title: Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters.
abstract: Although biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram-negative cell biology.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Cimermancic
authors.affiliation: Department of Microbial Physiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands; Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Marnix H
authors.initials: MH
authors.lastname: Medema
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Claesen
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurita
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Wieland Brown
authors.affiliation: US Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mavrommatis
authors.affiliation: US Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Pati
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Godfrey
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Koehrsen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.affiliation: Department of Microbial Physiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Eriko
authors.initials: E
authors.lastname: Takano
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: fischbach@fischbachgroup.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
mesh_terms: D000465:Algorithms; D001419:Bacteria / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D018384:Oxidative Stress; D010802:Phylogeny; D064210:Secondary Metabolism