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Lichens have been widely used in traditional medicine, especially by indigenous communities worldwide. However, their slow growth and difficulties in the isolation of lichen symbionts and associated microbes have hindered the pharmaceutical utilisation of lichen-produced compounds. Advances in high-throughput sequencing techniques now permit detailed investigations of the complex microbial communities formed by fungi, green algae, cyanobacteria, and other bacteria within the lichen thalli. Here, we used amplicon sequencing, shotgun metagenomics, and in silico metabolomics together with compound extractions to study reindeer lichens collected from Southern Finland. Our aim was to evaluate the potential of Cladonia species as sources of novel natural products. We compared the predicted biosynthetic pathways of lichen compounds from isolated genome-sequenced lichen fungi and our environmental samples. Potential biosynthetic genes could then be further used to produce secondary metabolites in more tractable hosts. Furthermore, we detected multiple compounds by metabolite analyses, which revealed connections between the identified biosynthetic gene clusters and their products. Taken together, our results contribute to metagenomic data studies from complex lichen-symbiotic communities and provide valuable new information for use in further biochemical and pharmacological studies.
Tânia Shishido; Matti Wahlsten; Pia Laine; Jouko Rikkinen; Taina Lundell; Petri Auvinen. Microbial Communities of Cladonia Lichens and Their Biosynthetic Gene Clusters Potentially Encoding Natural Products. Microorganisms 2021, 9, 1347 .
AMA StyleTânia Shishido, Matti Wahlsten, Pia Laine, Jouko Rikkinen, Taina Lundell, Petri Auvinen. Microbial Communities of Cladonia Lichens and Their Biosynthetic Gene Clusters Potentially Encoding Natural Products. Microorganisms. 2021; 9 (7):1347.
Chicago/Turabian StyleTânia Shishido; Matti Wahlsten; Pia Laine; Jouko Rikkinen; Taina Lundell; Petri Auvinen. 2021. "Microbial Communities of Cladonia Lichens and Their Biosynthetic Gene Clusters Potentially Encoding Natural Products." Microorganisms 9, no. 7: 1347.
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.
Tania Keiko Shishido; Rafael Vicentini Popin; Jouni Jokela; Matti Wahlsten; Marli Fatima Fiore; David P. Fewer; Lars Herfindal; Kaarina Sivonen. Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria. Toxins 2019, 12, 12 .
AMA StyleTania Keiko Shishido, Rafael Vicentini Popin, Jouni Jokela, Matti Wahlsten, Marli Fatima Fiore, David P. Fewer, Lars Herfindal, Kaarina Sivonen. Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria. Toxins. 2019; 12 (1):12.
Chicago/Turabian StyleTania Keiko Shishido; Rafael Vicentini Popin; Jouni Jokela; Matti Wahlsten; Marli Fatima Fiore; David P. Fewer; Lars Herfindal; Kaarina Sivonen. 2019. "Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria." Toxins 12, no. 1: 12.
Microcystins are a family of chemically diverse hepatotoxins produced by distantly related cyanobacteria and are potent inhibitors of eukaryotic protein phosphatases 1 and 2A. Here we provide evidence for the biosynthesis of rare variants of microcystin that contain a selection of homo-amino acids by the benthic strain Phormidium sp. LP904c. This strain produces at least 16 microcystin chemical variants many of which contain homophenylalanine or homotyrosine. We retrieved the complete 54.2 kb microcystin (mcy) gene cluster from a draft genome assembly. Analysis of the substrate specificity of McyB1 and McyC adenylation domain binding pockets revealed divergent substrate specificity sequences, which could explain the activation of homo-amino acids which were present in 31% of the microcystins detected and included variants such as MC-LHty, MC-HphHty, MC-LHph and MC-HphHph. The mcy gene cluster did not encode enzymes for the synthesis of homo-amino acids but may instead activate homo-amino acids produced during the synthesis of anabaenopeptins. We observed the loss of microcystin during cultivation of a closely related strain, Phormidium sp. DVL1003c. This study increases the knowledge of benthic cyanobacterial strains that produce microcystin variants and broadens the structural diversity of known microcystins.
Tânia Keiko Shishido; Jouni Jokela; Anu Humisto; Suvi Suurnäkki; Matti Wahlsten; Danillo O. Alvarenga; Kaarina Sivonen; David P. Fewer. The Biosynthesis of Rare Homo-Amino Acid Containing Variants of Microcystin by a Benthic Cyanobacterium. Marine Drugs 2019, 17, 271 .
AMA StyleTânia Keiko Shishido, Jouni Jokela, Anu Humisto, Suvi Suurnäkki, Matti Wahlsten, Danillo O. Alvarenga, Kaarina Sivonen, David P. Fewer. The Biosynthesis of Rare Homo-Amino Acid Containing Variants of Microcystin by a Benthic Cyanobacterium. Marine Drugs. 2019; 17 (5):271.
Chicago/Turabian StyleTânia Keiko Shishido; Jouni Jokela; Anu Humisto; Suvi Suurnäkki; Matti Wahlsten; Danillo O. Alvarenga; Kaarina Sivonen; David P. Fewer. 2019. "The Biosynthesis of Rare Homo-Amino Acid Containing Variants of Microcystin by a Benthic Cyanobacterium." Marine Drugs 17, no. 5: 271.
Anabaenopeptins are a diverse group of cyclic peptides, which contain an unusual ureido linkage. Namalides are shorter structural homologues of anabaenopeptins, which also contain an ureido linkage. The biosynthetic origins of namalides are unknown despite a strong resemblance to anabaenopeptins. Here, we show the cyanobacterium Nostoc sp. CENA543 strain producing new (nostamide B–E (2, 4, 5, and 6)) and known variants of anabaenopeptins (schizopeptin 791 (1) and anabaenopeptin 807 (3)). Surprisingly, Nostoc sp. CENA543 also produced namalide B (8) and the new namalides D (7), E (9), and F (10) in similar amounts to anabaenopeptins. Analysis of the complete Nostoc sp. CENA543 genome sequence indicates that both anabaenopeptins and namalides are produced by the same biosynthetic pathway through module skipping during biosynthesis. This unique process involves the skipping of two modules present in different nonribosomal peptide synthetases during the namalide biosynthesis. This skipping is an efficient mechanism since both anabaenopeptins and namalides are synthesized in similar amounts by Nostoc sp. CENA543. Consequently, gene skipping may be used to increase and possibly broaden the chemical diversity of related peptides produced by a single biosynthetic gene cluster. Genome mining demonstrated that the anabaenopeptin gene clusters are widespread in cyanobacteria and can also be found in tectomicrobia bacteria.
Tânia K. Shishido; Jouni Jokela; David P. Fewer; Matti Wahlsten; Marli F. Fiore; Kaarina Sivonen. Simultaneous Production of Anabaenopeptins and Namalides by the Cyanobacterium Nostoc sp. CENA543. ACS Chemical Biology 2017, 12, 2746 -2755.
AMA StyleTânia K. Shishido, Jouni Jokela, David P. Fewer, Matti Wahlsten, Marli F. Fiore, Kaarina Sivonen. Simultaneous Production of Anabaenopeptins and Namalides by the Cyanobacterium Nostoc sp. CENA543. ACS Chemical Biology. 2017; 12 (11):2746-2755.
Chicago/Turabian StyleTânia K. Shishido; Jouni Jokela; David P. Fewer; Matti Wahlsten; Marli F. Fiore; Kaarina Sivonen. 2017. "Simultaneous Production of Anabaenopeptins and Namalides by the Cyanobacterium Nostoc sp. CENA543." ACS Chemical Biology 12, no. 11: 2746-2755.
Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.
Tânia K. Shishido; Anu Humisto; Jouni Jokela; Liwei Liu; Matti Wahlsten; Anisha Tamrakar; David P. Fewer; Perttu Permi; Ana P. D. Andreote; Marli F. Fiore; Kaarina Sivonen. Antifungal Compounds from Cyanobacteria. Marine Drugs 2015, 13, 2124 -2140.
AMA StyleTânia K. Shishido, Anu Humisto, Jouni Jokela, Liwei Liu, Matti Wahlsten, Anisha Tamrakar, David P. Fewer, Perttu Permi, Ana P. D. Andreote, Marli F. Fiore, Kaarina Sivonen. Antifungal Compounds from Cyanobacteria. Marine Drugs. 2015; 13 (4):2124-2140.
Chicago/Turabian StyleTânia K. Shishido; Anu Humisto; Jouni Jokela; Liwei Liu; Matti Wahlsten; Anisha Tamrakar; David P. Fewer; Perttu Permi; Ana P. D. Andreote; Marli F. Fiore; Kaarina Sivonen. 2015. "Antifungal Compounds from Cyanobacteria." Marine Drugs 13, no. 4: 2124-2140.
In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81) cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T) fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML) activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells.
Liwei Liu; Lars Herfindal; Jouni Jokela; Tânia Keiko Shishido; Matti Wahlsten; Stein Ove Døskeland; Kaarina Sivonen. Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells. Marine Drugs 2014, 12, 2036 -2053.
AMA StyleLiwei Liu, Lars Herfindal, Jouni Jokela, Tânia Keiko Shishido, Matti Wahlsten, Stein Ove Døskeland, Kaarina Sivonen. Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells. Marine Drugs. 2014; 12 (4):2036-2053.
Chicago/Turabian StyleLiwei Liu; Lars Herfindal; Jouni Jokela; Tânia Keiko Shishido; Matti Wahlsten; Stein Ove Døskeland; Kaarina Sivonen. 2014. "Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells." Marine Drugs 12, no. 4: 2036-2053.
Many important toxins and antibiotics are produced by non-ribosomal biosynthetic pathways. Microcystins are a chemically diverse family of potent peptide toxins and the end-products of a hybrid NRPS and PKS secondary metabolic pathway. They are produced by a variety of cyanobacteria and are responsible for the poisoning of humans as well as the deaths of wild and domestic animals around the world. The chemical diversity of the microcystin family is attributed to a number of genetic events that have resulted in the diversification of the pathway for microcystin assembly.
Tânia Keiko Shishido; Ulla Kaasalainen; David P Fewer; Leo Rouhiainen; Jouni Jokela; Matti Wahlsten; Marli Fátima Fiore; João Sarkis Yunes; Jouko Rikkinen; Kaarina Sivonen. Convergent evolution of [D-Leucine1] microcystin-LR in taxonomically disparate cyanobacteria. BMC Evolutionary Biology 2013, 13, 86 -86.
AMA StyleTânia Keiko Shishido, Ulla Kaasalainen, David P Fewer, Leo Rouhiainen, Jouni Jokela, Matti Wahlsten, Marli Fátima Fiore, João Sarkis Yunes, Jouko Rikkinen, Kaarina Sivonen. Convergent evolution of [D-Leucine1] microcystin-LR in taxonomically disparate cyanobacteria. BMC Evolutionary Biology. 2013; 13 (1):86-86.
Chicago/Turabian StyleTânia Keiko Shishido; Ulla Kaasalainen; David P Fewer; Leo Rouhiainen; Jouni Jokela; Matti Wahlsten; Marli Fátima Fiore; João Sarkis Yunes; Jouko Rikkinen; Kaarina Sivonen. 2013. "Convergent evolution of [D-Leucine1] microcystin-LR in taxonomically disparate cyanobacteria." BMC Evolutionary Biology 13, no. 1: 86-86.