title: Discovery of anabaenopeptin 679 from freshwater algal bloom material: Insights into the structure-activity relationship of anabaenopeptin protease inhibitors.
abstract: Cyanobacteria possess a unique capacity for the production of structurally novel secondary metabolites compared to the biosynthetic abilities of other environmental prokaryotes such as bacteria of the genus Streptomyces. Two different strategies to explore cyanobacteria-derived natural products have been explored previously: (1) cultivation of single cyanobacterial strains, in bioreactors for example; (2) bulk collections from the environment of so called 'algal blooms' that are dominated by cyanobacteria. In this study a new environmentally friendly collection technique for obtaining large quantities of algal bloom biomass was utilized. Algal biomass derived from eight million liters of lake water was concentrated using a novel continuous countercurrent filtration system. Analysis of this freshwater algal bloom from Grand Lake-Saint Marys, Ohio led to the discovery of anabaenopeptin 679 (1), as well as the known anabaenopeptins B, F, H and 908. Anabaenopeptin 679 is unusual in that it possesses the classical anabaenopeptin-like cyclic pentapeptide core, but lacks the typical sidechain attached to the constitutive ureido group. Screening of all anabaenopeptin derivatives in an enzymatic assay for inhibitory activity toward carboxypeptidase A identified anabaenopeptin 679 as a strong inhibitor of carboxypeptidase A with an IC50value of 4.6μg/mL. This result defines a new minimal core structure for carboxypeptidase activity among the anabaenopeptin class, and provides further insight into the structure-activity relationship of anabaenopeptin-like carboxypeptidase A inhibitors.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Harms
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Kenji L
authors.initials: KL
authors.lastname: Kurita
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: Biosortia Pharmaceuticals, Hollings Marine Lab, 331 Ft. Johnson Road, Charleston, SC 29412 USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wahome
authors.affiliation: Biosortia Pharmaceuticals, Hollings Marine Lab, 331 Ft. Johnson Road, Charleston, SC 29412 USA.
authors.forename: Haiyin
authors.initials: H
authors.lastname: He
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.affiliation: Biosortia Pharmaceuticals, Hollings Marine Lab, 331 Ft. Johnson Road, Charleston, SC 29412 USA.
authors.forename: Guy T
authors.initials: GT
authors.lastname: Carter
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA; Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. Electronic address: rliningt@sfu.ca.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
mesh_terms: D018533:Biomass; D000458:Cyanobacteria / Q000378:metabolism*; D005068:Eutrophication; D005618:Fresh Water; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C000621712:anabaenopeptin 679
keywords: Algal bloom; Anabaenopeptin; Carboxypeptidase inhibitor; Cyanobacteria