Browsing by Subject "MARINE CYANOBACTERIA"

Sort by: Order: Results:

Now showing items 1-6 of 6
  • Jokela, Jouni; Oftedal, Linn; Herfindal, Lars; Permi, Perttu; Wahlsten, Matti; Doskeland, Stein Ove; Sivonen, Kaarina (2012)
  • Humisto, Anu; Jokela, Jouni; Teigen, Knut; Wahlsten, Matti; Permi, Perttu; Sivonen, Kaarina; Herfindal, Lars (2019)
    Hassallidins are cyclic glycolipopeptides produced by cyanobacteria and other prokaryotes. The hassallidin structure consists of a peptide ring of eight amino acids where a fatty acid chain, additional amino acids, and sugar moieties are attached. Hassallidins show antifungal activity against several opportunistic human pathogenic fungi, but does not harbor antibacterial effects. However, they have not been studied on mammalian cells, and the mechanism of action is unknown. We purified hassallidin D from cultured cyanobacterium Anabaena sp. UHCC 0258 and characterized its effect on mammalian and fungal cells. Ultrastructural analysis showed that hassallidin D disrupts cell membranes, causing a lytic/necrotic cell death with rapid presence of disintegrated outer membrane, accompanied by internalization of small molecules such as propidium iodide into the cells. Furthermore, artificial liposomal membrane assay showed that hassallidin D selectively targets sterol-containing membranes. Finally, in silico membrane modeling allowed us to study the interaction between hassallidin D and membranes in detail, and confirm the role of cholesterol for hassallidin-insertion into the membrane. This study demonstrates the mechanism of action of the natural compound hassallidin, and gives further insight into how bioactive lipopeptide metabolites selectively target eukaryotic cell membranes.
  • Tranter, Dale; Paatero, Anja O.; Kawaguchi, Shinsaku; Kazemi, Soheila; Serrill, Jeffrey D.; Kellosalo, Juho; Vogel, Walter K.; Richter, Uwe; Mattos, Daphne R.; Wan, Xuemei; Thornburg, Christopher C.; Oishi, Shinya; McPhail, Kerry L.; Ishmael, Jane E.; Paavilainen, Ville O. (2020)
    Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61 alpha subunit of the Sec61 protein translocon. CbA binding to Sec61 results in broad substratenonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61 that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61 alpha mutations identified from human HCT116 cells su ests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61 alpha mutant R66I remains sensitive to CbA. A further unbiased screen for Sec61 alpha resistance mutations identified the CbA-resistant mutation S71P, which confirms nonidentical binding sites for CbA and apratoxin A and supports the susceptibility of the Sec61 plug region for channel inhibition. Remarkably, CbA, apratoxin A, and ipomoeassin F do not display comparable patterns of potency and selectivity in the NCI60 panel of human cancer cell lines. Our work connecting CbA activity with selective prevention of secretory and membrane protein biogenesis by inhibition of Sec61 opens up possibilities for developing new Sec61 inhibitors with improved druglike properties that are based on the coibamide pharmacophore.
  • Shishido, Tania Keiko; Popin, Rafael Vicentini; Jokela, Jouni; Wahlsten, Matti; Fiore, Marli Fatima; Fewer, David P.; Herfindal, Lars; Sivonen, Kaarina (2020)
    Cyanobacteria are photosynthetic organisms that produce a large diversity of natural products with interesting bioactivities for biotechnological and pharmaceutical applications. Cyanobacterial extracts exhibit toxicity towards other microorganisms and cancer cells and, therefore, represent a source of potentially novel natural products for drug discovery. We tested 62 cyanobacterial strains isolated from various Brazilian biomes for antileukemic and antimicrobial activities. Extracts from 39 strains induced selective apoptosis in acute myeloid leukemia (AML) cancer cell lines. Five of these extracts also exhibited antifungal and antibacterial activities. Chemical and dereplication analyses revealed the production of nine known natural products. Natural products possibly responsible for the observed bioactivities and five unknown, chemically related chlorinated compounds present only in Brazilian cyanobacteria were illustrated in a molecular network. Our results provide new information on the vast biosynthetic potential of cyanobacteria isolated from Brazilian environments.
  • Vicentini Popin, Rafael; Oliveira de Alvarenga, Danillo; Castelo-Branco, Raquel; Fewer, David; Sivonen, Kaarina (2021)
    Microbial natural products are compounds with unique chemical structures and diverse biological activities. Cyanobacteria commonly possess a wide range of biosynthetic gene clusters (BGCs) to produce natural products. Although natural product BGCs have been found in almost all cyanobacterial genomes, little attention has been given in cyanobacterial research to the partitioning of these biosynthetic pathways in chromosomes and plasmids. Cyanobacterial plasmids are believed to disperse several natural product BGCs, such as toxins, by plasmids through horizontal gene transfer. Therefore, plasmids may confer the ability to produce toxins and may play a role in the evolution of diverse natural product BGCs from cyanobacteria. Here, we performed an analysis of the distribution of natural product BGCs in 185 genomes and mapped the presence of genes involved in the conjugation in plasmids. The 185 analyzed genomes revealed 1817 natural products BGCs. Individual genomes contained 1-42 biosynthetic pathways (mean 8), 95% of which were present in chromosomes and the remaining 5% in plasmids. Of the 424 analyzed cyanobacterial plasmids, 12% contained homologs of genes involved in conjugation and natural product biosynthetic pathways. Among the biosynthetic pathways in plasmids, manual curation identified those to produce aeruginosin, anabaenopeptin, ambiguine, cryptophycin, hassallidin, geosmin, and microcystin. These compounds are known toxins, protease inhibitors, odorous compounds, antimicrobials, and antitumorals. The present study provides in silico evidence using genome mining that plasmids may be involved in the distribution of natural product BGCs in cyanobacteria. Consequently, cyanobacterial plasmids have importance in the context of biotechnology, water management, and public health risk assessment. Future research should explore in vivo conjugation and the end products of natural product BGCs in plasmids via chemical analyses.
  • Humisto, Anu Karoliina; Jokela, Jouni Kalevi; Liu, Liwei; Wahlsten, Matti Per-Vilhelm; Wang, Hao; Permi, Perttu Esko Ilari; Machado, João Paulo; Antunes, Agostinho; Fewer, David Peter; Sivonen, Anna Kaarina (2018)
    Swinholides are 42-carbon ring polyketides with a 2-fold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of a symbiotic heterotrophic proteobacterium. Here, we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. strain UHCC 0450. We located the 85-kb trans-AT polyketide synthase (PKS) swinholide biosynthesis gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthesis gene clusters share an almost identical order of catalytic domains, with 85% nucleotide sequence identity, and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthesis cluster from Anabaena sp. strain UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthesis gene clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans-AT PKSs of cyanobacteria and proteobacteria. IMPORTANCE Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here, we show that a terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a 2-fold axis of symmetry, and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthesis gene clusters of swinholide from Nostoc cyanobacteria, as well as the related cytotoxic and antifungal scytophycin from Anabaena cyanobacteria, and we study the evolution of their trans-AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products.