Sch 1385568, a new azaphilone from Aspergillus sp.

Yang, Shu‐Wei; Chan, Tze‐Ming; Terracciano, Joseph; Loebenberg, David; Patel, Mahesh; Gullo, Vincent P.; Chu, Min

doi:10.1038/ja.2009.51

Cited by 19 publications

(20 citation statements)

References 22 publications

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“…Osmanova et al and Yang et al even isolated metabolites from Aspergillus sp. synthesized from azaphilones and orsellinic acid (50,72). Perhaps, the neighboring dba and ors clusters work together to synthesize metabolites related to those identified previously by Yang et al (72), as both gene clusters are activated in the ⌬csnE mutant.…”

Section: Discussionmentioning

confidence: 95%

Breaking the Silence: Protein Stabilization Uncovers Silenced Biosynthetic Gene Clusters in the Fungus Aspergillus nidulans

Gerke

Bayram

Feussner

et al. 2012

Appl Environ Microbiol

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The genomes of filamentous fungi comprise numerous putative gene clusters coding for the biosynthesis of chemically and structurally diverse secondary metabolites (SMs), which are rarely expressed under laboratory conditions. Previous approaches to activate these genes were based primarily on artificially targeting the cellular protein synthesis apparatus. Here, we applied an alternative approach of genetically impairing the protein degradation apparatus of the model fungus Aspergillus nidulans by deleting the conserved eukaryotic csnE/CSN5 deneddylase subunit of the COP9 signalosome. This defect in protein degradation results in the activation of a previously silenced gene cluster comprising a polyketide synthase gene producing the antibiotic 2,4-dihydroxy-3-methyl-6-(2-oxopropyl)benzaldehyde (DHMBA). The csnE/CSN5 gene is highly conserved in fungi, and therefore, the deletion is a feasible approach for the identification of new SMs. Since its discovery by Fleming in the 1920s, fungal penicillin has saved the lives of millions. Currently, the World Health Organization forecasts that the dramatic increase in antimicrobial resistance all over the world might lead to a disaster and proclaims a need for novel drugs (22). Certain fungi, plants, and bacteria produce various potent secondary metabolites (SMs) that span a wide field of structurally and chemically diverse natural products. With almost 1.5 million species (33), the fungal kingdom is a major reservoir for bioactive natural products as beneficial antibiotics and antitumor drugs but also as deleterious mycotoxins and food contaminants (28,38). Although many fungal SMs have been described and tested, their complete potential is by far not exploited.In recent years, different approaches were applied to find novel bioactive SMs either in new species or in already established model organisms. New geographical spots exhibiting extreme conditions were explored in order to find new species producing as-yet-unknown natural products (37). An alternative approach is the exploration of the full genomic potential of already known species by genomic mining (13,14,30,76). Genomic sequencing revealed that there are many more genes for the biosynthesis of SMs than the metabolites already identified. These genes are often clustered, but most of them are rarely expressed under laboratory conditions (35), making the identification of their chemical products challenging. Two major strategies were applied to activate hidden genes: (i) changing the environment or (ii) genetic engineering (19,35,56). (i) The OSMAC (one strain, many compounds) approach activates silent gene clusters by cultivating microorganisms under different conditions (10, 75). Alternatively, physical contact with an opponent results in the uncovering of hidden clusters by activating defense mechanisms (58). (ii) Genetic engineering is focused primarily on expressing complete gene clusters in heterologous hosts (53, 77) or on altering the cellular transcription or protein synthesis machinery. Thus, SM synthesi...

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Section: Discussionmentioning

confidence: 95%

Breaking the Silence: Protein Stabilization Uncovers Silenced Biosynthetic Gene Clusters in the Fungus Aspergillus nidulans

Gerke

Bayram

Feussner

et al. 2012

Appl Environ Microbiol

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“…To identify the newly produced compounds in the ΔrbtJ strain, a large-scale fermentation (13 kg) in rice was carried out, following by various chromatography, which resulted in the isolation of a total of 36 compounds from part fractions ( Fig. 2 ), of which 23 compounds possess new structure, including 9 azaphilone monomers ( 4–9 , 18–19 and 34 ), 8 azaphilone dimers ( 20 – 25 , 27 and 28 ), 5 azaphilone trimers ( 29 – 33 ), and 1 unclassified polyketide ( 35 ), along with 13 known ones including polyketides Sch 725680 ( 10 ) 19 , pinophilin B ( 11 ) 20 , pinazaphilone B ( 12 ) 21 , Sch 1385568 ( 13 ) 22 , talaraculone F ( 14 ) 23 , (+)-mitorubrinic acid B ( 15 ) 24 , (−)-mitorubrin ( 16 ) 25 , 26 , (−)-mitorubrinol ( 17 ) 25 , diazaphilonic acid ( 26 ) 27 , 28 , (±)-asperlones A ( 36 ) 29 and orsellinic acid ( 37 ) 30 , alkaloid terreusinone ( 38 ) 31 , and a siderophore desferritriacetylfusigen ( 39 ) 32 , 33 . Remarkably, three types of novel azaphilones polymers were discovered for the first time, including 5 unusual methylene-bridged azaphilone dimers ( 20 – 24 ), 2 rare spiro-polycyclic azaphilone dimers ( 27 and 28 ), and 5 unprecedented azaphilone trimers ( 29 – 33 ) featuring both methylene and polycyclic bridged heterocycle and spiral structures, tetrahydro-3-oxaspiro[bicyclo[3.3.1]nonane-2,2′-pyran] core.…”

Section: Resultsmentioning

confidence: 99%

Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products

Qian

Bai

Yan

et al. 2021

Acta Pharmaceutica Sinica B

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Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters, exhibited its strong ability to produce numbers of secondary metabolites. However, this strain mainly produce rubratoxins alone with high yield in varied culture conditions, suggested most gene clusters are silent. Efforts for mining the cryptic gene clusters in P. dangeardii , including epigenetic regulation and one-strain-many-compounds (OSMAC) approach were failed probably due to the high yield of rubratoxins. A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases (PKSs), and led to the trace compounds detectable. As a result, a total of 23 new compounds including azaphilone monomers, dimers, trimers with unprecedented polycyclic bridged heterocycle and spiral structures, as well as siderophores were identified. Some compounds showed significant cytotoxicities, anti-inflammatory or antioxidant activities. The attractive dual PKSs gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor. Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.

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“…The co‐isolated known compounds were identified by comparison of spectroscopic data with the literatures, which were penicitor A ( 2 ), aspergillumarins A ( 3 ) and B ( 4 ), vermistatin ( 5 ), dihydrovermistatin ( 6 ), Sch 1385568 ( 7 ), Sch725680 ( 8 ), aculenes C ( 9 ), and D ( 10 ) . All of the obtained compounds ( 1 – 10 ) were evaluated for the in vitro cytotoxicity against a panel of human tumor cell lines, MDA‐MB‐231, C4‐2B, MGC803, 143B, and A549 (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

A new naphthopyranone from the sponge‐associated fungus Penicillium sp. XWS02F62

Luo

Gao

Han

et al. 2019

Magnetic Reson in Chemistry

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Sch 1385568, a new azaphilone from Aspergillus sp.

Cited by 19 publications

References 22 publications

Breaking the Silence: Protein Stabilization Uncovers Silenced Biosynthetic Gene Clusters in the Fungus Aspergillus nidulans

Breaking the Silence: Protein Stabilization Uncovers Silenced Biosynthetic Gene Clusters in the Fungus Aspergillus nidulans

Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products

A new naphthopyranone from the sponge‐associated fungus Penicillium sp. XWS02F62

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