Toward awakening cryptic secondary metabolite gene clusters in filamentous fungi.

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.

[1]  J. Frisvad,et al.  Requirement of LaeA for secondary metabolism and sclerotial production in Aspergillus flavus. , 2008, Fungal genetics and biology : FG & B.

[2]  Changxing Hu,et al.  Molecular cloning and characterization of the global regulator LaeA in Penicillium citrinum , 2010, Biotechnology Letters.

[3]  A. Gasch,et al.  An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR , 2012, Molecular microbiology.

[4]  H. Humpf,et al.  FfVel1 and FfLae1, components of a velvet‐like complex in Fusarium fujikuroi, affect differentiation, secondary metabolism and virulence , 2010, Molecular microbiology.

[5]  J. Palmer,et al.  H3K9 Methylation Regulates Growth and Development in Aspergillus fumigatus , 2008, Eukaryotic Cell.

[6]  Jennifer R Wortman,et al.  Transcriptional Regulation of Chemical Diversity in Aspergillus fumigatus by LaeA , 2007, PLoS pathogens.

[7]  W. Nierman,et al.  Transcriptional Profiling Identifies a Role for BrlA in the Response to Nitrogen Depletion and for StuA in the Regulation of Secondary Metabolite Clusters in Aspergillus fumigatus , 2008, Eukaryotic Cell.

[8]  D. Haft,et al.  SMURF: Genomic mapping of fungal secondary metabolite clusters. , 2010, Fungal genetics and biology : FG & B.

[9]  Y. Reyes-Domínguez,et al.  Chromatin-level regulation of biosynthetic gene clusters. , 2009, Nature chemical biology.

[10]  N. Kelleher,et al.  A Proteomics Approach to Discovery of Natural Products and Their Biosynthetic Pathways , 2009, Nature Biotechnology.

[11]  D. Kontoyiannis,et al.  Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. , 2005, Blood.

[12]  Kai Blin,et al.  antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences , 2011, Nucleic Acids Res..

[13]  J. Frisvad,et al.  GliZ, a Transcriptional Regulator of Gliotoxin Biosynthesis, Contributes to Aspergillus fumigatus Virulence , 2006, Infection and Immunity.

[14]  K. Kitamoto,et al.  Identification of csypyrone B1 as the novel product of Aspergillus oryzae type III polyketide synthase CsyB. , 2010, Bioorganic & medicinal chemistry.

[15]  Shu-Lin Chang,et al.  Recent advances in awakening silent biosynthetic gene clusters and linking orphan clusters to natural products in microorganisms. , 2011, Current opinion in chemical biology.

[16]  A. Brakhage,et al.  Activation of a Silent Fungal Polyketide Biosynthesis Pathway through Regulatory Cross Talk with a Cryptic Nonribosomal Peptide Synthetase Gene Cluster , 2010, Applied and Environmental Microbiology.

[17]  W. Timberlake,et al.  Transformation of Aspergillus nidulans by using a trpC plasmid. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[18]  F. Kempken,et al.  Secondary chemicals protect mould from fungivory , 2007, Biology Letters.

[19]  Yi Xiong,et al.  Fusion PCR and gene targeting in Aspergillus nidulans , 2006, Nature Protocols.

[20]  G. Goldman,et al.  The akuBKU80 Mutant Deficient for Nonhomologous End Joining Is a Powerful Tool for Analyzing Pathogenicity in Aspergillus fumigatus , 2006, Eukaryotic Cell.

[21]  J. Bok,et al.  LaeA, a Regulator of Secondary Metabolism in Aspergillus spp , 2004, Eukaryotic Cell.

[22]  Axel A Brakhage,et al.  Fungal secondary metabolites - strategies to activate silent gene clusters. , 2011, Fungal genetics and biology : FG & B.

[23]  M. Tribus,et al.  Histone Deacetylase Activity Regulates Chemical Diversity in Aspergillus , 2007, Eukaryotic Cell.

[24]  J. Palmer,et al.  Secondary metabolism in fungi: does chromosomal location matter? , 2010, Current opinion in microbiology.

[25]  A. Brakhage,et al.  Activation of fungal silent gene clusters: a new avenue to drug discovery. , 2008, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[26]  N. Keller,et al.  Transcriptional regulatory elements in fungal secondary metabolism , 2011, The Journal of Microbiology.

[27]  C. Hertweck.  Hidden biosynthetic treasures brought to light. , 2009, Nature chemical biology.

[28]  J. Frisvad,et al.  LaeA, a Regulator of Morphogenetic Fungal Virulence Factors , 2005, Eukaryotic Cell.

[29]  G. Payne,et al.  Overexpression of aflR Leads to Upregulation of Pathway Gene Transcription and Increased Aflatoxin Production in Aspergillus flavus , 1997, Applied and environmental microbiology.

[30]  D. Andes,et al.  HdaA, a class 2 histone deacetylase of Aspergillus fumigatus, affects germination and secondary metabolite production. , 2009, Fungal genetics and biology : FG & B.

[31]  C. Scazzocchio,et al.  Double-joint PCR: a PCR-based molecular tool for gene manipulations in filamentous fungi. , 2004, Fungal genetics and biology : FG & B.

[32]  Russell E. Lewis,et al.  Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites. , 2009, Blood.

[33]  R. Cichewicz,et al.  Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. , 2010, Natural product reports.

[34]  Russell B Williams,et al.  Epigenetic remodeling of the fungal secondary metabolome. , 2008, Organic & biomolecular chemistry.

[35]  C. Scazzocchio,et al.  Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans , 2010, Molecular microbiology.

[36]  J. Frisvad,et al.  Effect of competition on the production and activity of secondary metabolites in Aspergillus species. , 2009, Medical mycology.

[37]  William R. Kirkpatrick,et al.  Disruption of a Nonribosomal Peptide Synthetase in Aspergillus fumigatus Eliminates Gliotoxin Production , 2006, Eukaryotic Cell.

[38]  S. Osmani,et al.  Rapid Production of Gene Replacement Constructs and Generation of a Green Fluorescent Protein-Tagged Centromeric Marker in Aspergillus nidulans , 2004, Eukaryotic Cell.

[39]  J. Walton,et al.  Horizontal gene transfer and the evolution of secondary metabolite gene clusters in fungi: an hypothesis. , 2000, Fungal genetics and biology : FG & B.

[40]  T. Nihira,et al.  Heterologous expression system in Aspergillus oryzae for fungal biosynthetic gene clusters of secondary metabolites , 2011, Applied Microbiology and Biotechnology.

[41]  D. Powell,et al.  Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. , 2010, Journal of natural products.

[42]  Y. Reyes-Domínguez,et al.  Regulation of secondary metabolism by chromatin structure and epigenetic codes. , 2011, Fungal genetics and biology : FG & B.

[43]  N. Keller,et al.  Metabolic pathway gene clusters in filamentous fungi. , 1997, Fungal genetics and biology : FG & B.