title: Enhancing Nonribosomal Peptide Biosynthesis in Filamentous Fungi.
abstract: Filamentous fungi are historically known as rich sources for production of biologically active natural products, so-called secondary metabolites. One particularly pharmaceutically relevant chemical group of secondary metabolites is the nonribosomal peptides synthesized by nonribosomal peptide synthetases (NRPSs). As most of the fungal NRPS gene clusters leading to production of the desired molecules are not expressed under laboratory conditions, efforts to overcome this impediment are crucial to unlock the full chemical potential of each fungal species. One way to activate these silent clusters is by overexpressing and deleting global regulators of secondary metabolism. The conserved fungal-specific regulator of secondary metabolism, LaeA, was shown to be a valuable target for sleuthing of novel gene clusters and metabolites. Additionally, modulation of chromatin structures by either chemical or genetic manipulation has been shown to activate cryptic metabolites. Furthermore, NRPS-derived molecules seem to be affected by cross talk between the specific gene clusters and some of these metabolites have a tissue- or developmental-specific regulation. This chapter summarizes how this knowledge of different tiers of regulation can be combined to increase production of NRPS-derived metabolites in fungal species.
authors.affiliation: Department of Genetics, University of Wisconsin-Madison, 1550 Linden Drive, Madison, WI, 53706, USA.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Soukup
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Drive, Madison, WI, 53706, USA. npkeller@wisc.edu.|Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 3455 Microbial Sciences, 1550 Linden Drive, Madison, WI, 53706, USA. npkeller@wisc.edu.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 3455 Microbial Sciences, 1550 Linden Drive, Madison, WI, 53706, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wiemann
mesh_terms: D000595:Amino Acid Sequence; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005658:Fungi / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D005818:Genetic Engineering / Q000379:methods*; D008969:Molecular Sequence Data; D005810:Multigene Family; D046908:Peptide Biosynthesis, Nucleic Acid-Independent; D010453:Peptide Synthases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014170:Transformation, Genetic
chemical_list: D002843:Chromatin; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase
keywords: Chromatin regulation; Cross talk; LaeA regulation; Transcription factor
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