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More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives
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SYSNO ASEP 0582359 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives Author(s) Schwark, M. (DE)
Martinez Yerena, Jose A. (MBU-M)
Roehrborn, K. (DE)
Hrouzek, Pavel (MBU-M) ORCID
Divoká, Petra (MBU-M)
Štenclová, L. (CZ)
Delawská, Kateřina (MBU-M) ORCID
Enke, H. (DE)
Vorreiter, C. (DE)
Wiley, F. (US)
Sippl, W. (DE)
Sobotka, Roman (MBU-M) RID, ORCID
Saha, Subhasish (MBU-M) ORCID
Wilde, Susan B. (US)
Mareš, Jan (MBU-M) ORCID
Niedermeyer, T. H. J. (DE)Article number e2219230120 Source Title Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences - ISSN 0027-8424
Roč. 120, č. 40 (2023)Number of pages 9 s. Language eng - English Country US - United States Keywords antineoplastic agents ; marine ; anticancer ; analog ; inhibition ; tubulin ; biosynthesis ; efficacy ; targets ; binding ; cyanotoxin ; cytotoxicity ; aetokthonostatin ; dolastatin ; biosynthesis OECD category Microbiology R&D Projects GC19-21649J GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 001119347300016 EID SCOPUS 85172660177 DOI 10.1073/pnas.2219230120 Annotation 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 non-ribosomal 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2024 Electronic address https://www.pnas.org/doi/10.1073/pnas.2219230120
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