Cyanobacteria are infamous producers of toxins. While the toxic potential of planktonic cyanobacterial blooms is well documented, the ecosystem level effects of toxigenic benthic and epiphytic cyanobacteria are an understudied threat. The freshwater epiphytic cyanobacterium Aetokthonos hydrillicola has recently been shown to produce the "eagle killer" neurotoxin aetokthonotoxin (AETX) causing the fatal neurological disease vacuolar myelinopathy. The disease affects a wide array of wildlife in the southeastern United States, most notably waterfowl and birds of prey, including the bald eagle. In an assay for cytotoxicity, we found the crude extract of the cyanobacterium to be much more potent than pure AETX, prompting further investigation. Here, we describe the isolation and structure elucidation of the aetokthonostatins (AESTs), linear peptides belonging to the dolastatin compound family, featuring a unique modification of the C-terminal phenylalanine-derived moiety. Using immunofluorescence microscopy and molecular modeling, we confirmed that AEST potently impacts microtubule dynamics and can bind to tubulin in a similar matter as dolastatin 10. We also show that AEST inhibits reproduction of the nematode Caenorhabditis elegans. Bioinformatic analysis revealed the AEST biosynthetic gene cluster encoding a nonribosomal peptide synthetase/polyketide synthase accompanied by a unique tailoring machinery. The biosynthetic activity of a specific N-terminal methyltransferase was confirmed by in vitro biochemical studies, establishing a mechanistic link between the gene cluster and its product.

• Klíčová slova
• aetokthonostatin, biosynthesis, cyanotoxin, cytotoxicity, dolastatin,
• MeSH
• Accipitridae * MeSH
• Caenorhabditis elegans MeSH
• ekosystém MeSH
• sinice * genetika   MeSH
• sladká voda MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aetokthonotoxin MeSH Prohlížeč

Vacuolar myelinopathy is a fatal neurological disease that was initially discovered during a mysterious mass mortality of bald eagles in Arkansas in the United States. The cause of this wildlife disease has eluded scientists for decades while its occurrence has continued to spread throughout freshwater reservoirs in the southeastern United States. Recent studies have demonstrated that vacuolar myelinopathy is induced by consumption of the epiphytic cyanobacterial species Aetokthonos hydrillicola growing on aquatic vegetation, primarily the invasive Hydrilla verticillata Here, we describe the identification, biosynthetic gene cluster, and biological activity of aetokthonotoxin, a pentabrominated biindole alkaloid that is produced by the cyanobacterium A. hydrillicola We identify this cyanobacterial neurotoxin as the causal agent of vacuolar myelinopathy and discuss environmental factors-especially bromide availability-that promote toxin production.

• MeSH
• Accipitridae * MeSH
• bakteriální geny MeSH
• bakteriální toxiny biosyntéza   chemie   izolace a purifikace   toxicita   MeSH
• brom analýza   MeSH
• bromidy metabolismus   MeSH
• Caenorhabditis elegans účinky léků   MeSH
• dánio pruhované MeSH
• demyelinizační nemoci chemicky indukované   veterinární   MeSH
• Hydrocharitaceae metabolismus   mikrobiologie   MeSH
• indolové alkaloidy chemie   izolace a purifikace   toxicita   MeSH
• kur domácí MeSH
• LD50 MeSH
• multigenová rodina MeSH
• nemoci ptáků chemicky indukované   MeSH
• neurotoxiny biosyntéza   chemie   izolace a purifikace   toxicita   MeSH
• sinice * genetika   růst a vývoj   metabolismus   MeSH
• tryptofan metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• jihovýchod USA MeSH
• Názvy látek
• bakteriální toxiny MeSH
• brom MeSH
• bromidy MeSH
• indolové alkaloidy MeSH
• neurotoxiny MeSH
• tryptofan MeSH