the bibenzoquinone oosporein to evade insect immunity

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Cryptic Aspergillus nidulans Antimicrobials

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