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Fungal silent biosynthetic gene cluster

Colin J B Harvey, Mancheng Tang, Ulrich Schlecht, Joe Horecka, Curt R Fischer, Hsiao-Ching Lin, Jian Li, Brian Naughton, James Cherry, Molly Miranda, Yong Fuga Li, Angela M Chu, James R Hennessy, Gergana A Vandova, Diane Inglis, Raeka S Aiyar, Lars M Steinmetz, Ronald W Davis, Marnix H Medema, Elizabeth Sattely, Chaitan Khosla, Robert P St Onge, Yi Tang, Maureen E Hillenmeyer
For decades, fungi have been a source of U.S. Food and Drug Administration-approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae ...
April 2018: Science Advances
Eva-Maria Niehaus, Lena Rindermann, Slavica Janevska, Martin Münsterkötter, Ulrich Güldener, Bettina Tudzynski
The fungus Fusarium fujikuroi causes "bakanae" disease of rice due to its ability to produce gibberellins (GAs), a family of plant hormones. Recent genome sequencing revealed the genetic capacity for the biosynthesis of 46 additional secondary metabolites besides the industrially produced GAs. Among them are the pigments bikaverin and fusarubins, as well as mycotoxins, such as fumonisins, fusarin C, beauvericin, and fusaric acid. However, half of the potential secondary metabolite gene clusters are silent...
January 2018: Applied Microbiology and Biotechnology
Navid Adnani, Scott R Rajski, Tim S Bugni
Covering: 2010 up to 2017Life on Earth is characterized by a remarkable abundance of symbiotic and highly refined relationships among life forms. Defined as any kind of close, long-term association between two organisms, symbioses can be mutualistic, commensalistic or parasitic. Historically speaking, selective pressures have shaped symbioses in which one organism (typically a bacterium or fungus) generates bioactive small molecules that impact the host (and possibly other symbionts); the symbiosis is driven fundamentally by the genetic machineries available to the small molecule producer...
July 6, 2017: Natural Product Reports
Nicolau Sbaraini, Rafael Lucas Muniz Guedes, Fábio Carrer Andreis, Ângela Junges, Guilherme Loss de Morais, Marilene Henning Vainstein, Ana Tereza Ribeiro de Vasconcelos, Augusto Schrank
BACKGROUND: The described species from the Metarhizium genus are cosmopolitan fungi that infect arthropod hosts. Interestingly, while some species infect a wide range of hosts (host-generalists), other species infect only a few arthropods (host-specialists). This singular evolutionary trait permits unique comparisons to determine how pathogens and virulence determinants emerge. Among the several virulence determinants that have been described, secondary metabolites (SMs) are suggested to play essential roles during fungal infection...
October 25, 2016: BMC Genomics
Daniel Montiel, Hahk-Soo Kang, Fang-Yuan Chang, Zachary Charlop-Powers, Sean F Brady
Large-scale sequencing of prokaryotic (meta)genomic DNA suggests that most bacterial natural product gene clusters are not expressed under common laboratory culture conditions. Silent gene clusters represent a promising resource for natural product discovery and the development of a new generation of therapeutics. Unfortunately, the characterization of molecules encoded by these clusters is hampered owing to our inability to express these gene clusters in the laboratory. To address this bottleneck, we have developed a promoter-engineering platform to transcriptionally activate silent gene clusters in a model heterologous host...
July 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
Eva-Maria Niehaus, Slavica Janevska, Katharina W von Bargen, Christian M K Sieber, Henning Harrer, Hans-Ulrich Humpf, Bettina Tudzynski
The fungus F. fujikuroi is well known for its production of gibberellins causing the 'bakanae' disease of rice. Besides these plant hormones, it is able to produce other secondary metabolites (SMs), such as pigments and mycotoxins. Genome sequencing revealed altogether 45 potential SM gene clusters, most of which are cryptic and silent. In this study we characterize a new non-ribosomal peptide synthetase (NRPS) gene cluster that is responsible for the production of the cyclic tetrapeptide apicidin F (APF). This new SM has structural similarities to the known histone deacetylase inhibitor apicidin...
2014: PloS One
Junko Yaegashi, Berl R Oakley, Clay C C Wang
Fungi are prolific producers of secondary metabolites (SMs) that show a variety of biological activities. Recent advances in genome sequencing have shown that fungal genomes harbor far more SM gene clusters than are expressed under conventional laboratory conditions. Activation of these "silent" gene clusters is a major challenge, and many approaches have been taken to attempt to activate them and, thus, unlock the vast treasure chest of fungal SMs. This review will cover recent advances in genome mining of SMs in Aspergillus nidulans...
February 2014: Journal of Industrial Microbiology & Biotechnology
Christoph Zutz, Agnieszka Gacek, Michael Sulyok, Martin Wagner, Joseph Strauss, Kathrin Rychli
The filamentous fungus Aspergillus clavatus is known to produce a variety of secondary metabolites (SM) such as patulin, pseurotin A, and cytochalasin E. In fungi, the production of most SM is strongly influenced by environmental factors and nutrients. Furthermore, it has been shown that the regulation of SM gene clusters is largely based on modulation of a chromatin structure. Communication between fungi and bacteria also triggers chromatin-based induction of silent SM gene clusters. Consequently, chemical chromatin effectors known to inhibit histone deacetylases (HDACs) and DNA-methyltransferases (DNMTs) influence the SM profile of several fungi...
October 2013: Toxins
Hans-Wilhelm Nützmann, Juliane Fischer, Kirstin Scherlach, Christian Hertweck, Axel A Brakhage
Chromatin remodelling events play an important role in the secondary metabolism of filamentous fungi. Previously, we showed that a bacterium, Streptomyces rapamycinicus, is able to reprogram the histone-modifying Spt-Ada-Gcn5-acetyltransferase/ADA (SAGA/ADA) complex of the model fungus Aspergillus nidulans. Consequently, the histone H3 amino acids lysine 9 and lysine 14 at distinct secondary metabolism genes were specifically acetylated during the bacterial fungal interaction, which, furthermore, was associated with the activation of the otherwise silent orsellinic acid gene cluster...
October 2013: Applied and Environmental Microbiology
Yi-Ming Chiang, C Elizabeth Oakley, Manmeet Ahuja, Ruth Entwistle, Aric Schultz, Shu-Lin Chang, Calvin T Sung, Clay C C Wang, Berl R Oakley
Fungal secondary metabolites (SMs) are an important source of medically valuable compounds. Genome projects have revealed that fungi have many SM biosynthetic gene clusters that are not normally expressed. To access these potentially valuable, cryptic clusters, we have developed a heterologous expression system in Aspergillus nidulans . We have developed an efficient system for amplifying genes from a target fungus, placing them under control of a regulatable promoter, transferring them into A. nidulans , and expressing them...
May 22, 2013: Journal of the American Chemical Society
Jane M Moore, Elizabeth Bradshaw, Ryan F Seipke, Matthew I Hutchings, Michael McArthur
Secondary metabolite production from Streptomyces bacteria is primarily controlled at the level of transcription. Under normal laboratory conditions, the majority of the biosynthetic pathways of Streptomyces coelicolor are transcriptionally silent. These are often referred to as "cryptic" pathways and it is thought that they may encode the biosynthesis of yet unseen natural products with novel structures that may be valuable leads for therapeutics and as bioactive compounds. Sequencing of microbial genomes has supported the notion that cryptic pathways are widely distributed and likely to be a source of new chemical diversity...
2012: Methods in Enzymology
Fang Yun Lim, James F Sanchez, Clay C C Wang, Nancy P Keller
Mining for novel natural compounds is of eminent importance owing to the continuous need for new pharmaceuticals. Filamentous fungi are historically known to harbor the genetic capacity for an arsenal of natural compounds, both beneficial and detrimental to humans. The majority of these metabolites are still cryptic or silent under standard laboratory culture conditions. Mining for these cryptic natural products can be an excellent source for identifying new compound classes. Capitalizing on the current knowledge on how secondary metabolite gene clusters are regulated has allowed the research community to unlock many hidden fungal treasures, as described in this chapter...
2012: Methods in Enzymology
Angelica O Zabala, Wei Xu, Yit-Heng Chooi, Yi Tang
Azaphilones are a class of fungal metabolites characterized by a highly oxygenated pyrano-quinone bicyclic core and exhibiting a broad range of bioactivities. Although widespread among various fungi, their biosynthesis has not been thoroughly elucidated. By activation of a silent (aza) gene cluster in Aspergillus niger ATCC 1015, we discovered six azaphilone compounds, azanigerones A-F (1, 3-7). Transcriptional analysis and deletion of a key polyketide synthase (PKS) gene further confirmed the involvement of the aza gene cluster...
August 24, 2012: Chemistry & Biology
Kirsi Bromann, Mervi Toivari, Kaarina Viljanen, Anu Vuoristo, Laura Ruohonen, Tiina Nakari-Setälä
Fungal secondary metabolites are a rich source of medically useful compounds due to their pharmaceutical and toxic properties. Sequencing of fungal genomes has revealed numerous secondary metabolite gene clusters, yet products of many of these biosynthetic pathways are unknown since the expression of the clustered genes usually remains silent in normal laboratory conditions. Therefore, to discover new metabolites, it is important to find ways to induce the expression of genes in these otherwise silent biosynthetic clusters...
2012: PloS One
Takehito Nakazawa, Kan'ichiro Ishiuchi, Alex Praseuth, Hiroshi Noguchi, Kinya Hotta, Kenji Watanabe
Fungal genomes carry many gene clusters seemingly capable of natural product biosynthesis, yet most clusters remain silent. This places a major constraint on the conventional approach of cloning these genes in more amenable heterologous host for the natural product biosynthesis. One way to overcome this difficulty is to activate the silent gene clusters within the context of the target fungus. Here, we successfully activated a silent polyketide biosynthetic gene cluster in Aspergillus oryzae by overexpressing a transcriptional regulator found within the cluster from a plasmid...
April 16, 2012: Chembiochem: a European Journal of Chemical Biology
Anindita Sarkar, Alexander N Funk, Kirstin Scherlach, Fabian Horn, Volker Schroeckh, Pranatchareeya Chankhamjon, Martin Westermann, Martin Roth, Axel A Brakhage, Christian Hertweck, Uwe Horn
The genome of the fungal model organism Aspergillus nidulans harbors nearly 30 polyketide synthase genes, yet the majority of these genes remain silent in the absence of particular stimuli. In this study, environmental conditions such as low specific microbial growth rate as well as nitrate, orthophosphate and glucose limitations were simulated under a continuous cultivation regime to induce the expression of silent polyketide synthase genes. In addition to offline and online bioprocess parameters, the physiological equilibrium was defined at the transcript level in terms of indicator gene expression...
July 31, 2012: Journal of Biotechnology
Jens Laurids Sørensen, Frederik Teilfeldt Hansen, Teis Esben Sondergaard, Dan Staerk, T Verne Lee, Reinhard Wimmer, Louise Graabaek Klitgaard, Stig Purup, Henriette Giese, Rasmus John Normand Frandsen
Like many other filamentous fungi, Fusarium graminearum has the genetic potential to produce a vast array of unknown secondary metabolites. A promising approach to determine the nature of these is to activate silent secondary metabolite gene clusters through constitutive expression of cluster specific transcription factors. We have developed a system in which an expression cassette containing the transcription factor from the targeted PKS cluster disrupts the production of the red mycelium pigment aurofusarin...
May 2012: Environmental Microbiology
Kanae Sakai, Hiroshi Kinoshita, Takuya Nihira
Fungal secondary metabolites have been considered promising resources in the search for novel bioactive compounds. Given the high potential of fungi as genetic resources, it is essential to find an efficient way to link biosynthetic genes to the product in a heterologous system, because many genes for the secondary metabolite in the original strain are silent under standard laboratory conditions. In a previous study, we constructed a heterologous expression system for a biosynthetic gene cluster using Aspergillus oryzae as the host...
March 2012: Applied Microbiology and Biotechnology
Steve S Giles, Alexandra A Soukup, Carrie Lauer, Mona Shaaban, Alexander Lin, Berl R Oakley, Clay C C Wang, Nancy P Keller
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...
June 2011: Applied and Environmental Microbiology
Robin K Pettit
Microbial natural products continue to be an unparalleled resource for pharmaceutical lead discovery, but the rediscovery rate is high. Bacterial and fungal sequencing studies indicate that the biosynthetic potential of many strains is much greater than that observed by fermentation. Prodding the expression of such silent (cryptic) pathways will allow us to maximize the chemical diversity available from microorganisms. Cryptic metabolic pathways can be accessed in the laboratory using molecular or cultivation-based approaches...
July 2011: Microbial Biotechnology
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