title: Rational biosynthetic approaches for the production of new-to-nature compounds in fungi.
abstract: Filamentous fungi have the ability to produce a wide range of secondary metabolites some of which are potent toxins whereas others are exploited as food additives or drugs. Fungal natural products still play an important role in the discovery of new chemical entities for potential use as pharmaceuticals. However, in most cases they cannot be directly used as drugs due to toxic side effects or suboptimal pharmacokinetics. To improve drug-like properties, including bioactivity and stability or to produce better precursors for semi-synthetic routes, one needs to generate non-natural derivatives from known fungal secondary metabolites. In this minireview, we describe past and recent biosynthetic approaches for the diversification of fungal natural products, covering examples from precursor-directed biosynthesis, mutasynthesis, metabolic engineering and biocombinatorial synthesis. To illustrate the current state-of-the-art, challenges and pitfalls, we lay particular emphasis on the class of fungal cyclodepsipeptides which have been studied longtime for product diversification and which are of pharmaceutical relevance as drugs.
authors.affiliation: Institut für Chemie, Fachgebiet für Biologische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623 Berlin, Germany; Institut für Biotechnologie, Fachgebiet für Angewandte und Molekulare Mikrobiologie, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: simon.boecker@chem.tu-berlin.de.
authors.forename: Simon
authors.initials: S
authors.lastname: Boecker
authors.affiliation: Institut für Chemie, Fachgebiet für Biologische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623 Berlin, Germany. Electronic address: zobel@chem.tu-berlin.de.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zobel
authors.affiliation: Institut für Biotechnologie, Fachgebiet für Angewandte und Molekulare Mikrobiologie, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany. Electronic address: vera.meyer@tu-berlin.de.
authors.forename: Vera
authors.initials: V
authors.lastname: Meyer
authors.affiliation: Institut für Chemie, Fachgebiet für Biologische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623 Berlin, Germany. Electronic address: roderich.suessmuth@tu-berlin.de.
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
mesh_terms: D001230:Aspergillus / Q000235:genetics / Q000378:metabolism*; D001688:Biological Products; D047630:Depsipeptides / Q000302:isolation & purification; D055808:Drug Discovery / Q000379:methods; D005658:Fungi / Q000235:genetics / Q000378:metabolism*; D060847:Metabolic Engineering / Q000379:methods*
chemical_list: D001688:Biological Products; D047630:Depsipeptides
keywords: Aspergillus; Combinatorial biosynthesis; Metabolic engineering; Mutasynthesis; Precursor-directed biosynthesis; Secondary metabolite