Waking Sleeping Pathways in Filamentous Fungi

Spraker, Joseph E.; Keller, Nancy P.

doi:10.1002/9781118794623.ch15

Cited by 4 publications

(6 citation statements)

References 76 publications

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“…Such regions are also linked with hyper-acetylated nucleosomal histones. Likewise, it has been reported that methylation of H3K9, H3K27, and H4K20 are typical markers of the heterochromatin, while in euchromatin methylation occurs at H3K4 ( Brosch et al, 2008 ; Strauss and Reyes-Dominguez, 2011 ; Gacek and Strauss, 2012 ; Spraker and Keller, 2014 ; Rutledge and Challis, 2015 ).…”

Section: Strategies For Activation Of Bgc Smentioning

confidence: 87%

“…The latter is for instance exploited for the production of terrain by A. terreus ( Bode et al, 2002 ; Brakhage and Schroeckh, 2011 ; Gressler et al, 2015 ). This strategy can readily be implemented using high-throughput methods, where an array of culture conditions can be screened for new metabolite profiles ( Spraker and Keller, 2014 ). In combination with bioinformatics tools, this strategy can be a powerful tool to investigate the production of new molecules, as exemplified by the discovery of aspoquinolones A–D in A. nidulans ( Scherlach and Hertweck, 2006 ).…”

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

“…Another mechanism to stimulate the expression of silent BGCs in P. chrysogenum is by genetic interference, for instance by direct manipulation of the regulatory network related to BGCs expression. The regulation of BGCs is effected at many levels, through specific (or local) and global regulators up to epigenetic regulation involving the modification of the chromatin landscape ( Lim et al, 2012 ; Spraker and Keller, 2014 ).…”

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

“…In A. nidulans , deletion of the sumO gene enhanced the production of asperthecin, whereas synthesis of austinol, dehydroaustinol, and sterigmatocystin was reduced. Although the molecular mechanism still needs to be elucidated, it is thought that sumoylation acts at several levels, such as on epigenetic regulators (COMPASS, Clr4, SAGA/ADA and HDACs) or at the level of transcriptional regulators ( Brakhage and Schroeckh, 2011 ; Spraker and Keller, 2014 ; Wu and Yu, 2015 ).…”

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

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Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products

et al. 2018

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Penicillium chrysogenum (renamed P. rubens) is the most studied member of a family of more than 350 Penicillium species that constitute the genus. Since the discovery of penicillin by Alexander Fleming, this filamentous fungus is used as a commercial β-lactam antibiotic producer. For several decades, P. chrysogenum was subjected to a classical strain improvement (CSI) program to increase penicillin titers. This resulted in a massive increase in the penicillin production capacity, paralleled by the silencing of several other biosynthetic gene clusters (BGCs), causing a reduction in the production of a broad range of BGC encoded natural products (NPs). Several approaches have been used to restore the ability of the penicillin production strains to synthetize the NPs lost during the CSI. Here, we summarize various re-activation mechanisms of BGCs, and how interference with regulation can be used as a strategy to activate or silence BGCs in filamentous fungi. To further emphasize the versatility of P. chrysogenum as a fungal production platform for NPs with potential commercial value, protein engineering of biosynthetic enzymes is discussed as a tool to develop de novo BGC pathways for new NPs.

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Section: Strategies For Activation Of Bgc Smentioning

confidence: 87%

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

Section: Strategies For Activation Of Bgc Smentioning

confidence: 99%

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Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products

et al. 2018

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“…Marine fungi have been proved to possess the potential ability to produce structurally unique and biologically active secondary metabolites (Blunt et al, 2018). However, it has become a crucial issue to discover microbial natural products due to repeating isolation of known compounds at the traditional methods involving bulk culture of the organism and subsequent fractionation and bioassay to determine if specific fractions hold any bioactive metabolites (Spraker and Keller, 2014). It has been revealed that fungi possess far more gene clusters encoding secondary metabolites than their characterized compounds (Khaldi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Terpenoids From the Coral-Derived Fungus Trichoderma harzianum (XS-20090075) Induced by Chemical Epigenetic Manipulation

et al. 2020

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The soft coral-derived fungus Trichoderma harzianum (XS-20090075) was found to be a potential strain to produce substantial new compounds in our previous study. In order to explore its potential to produce more metabolites, chemical epigenetic manipulation was used on this fungus to wake its sleeping genes, leading to the significant changes of its secondary metabolites by using a histone deacetylase (HDAC) inhibitor. The most obvious difference was the original main products harziane diterpenoids were changed into cyclonerane sesquiterpenoids. Three new terpenoids were isolated from the fungal culture treated with 10 µM sodium butyrate, including cleistanthane diterpenoid, harzianolic acid A (1), harziane diterpenoid, harzianone E (2), and cyclonerane sesquiterpenoid, 3,7,11-trihydroxy-cycloneran (3), together with 11 known sesquiterpenoids (4-14). The absolute configurations of 1-3 were determined by single-crystal X-ray diffraction, ECD and OR calculations, and biogenetic considerations. This was the first time to obtain cleistanthane diterpenoid and africane sesquiterpenoid from genus Trichoderma, and this was the first chlorinated cleistanthane diterpenoid. These results demonstrated that the chemical epigenetic manipulation should be an efficient technique for the discovery of new secondary metabolites from marinederived fungi.

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Natural product drug discovery in the genomic era: realities, conjectures, misconceptions, and opportunities

Baltz¹

2019

Journal of Industrial Microbiology and Biotechnology

136

128

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Natural product discovery from microorganisms provided important sources for antibiotics, anti-cancer agents, immune-modulators, anthelminthic agents, and insecticides during a span of 50 years starting in the 1940s, then became less productive because of rediscovery issues, low throughput, and lack of relevant new technologies to unveil less abundant or not easily detected drug-like natural products. In the early 2000s, it was observed from genome sequencing that Streptomyces species encode about ten times as many secondary metabolites as predicted from known secondary metabolomes. This gave rise to a new discovery approach—microbial genome mining. As the cost of genome sequencing dropped, the numbers of sequenced bacteria, fungi and archaea expanded dramatically, and bioinformatic methods were developed to rapidly scan whole genomes for the numbers, types, and novelty of secondary metabolite biosynthetic gene clusters. This methodology enabled the identification of microbial taxa gifted for the biosynthesis of drug-like secondary metabolites. As genome sequencing technology progressed, the realities relevant to drug discovery have emerged, the conjectures and misconceptions have been clarified, and opportunities to reinvigorate microbial drug discovery have crystallized. This perspective addresses these critical issues for drug discovery.

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Waking Sleeping Pathways in Filamentous Fungi

Cited by 4 publications

References 76 publications

Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products

Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products

Terpenoids From the Coral-Derived Fungus Trichoderma harzianum (XS-20090075) Induced by Chemical Epigenetic Manipulation

Natural product drug discovery in the genomic era: realities, conjectures, misconceptions, and opportunities

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