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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 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives Tvůrce(i) 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)Číslo článku e2219230120 Zdroj.dok. 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)Poč.str. 9 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova antineoplastic agents ; marine ; anticancer ; analog ; inhibition ; tubulin ; biosynthesis ; efficacy ; targets ; binding ; cyanotoxin ; cytotoxicity ; aetokthonostatin ; dolastatin ; biosynthesis Obor OECD Microbiology CEP GC19-21649J GA ČR - Grantová agentura ČR Způsob publikování Open access Institucionální podpora MBU-M - RVO:61388971 UT WOS 001119347300016 EID SCOPUS 85172660177 DOI 10.1073/pnas.2219230120 Anotace 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. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2024 Elektronická adresa https://www.pnas.org/doi/10.1073/pnas.2219230120
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