More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives.

Autor:	Schwark M; Institute of Pharmacy, Pharmacognosy, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany., Martínez Yerena JA; Biology Centre of the Czech Academy of Sciences, Institute of Hydrobiology, České Budějovice 37005, Czech Republic.; Faculty of Science, University of South Bohemia, České Budějovice 37005, Czech Republic.; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Röhrborn K; Institute of Pharmacy, Pharmacognosy, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany., Hrouzek P; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Divoká P; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Štenclová L; Biology Centre of the Czech Academy of Sciences, Institute of Hydrobiology, České Budějovice 37005, Czech Republic., Delawská K; Faculty of Science, University of South Bohemia, České Budějovice 37005, Czech Republic.; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Enke H; Simris Biologics GmbH, Berlin 12489, Germany., Vorreiter C; Institute of Pharmacy, Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany., Wiley F; Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, National Oceanic and Atmospheric Administration/National Ocean Service, Charleston, SC 29412., Sippl W; Institute of Pharmacy, Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany., Sobotka R; Faculty of Science, University of South Bohemia, České Budějovice 37005, Czech Republic.; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Saha S; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Wilde SB; Warnell School of Forestry and Natural Resources, Fisheries and Wildlife, University of Georgia, Athens, GA 30602., Mareš J; Biology Centre of the Czech Academy of Sciences, Institute of Hydrobiology, České Budějovice 37005, Czech Republic.; Faculty of Science, University of South Bohemia, České Budějovice 37005, Czech Republic.; Centre Algatech, Institute of Microbiology of the Czech Academy of Sciences, Třeboň 37901, Czech Republic., Niedermeyer THJ; Institute of Pharmacy, Pharmacognosy, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06120, Germany.; Institute of Pharmacy, Pharmaceutical Biology, Free University of Berlin, Berlin 14195, Germany.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Oct 03; Vol. 120 (40), pp. e2219230120. Date of Electronic Publication: 2023 Sep 26.
DOI:	10.1073/pnas.2219230120
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu