title: Plant-like biosynthesis of isoquinoline alkaloids in Aspergillus fumigatus.
abstract: Natural product discovery efforts have focused primarily on microbial biosynthetic gene clusters (BGCs) containing large multimodular polyketide synthases and nonribosomal peptide synthetases; however, sequencing of fungal genomes has revealed a vast number of BGCs containing smaller NRPS-like genes of unknown biosynthetic function. Using comparative metabolomics, we show that a BGC in the human pathogen Aspergillus fumigatus named fsq, which contains an NRPS-like gene lacking a condensation domain, produces several new isoquinoline alkaloids known as the fumisoquins. These compounds derive from carbon-carbon bond formation between two amino acid-derived moieties followed by a sequence that is directly analogous to isoquinoline alkaloid biosynthesis in plants. Fumisoquin biosynthesis requires the N-methyltransferase FsqC and the FAD-dependent oxidase FsqB, which represent functional analogs of coclaurine N-methyltransferase and berberine bridge enzyme in plants. Our results show that BGCs containing incomplete NRPS modules may reveal new biosynthetic paradigms and suggest that plant-like isoquinoline biosynthesis occurs in diverse fungi.
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Joshua A
authors.identifier: 0000-0003-4334-755X
authors.initials: JA
authors.lastname: Baccile
authors.affiliation: Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Joseph E
authors.identifier: 0000-0002-5429-0328
authors.initials: JE
authors.lastname: Spraker
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Henry H
authors.identifier: 0000-0003-2942-2357
authors.initials: HH
authors.lastname: Le
authors.affiliation: Department of Pharmaceutical Microbiology at the Hans-Knöll-Institute, Friedrich Schiller University, Jena, Germany.
authors.forename: Eileen
authors.initials: E
authors.lastname: Brandenburger
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Gomez
authors.affiliation: Institute for Microbiology, Friedrich Schiller University, Jena, Germany.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Bok
authors.affiliation: Institute for Microbiology, Friedrich Schiller University, Jena, Germany.|Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Macheleidt
authors.affiliation: Institute for Microbiology, Friedrich Schiller University, Jena, Germany.|Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Department of Pharmaceutical Microbiology at the Hans-Knöll-Institute, Friedrich Schiller University, Jena, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hoffmeister
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
mesh_terms: D000470:Alkaloids / Q000096:biosynthesis* / Q000737:chemistry; D001232:Aspergillus fumigatus / Q000235:genetics* / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism*; D055432:Metabolomics; D015394:Molecular Structure; D005810:Multigene Family; D010944:Plants / Q000235:genetics / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; C039109:isoquinoline