Epigenetic Genome Mining of an Endophytic Fungus Leads to the Pleiotropic Biosynthesis of Natural Products

Mao, Xu‐Ming; Xu, Wei; Li, Dehai; Yin, Wen‐Bing; Chooi, Yit‐Heng; Li, Yongquan; Tang, Yi; Hu, Youcai

doi:10.1002/ange.201502452

Cited by 21 publications

(25 citation statements)

References 39 publications

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“…7 One such strategy involves the inhibition of histone deacetylase activity (HDACi) and has shown some promise. 8–10 HDACi increases global histone acetylation levels and can increase transcription of otherwise repressed natural product BGCs. Our previous work used quantitative mass spectrometry-based analyses to compare the extracellular metabolomes of A. nidulans before and after both chemical and genetic HDACi.…”

mentioning

confidence: 99%

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

et al. 2016

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Unlocking the biochemical stores of fungi is key for developing future pharmaceuticals. Through reduced expression of a critical histone deacetylase in Aspergillus nidulans, increases of up to 100-fold were observed in the levels of 15 new aspercryptins, recently described lipopeptides with two non-canonical amino acids derived from octanoic and dodecanoic acids. In addition to two NMR-verified structures, MS/MS networking helped uncover an additional 13 aspercryptins. The aspercryptins break the conventional structural orientation of lipopeptides and appear “backward” when compared to known compounds of this class. We have also confirmed the 14-gene aspercryptin biosynthetic gene cluster, which encodes two fatty acid synthases and several enzymes to convert saturated octanoic and dodecanoic acid to α-amino acids.

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confidence: 99%

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

et al. 2016

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“…We hypothesize that the expansion of GH18 family and GH2 family in C. arbuscula genome may contribute to help the host to resist the attack of other fungi. C. arbuscula is an endophytic filamentous fungus, estimated to have 65 BGCs, but most of them are silenced [16,19]. Although some gene clusters are expressed at the transcription levels by RNA-Seq, we have not detected their corresponding products, and it is likely that the translation level of the main proteins in the gene clusters is still low.…”

Section: Discussionmentioning

confidence: 78%

Genomic and transcriptomic survey of an endophytic fungus Calcarisporium arbuscula NRRL 3705 and potential overview of its secondary metabolites

Cheng

Cao

Chen

et al. 2020

Preprint

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Background: Secondary metabolites as natural products from endophytic fungi are important sources of pharmaceuticals. However, there is currently little understanding of endophytic fungi at the omics levels about their potential in secondary metabolites. Calcarisporium arbuscula , an endophytic fungus from the fruit bodies of Russulaceae, produces a variety of secondary metabolites with anti-cancer, anti-nematode and antibiotic activities. A comprehensive survey of the genome and transcriptome of this endophytic fungus will help to understand its capacity to biosynthesize secondary metabolites and will lay the foundation for the development of this precious resource. Results: In this study, we reported the high-quality genome sequence of C. arbuscula NRRL 3705 based on Single Molecule Real-Time sequencing technology. The genome of this fungus is over 45 Mb in size, larger than other typical filamentous fungi, and comprises 10,001 predicted genes, encoding at least 762 secretory-proteins, 386 carbohydrate-active enzymes and 177 P450 enzymes. 398 virulence factors and 228 genes related to pathogen-host interactions were also predicted in this fungus. Moreover , 65 secondary metabolite biosynthetic gene clusters were revealed, including the gene cluster for the mycotoxin aurovertins. In addition, several gene clusters were predicted to produce mycotoxins, including aflatoxin, alternariol, destruxin, citrinin and isoflavipucine. Notably, two independent gene clusters were shown that are potentially involved in thebiosynthesis of alternariol. Furthermore, RNA-Seq assays showed that only expression of the aurovertin gene cluster is much stronger than expression of the housekeeping genes under laboratory conditions, consistent with the observation that aurovertins are the predominant metabolites. Gene expression of the remaining 64 gene clusters for compound backbone biosynthesis was all lower than expression of the housekeeping genes, which partially explained poor production of other secondary metabolites in this fungus. Conclusions : Our omics data, along with bioinformatics analysis, indicated that C. arbuscula NRRL 3705 contains a large number of biosynthetic gene clusters and has a huge potential to produce a profound number of secondary metabolites. This work also provides the basis for development of endophytic fungi as a new resource of natural products with promising biological activities. Keywords: Endophytic Fungus, Calcarisporium arbuscula , Genome, Transcriptome, Secondary Metabolite

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“…To find and collect more diverse metabolites from Calcarisporium arbuscula , removal of its hdaA gene, which encodes histone H3 deacetylase, successfully resulted in the global overexpression of 75% of the PKS genes, 78% of the nonribosomal peptide synthetase (NRPS) genes, and 78% of the terpene synthase (TS) genes, and ultimately led to the production of ten structurally diverse compounds, four of which had novel structures (Fig. ), including two cyclic peptides (arbumycin 45 , arbumelin 46 ), a diterpenoid ( 47 ) and a meroterpenoid ( 48 ) …”

Section: Biological Synthetic and Semisynthetic Approachesmentioning

confidence: 99%

Strategies to diversify natural products for drug discovery

Lou

2017

Medicinal Research Reviews

215

130

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Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

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Epigenetic Genome Mining of an Endophytic Fungus Leads to the Pleiotropic Biosynthesis of Natural Products

Cited by 21 publications

References 39 publications

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

Genomic and transcriptomic survey of an endophytic fungus Calcarisporium arbuscula NRRL 3705 and potential overview of its secondary metabolites

Strategies to diversify natural products for drug discovery

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