Analysis of Rhizonin Biosynthesis Reveals Origin of Pharmacophoric Furylalanine Moieties in Diverse Cyclopeptides |
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Authors: | Friedrich J Ehinger Dr Sarah P Niehs Dr Benjamin Dose Dr Maria Dell Dr Jana Krabbe Dr Sacha J Pidot Prof Timothy P Stinear Dr Kirstin Scherlach Dr Claudia Ross Dr Gerald Lackner Prof Dr Christian Hertweck |
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Institution: | 1. Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstraße 11a, 07745 Jena, Germany;2. Department of Microbiology and Immunology, Doherty Institute, 792 Elizabeth Street, Melbourne, 3000 Australia |
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Abstract: | Rhizonin A and B are hepatotoxic cyclopeptides produced by bacterial endosymbionts (Mycetohabitans endofungorum) of the fungus Rhizopus microsporus. Their toxicity critically depends on the presence of 3-furylalanine (Fua) residues, which also occur in pharmaceutically relevant cyclopeptides of the endolide and bingchamide families. The biosynthesis and incorporation of Fua by non-ribosomal peptide synthetases (NRPS), however, has remained elusive. By genome sequencing and gene inactivation we elucidated the gene cluster responsible for rhizonin biosynthesis. A suite of isotope labeling experiments identified tyrosine and l -DOPA as Fua precursors and provided the first mechanistic insight. Bioinformatics, mutational analysis and heterologous reconstitution identified dioxygenase RhzB as necessary and sufficient for Fua formation. RhzB is a novel type of heme-dependent aromatic oxygenases (HDAO) that enabled the discovery of the bingchamide biosynthesis gene cluster through genome mining. |
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Keywords: | Amino Acids Biosynthesis Genome Mining Stable Isotope Labeling Toxins |
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