title: Combining Mass Spectrometric Metabolic Profiling with Genomic Analysis: A Powerful Approach for Discovering Natural Products from Cyanobacteria.
abstract: An innovative approach was developed for the discovery of new natural products by combining mass spectrometric metabolic profiling with genomic analysis and resulted in the discovery of the columbamides, a new class of di- and trichlorinated acyl amides with cannabinomimetic activity. Three species of cultured marine cyanobacteria, Moorea producens 3L, Moorea producens JHB, and Moorea bouillonii PNG, were subjected to genome sequencing and analysis for their recognizable biosynthetic pathways, and this information was then compared with their respective metabolomes as detected by MS profiling. By genome analysis, a presumed regulatory domain was identified upstream of several previously described biosynthetic gene clusters in two of these cyanobacteria, M. producens 3L and M. producens JHB. A similar regulatory domain was identified in the M. bouillonii PNG genome, and a corresponding downstream biosynthetic gene cluster was located and carefully analyzed. Subsequently, MS-based molecular networking identified a series of candidate products, and these were isolated and their structures rigorously established. On the basis of their distinctive acyl amide structure, the most prevalent metabolite was evaluated for cannabinomimetic properties and found to be moderate affinity ligands for CB1.
authors.forename: Karin
authors.initials: K
authors.lastname: Kleigrewe
authors.forename: Jehad
authors.initials: J
authors.lastname: Almaliti
authors.affiliation: ‡University of California Berkeley, Berkeley, California, United States.
authors.forename: Isaac Yuheng
authors.initials: IY
authors.lastname: Tian
authors.affiliation: §Hamilton College, Clinton, New York, United States.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Kinnel
authors.affiliation: ¶Algorithmic Biology Laboratory, Saint Petersburg Academic University, St. Petersburg, Russian Federation.
authors.forename: Anton
authors.initials: A
authors.lastname: Korobeynikov
authors.affiliation: ∇Department of Biology, William Paterson University of New Jersey, Wayne, New Jersey, United States.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Monroe
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Duggan
authors.affiliation: #Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: ◊Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.forename: Lena
authors.initials: L
authors.lastname: Gerwick
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D053898:Biosynthetic Pathways / Q000235:genetics; D000458:Cyanobacteria / Q000737:chemistry* / Q000235:genetics; D023281:Genomics; D055442:Metabolome; D055432:Metabolomics; D015394:Molecular Structure; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism
chemical_list: D001688:Biological Products; D043884:Receptor, Cannabinoid, CB1