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David P. Fewer
Department of Microbiology University of Helsinki Helsinki Finland

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Special issue article
Published: 18 June 2021 in Physiologia Plantarum
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Cyanobacteria produce a variety of chemically diverse cyclic lipopeptides with potent antifungal activities. These cyclic lipopeptides have an amphipathic structure comprised of a polar peptide cycle and hydrophobic fatty acid side chain. Many have antibiotic activity against a range of human and plant fungal pathogens. This review article aims to summarize the present knowledge on the chemical diversity and cellular effects of cyanobacterial cyclic lipopeptides that display antifungal activity. Cyclic antifungal lipopeptides from cyanobacteria commonly fall into four structural classes; hassallidins, puwainaphycins, laxaphycins, and anabaenolysins. Many of these antifungal cyclic lipopeptides act through cholesterol and ergosterol-dependent disruption of membranes. In many cases, the cyclic lipopeptides also exert cytotoxicity in human cells, and a more extensive examination of their biological activity and structure–activity relationship is warranted. The hassallidin, puwainaphycin, laxaphycin, and anabaenolysin structural classes are unified through shared complex biosynthetic pathways that encode a variety of unusual lipoinitiation mechanisms and branched biosynthesis that promote their chemical diversity. However, the biosynthetic origins of some cyanobacterial cyclic lipopeptides and the mechanisms, which drive their structural diversification in general, remain poorly understood. The strong functional convergence of differently organized chemical structures suggests that the production of lipopeptide confers benefits for their producer. Whether these benefits originate from their antifungal activity or some other physiological function remains to be answered in the future. However, it is clear that cyanobacteria encode a wealth of new cyclic lipopeptides with novel biotechnological and therapeutic applications.

ACS Style

David P. Fewer; Jouni Jokela; Lassi Heinilä; Reidun Aesoy; Kaarina Sivonen; Tomáš Galica; Pavel Hrouzek; Lars Herfindal. Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria. Physiologia Plantarum 2021, 1 .

AMA Style

David P. Fewer, Jouni Jokela, Lassi Heinilä, Reidun Aesoy, Kaarina Sivonen, Tomáš Galica, Pavel Hrouzek, Lars Herfindal. Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria. Physiologia Plantarum. 2021; ():1.

Chicago/Turabian Style

David P. Fewer; Jouni Jokela; Lassi Heinilä; Reidun Aesoy; Kaarina Sivonen; Tomáš Galica; Pavel Hrouzek; Lars Herfindal. 2021. "Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria." Physiologia Plantarum , no. : 1.

Paper
Published: 04 June 2021 in Organic & Biomolecular Chemistry
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Laxaphycins are a family of cyclic lipopeptides with synergistic antifungal and antiproliferative activities.

ACS Style

Lassi Matti Petteri Heinilä; David Peter Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Xiaodan Ouyang; Perttu Permi; Anna Jortikka; Kaarina Sivonen. The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family. Organic & Biomolecular Chemistry 2021, 1 .

AMA Style

Lassi Matti Petteri Heinilä, David Peter Fewer, Jouni Kalevi Jokela, Matti Wahlsten, Xiaodan Ouyang, Perttu Permi, Anna Jortikka, Kaarina Sivonen. The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family. Organic & Biomolecular Chemistry. 2021; ():1.

Chicago/Turabian Style

Lassi Matti Petteri Heinilä; David Peter Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Xiaodan Ouyang; Perttu Permi; Anna Jortikka; Kaarina Sivonen. 2021. "The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family." Organic & Biomolecular Chemistry , no. : 1.

Journal article
Published: 24 May 2021 in Marine Drugs
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Sponges form symbiotic relationships with diverse and abundant microbial communities. Cyanobacteria are among the most important members of the microbial communities that are associated with sponges. Here, we performed a genus-wide comparative genomic analysis of the newly described marine benthic cyanobacterial genus Leptothoe (Synechococcales). We obtained draft genomes from Le. kymatousa TAU-MAC 1615 and Le. spongobia TAU-MAC 1115, isolated from marine sponges. We identified five additional Leptothoe genomes, host-associated or free-living, using a phylogenomic approach, and the comparison of all genomes showed that the sponge-associated strains display features of a symbiotic lifestyle. Le. kymatousa and Le. spongobia have undergone genome reduction; they harbored considerably fewer genes encoding for (i) cofactors, vitamins, prosthetic groups, pigments, proteins, and amino acid biosynthesis; (ii) DNA repair; (iii) antioxidant enzymes; and (iv) biosynthesis of capsular and extracellular polysaccharides. They have also lost several genes related to chemotaxis and motility. Eukaryotic-like proteins, such as ankyrin repeats, playing important roles in sponge-symbiont interactions, were identified in sponge-associated Leptothoe genomes. The sponge-associated Leptothoe stains harbored biosynthetic gene clusters encoding novel natural products despite genome reduction. Comparisons of the biosynthetic capacities of Leptothoe with chemically rich cyanobacteria revealed that Leptothoe is another promising marine cyanobacterium for the biosynthesis of novel natural products.

ACS Style

Despoina Konstantinou; Rafael Popin; David Fewer; Kaarina Sivonen; Spyros Gkelis. Genome Reduction and Secondary Metabolism of the Marine Sponge-Associated Cyanobacterium Leptothoe. Marine Drugs 2021, 19, 298 .

AMA Style

Despoina Konstantinou, Rafael Popin, David Fewer, Kaarina Sivonen, Spyros Gkelis. Genome Reduction and Secondary Metabolism of the Marine Sponge-Associated Cyanobacterium Leptothoe. Marine Drugs. 2021; 19 (6):298.

Chicago/Turabian Style

Despoina Konstantinou; Rafael Popin; David Fewer; Kaarina Sivonen; Spyros Gkelis. 2021. "Genome Reduction and Secondary Metabolism of the Marine Sponge-Associated Cyanobacterium Leptothoe." Marine Drugs 19, no. 6: 298.

Special issue article
Published: 07 May 2021 in Physiologia Plantarum
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The use of photosynthetic microbes as synthetic biology hosts for the sustainable production of commodity chemicals and even fuels has received increasing attention over the last decade. The number of studies published, tools implemented, and resources made available for microalgae have increased beyond expectations during the last few years. However, the tools available for genetic engineering in these organisms still lag those available for the more commonly used heterotrophic host organisms. In this mini‐review, we provide an overview of the photosynthetic microbes most commonly used in synthetic biology studies, namely cyanobacteria, chlorophytes, eustigmatophytes and diatoms. We provide basic information on the techniques and tools available for each model group of organisms, we outline the state‐of‐the‐art, and we list the synthetic biology tools that have been successfully used. We specifically focus on the latest CRISPR developments, as we believe that precision editing and advanced genetic engineering tools will be pivotal to the advancement of the field. Finally, we discuss the relative strengths and weaknesses of each group of organisms and examine the challenges that need to be overcome to achieve their synthetic biology potential.

ACS Style

Konstantinos Vavitsas; Amit Kugler; Alessandro Satta; Dimitris G. Hatzinikolaou; Peter Lindblad; David P. Fewer; Pia Lindberg; Mervi Toivari; Karin Stensjö. Doing synthetic biology with photosynthetic microorganisms. Physiologia Plantarum 2021, 1 .

AMA Style

Konstantinos Vavitsas, Amit Kugler, Alessandro Satta, Dimitris G. Hatzinikolaou, Peter Lindblad, David P. Fewer, Pia Lindberg, Mervi Toivari, Karin Stensjö. Doing synthetic biology with photosynthetic microorganisms. Physiologia Plantarum. 2021; ():1.

Chicago/Turabian Style

Konstantinos Vavitsas; Amit Kugler; Alessandro Satta; Dimitris G. Hatzinikolaou; Peter Lindblad; David P. Fewer; Pia Lindberg; Mervi Toivari; Karin Stensjö. 2021. "Doing synthetic biology with photosynthetic microorganisms." Physiologia Plantarum , no. : 1.

Comment
Published: 15 February 2021 in Nature Chemical Biology
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Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.

ACS Style

Michelle A. Schorn; Stefan Verhoeven; Lars Ridder; Florian Huber; Deepa D. Acharya; Alexander A. Aksenov; Gajender Aleti; Jamshid Amiri Moghaddam; Allegra T. Aron; Saefuddin Aziz; Anelize Bauermeister; Katherine D. Bauman; Martin Baunach; Christine Beemelmanns; J. Michael Beman; María Victoria Berlanga-Clavero; Alex A. Blacutt; Helge B. Bode; Anne Boullie; Asker Brejnrod; Tim S. Bugni; Alexandra Calteau; Liu Cao; Víctor J. Carrión; Raquel Castelo-Branco; Shaurya Chanana; Alexander B. Chase; Marc G. Chevrette; Leticia V. Costa-Lotufo; Jason M. Crawford; Cameron R. Currie; Bart Cuypers; Tam Dang; Tristan de Rond; Alyssa M. Demko; Elke Dittmann; Chao Du; Christopher Drozd; Jean-Claude Dujardin; Rachel J. Dutton; Anna Edlund; David P. Fewer; Neha Garg; Julia M. Gauglitz; Emily C. Gentry; Lena Gerwick; Evgenia Glukhov; Harald Gross; Muriel Gugger; Dulce G. Guillén Matus; Eric J. N. Helfrich; Benjamin-Florian Hempel; Jae-Seoun Hur; Marianna Iorio; Paul R. Jensen; Kyo Bin Kang; Leonard Kaysser; Neil L. Kelleher; Chung Sub Kim; Ki Hyun Kim; Irina Koester; Gabriele M. König; Tiago Leao; Seoung Rak Lee; Yi-Yuan Lee; Xuanji Li; Jessica C. Little; Katherine N. Maloney; Daniel Männle; Christian Martin H.; Andrew C. McAvoy; Willam W. Metcalf; Hosein Mohimani; Carlos Molina-Santiago; Bradley S. Moore; Michael W. Mullowney; Mitchell Muskat; Louis-Félix Nothias; Ellis C. O’Neill; Elizabeth I. Parkinson; Daniel Petras; Jörn Piel; Emily C. Pierce; Karine Pires; Raphael Reher; Diego Romero; M. Caroline Roper; Michael Rust; Hamada Saad; Carmen Saenz; Laura M. Sanchez; Søren Johannes Sørensen; Margherita Sosio; Roderich D. Süssmuth; Douglas Sweeney; Kapil Tahlan; Regan J. Thomson; Nicholas J. Tobias; Amaro E. Trindade-Silva; Gilles P. van Wezel; Mingxun Wang; Kelly C. Weldon; Fan Zhang; Nadine Ziemert; Katherine R. Duncan; Max Crüsemann; Simon Rogers; Pieter C. Dorrestein; Marnix H. Medema; Justin J. J. van der Hooft. A community resource for paired genomic and metabolomic data mining. Nature Chemical Biology 2021, 17, 363 -368.

AMA Style

Michelle A. Schorn, Stefan Verhoeven, Lars Ridder, Florian Huber, Deepa D. Acharya, Alexander A. Aksenov, Gajender Aleti, Jamshid Amiri Moghaddam, Allegra T. Aron, Saefuddin Aziz, Anelize Bauermeister, Katherine D. Bauman, Martin Baunach, Christine Beemelmanns, J. Michael Beman, María Victoria Berlanga-Clavero, Alex A. Blacutt, Helge B. Bode, Anne Boullie, Asker Brejnrod, Tim S. Bugni, Alexandra Calteau, Liu Cao, Víctor J. Carrión, Raquel Castelo-Branco, Shaurya Chanana, Alexander B. Chase, Marc G. Chevrette, Leticia V. Costa-Lotufo, Jason M. Crawford, Cameron R. Currie, Bart Cuypers, Tam Dang, Tristan de Rond, Alyssa M. Demko, Elke Dittmann, Chao Du, Christopher Drozd, Jean-Claude Dujardin, Rachel J. Dutton, Anna Edlund, David P. Fewer, Neha Garg, Julia M. Gauglitz, Emily C. Gentry, Lena Gerwick, Evgenia Glukhov, Harald Gross, Muriel Gugger, Dulce G. Guillén Matus, Eric J. N. Helfrich, Benjamin-Florian Hempel, Jae-Seoun Hur, Marianna Iorio, Paul R. Jensen, Kyo Bin Kang, Leonard Kaysser, Neil L. Kelleher, Chung Sub Kim, Ki Hyun Kim, Irina Koester, Gabriele M. König, Tiago Leao, Seoung Rak Lee, Yi-Yuan Lee, Xuanji Li, Jessica C. Little, Katherine N. Maloney, Daniel Männle, Christian Martin H., Andrew C. McAvoy, Willam W. Metcalf, Hosein Mohimani, Carlos Molina-Santiago, Bradley S. Moore, Michael W. Mullowney, Mitchell Muskat, Louis-Félix Nothias, Ellis C. O’Neill, Elizabeth I. Parkinson, Daniel Petras, Jörn Piel, Emily C. Pierce, Karine Pires, Raphael Reher, Diego Romero, M. Caroline Roper, Michael Rust, Hamada Saad, Carmen Saenz, Laura M. Sanchez, Søren Johannes Sørensen, Margherita Sosio, Roderich D. Süssmuth, Douglas Sweeney, Kapil Tahlan, Regan J. Thomson, Nicholas J. Tobias, Amaro E. Trindade-Silva, Gilles P. van Wezel, Mingxun Wang, Kelly C. Weldon, Fan Zhang, Nadine Ziemert, Katherine R. Duncan, Max Crüsemann, Simon Rogers, Pieter C. Dorrestein, Marnix H. Medema, Justin J. J. van der Hooft. A community resource for paired genomic and metabolomic data mining. Nature Chemical Biology. 2021; 17 (4):363-368.

Chicago/Turabian Style

Michelle A. Schorn; Stefan Verhoeven; Lars Ridder; Florian Huber; Deepa D. Acharya; Alexander A. Aksenov; Gajender Aleti; Jamshid Amiri Moghaddam; Allegra T. Aron; Saefuddin Aziz; Anelize Bauermeister; Katherine D. Bauman; Martin Baunach; Christine Beemelmanns; J. Michael Beman; María Victoria Berlanga-Clavero; Alex A. Blacutt; Helge B. Bode; Anne Boullie; Asker Brejnrod; Tim S. Bugni; Alexandra Calteau; Liu Cao; Víctor J. Carrión; Raquel Castelo-Branco; Shaurya Chanana; Alexander B. Chase; Marc G. Chevrette; Leticia V. Costa-Lotufo; Jason M. Crawford; Cameron R. Currie; Bart Cuypers; Tam Dang; Tristan de Rond; Alyssa M. Demko; Elke Dittmann; Chao Du; Christopher Drozd; Jean-Claude Dujardin; Rachel J. Dutton; Anna Edlund; David P. Fewer; Neha Garg; Julia M. Gauglitz; Emily C. Gentry; Lena Gerwick; Evgenia Glukhov; Harald Gross; Muriel Gugger; Dulce G. Guillén Matus; Eric J. N. Helfrich; Benjamin-Florian Hempel; Jae-Seoun Hur; Marianna Iorio; Paul R. Jensen; Kyo Bin Kang; Leonard Kaysser; Neil L. Kelleher; Chung Sub Kim; Ki Hyun Kim; Irina Koester; Gabriele M. König; Tiago Leao; Seoung Rak Lee; Yi-Yuan Lee; Xuanji Li; Jessica C. Little; Katherine N. Maloney; Daniel Männle; Christian Martin H.; Andrew C. McAvoy; Willam W. Metcalf; Hosein Mohimani; Carlos Molina-Santiago; Bradley S. Moore; Michael W. Mullowney; Mitchell Muskat; Louis-Félix Nothias; Ellis C. O’Neill; Elizabeth I. Parkinson; Daniel Petras; Jörn Piel; Emily C. Pierce; Karine Pires; Raphael Reher; Diego Romero; M. Caroline Roper; Michael Rust; Hamada Saad; Carmen Saenz; Laura M. Sanchez; Søren Johannes Sørensen; Margherita Sosio; Roderich D. Süssmuth; Douglas Sweeney; Kapil Tahlan; Regan J. Thomson; Nicholas J. Tobias; Amaro E. Trindade-Silva; Gilles P. van Wezel; Mingxun Wang; Kelly C. Weldon; Fan Zhang; Nadine Ziemert; Katherine R. Duncan; Max Crüsemann; Simon Rogers; Pieter C. Dorrestein; Marnix H. Medema; Justin J. J. van der Hooft. 2021. "A community resource for paired genomic and metabolomic data mining." Nature Chemical Biology 17, no. 4: 363-368.

Preprint content
Published: 30 May 2020
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Cyanobacteria produce a wide range of lipopeptides that exhibit potent membrane-disrupting activities. Laxaphycins consist of two families of structurally distinct macrocyclic lipopeptides that act in a synergistic manner to produce antifungal and antiproliferative activities. Laxaphycins are produced by range of cyanobacteria but their biosynthetic origins remain unclear. Here, we identified the biosynthetic pathways responsible for the biosynthesis of the laxaphycins produced by Scytonema hofmannii PCC 7110. We show that these laxaphycins, called scytocyclamides, are produced by this cyanobacterium and are encoded in a single biosynthetic gene cluster with shared polyketide synthase enzymes initiating two distinct non-ribosomal peptide synthetase pathways. To our knowledge, laxaphycins are the first clearly distinct polyketide synthase and non-ribosomal peptide synthetase hybrid natural products with shared branched biosynthesis. The unusual mechanism of shared enzymes synthesizing two distinct types of products may aid future research in identifying and expressing natural product biosynthetic pathways and in expanding the known biosynthetic logic of this important family of natural products.

ACS Style

Lassi Matti Petteri Heinilä; David P Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Anna Jortikka; Kaarina Sivonen. Shared PKS modules in biosynthesis of synergistic laxaphycins. 2020, 1 .

AMA Style

Lassi Matti Petteri Heinilä, David P Fewer, Jouni Kalevi Jokela, Matti Wahlsten, Anna Jortikka, Kaarina Sivonen. Shared PKS modules in biosynthesis of synergistic laxaphycins. . 2020; ():1.

Chicago/Turabian Style

Lassi Matti Petteri Heinilä; David P Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Anna Jortikka; Kaarina Sivonen. 2020. "Shared PKS modules in biosynthesis of synergistic laxaphycins." , no. : 1.

Preprint content
Published: 16 April 2020
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Cyanobacteria form harmful mass blooms in freshwater and marine environments around the world. A range of secondary metabolites has been identified from cultures of cyanobacteria and biomass collected from cyanobacterial bloom events. A comprehensive database is necessary to correctly identify cyanobacterial metabolites and advance research on their abundance, persistence and toxicity in natural environments. We consolidated open access databases and manually curated missing information from the literature published between 1970 and March 2020. The result is the database CyanoMetDB, which includes more than 2000 entries based on more than 750 literature references. This effort has more than doubled the total number of entries with complete literature metadata and structural composition (SMILES codes) compared to publicly available databases to this date. Over the past decade, more than one hundred additional secondary metabolites have been identified yearly. We organized all entries into structural classes and conducted substructure searches of the provided SMILES codes. This approach demonstrated, for example, that 65% of the compounds carry at least one peptide bond, 57% are cyclic compounds, and 30% carry at least one halogen atom. Structural searches by SMILES code can be further specified to identify structural motifs that are relevant for analytical approaches, research on biosynthetic pathways, bioactivity-guided analysis, or to facilitate predictive science and modeling efforts on cyanobacterial metabolites. This database facilitates rapid identification of cyanobacterial metabolites from toxic blooms, research on the biosynthesis of cyanobacterial natural products, and the identification of novel natural products from cyanobacteria.

ACS Style

Martin R. Jones; Ernani Pinto; Mariana A. Torres; Fabiane Doerr; Hanna Mazur-Marzec; Karolina Szubert; Luciana Tartaglione; Carmela Dell’Aversano; Christopher O. Miles; Daniel G. Beach; Pearse McCarron; Kaarina Sivonen; David P. Fewer; Jouni Jokela; Elisabeth M.-L. Janssen. Comprehensive database of secondary metabolites from cyanobacteria. 2020, 1 .

AMA Style

Martin R. Jones, Ernani Pinto, Mariana A. Torres, Fabiane Doerr, Hanna Mazur-Marzec, Karolina Szubert, Luciana Tartaglione, Carmela Dell’Aversano, Christopher O. Miles, Daniel G. Beach, Pearse McCarron, Kaarina Sivonen, David P. Fewer, Jouni Jokela, Elisabeth M.-L. Janssen. Comprehensive database of secondary metabolites from cyanobacteria. . 2020; ():1.

Chicago/Turabian Style

Martin R. Jones; Ernani Pinto; Mariana A. Torres; Fabiane Doerr; Hanna Mazur-Marzec; Karolina Szubert; Luciana Tartaglione; Carmela Dell’Aversano; Christopher O. Miles; Daniel G. Beach; Pearse McCarron; Kaarina Sivonen; David P. Fewer; Jouni Jokela; Elisabeth M.-L. Janssen. 2020. "Comprehensive database of secondary metabolites from cyanobacteria." , no. : 1.

Journal article
Published: 11 April 2020 in Toxins
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Cyanobacteria produce an array of toxins that pose serious health risks to humans and animals. The closely related diazotrophic genera, Anabaena, Dolichospermum and Aphanizomenon, frequently form poisonous blooms in lakes and brackish waters around the world. These genera form a complex now termed the Anabaena, Dolichospermum and Aphanizomenon (ADA) clade and produce a greater array of toxins than any other cyanobacteria group. However, taxonomic confusion masks the distribution of toxin biosynthetic pathways in cyanobacteria. Here we obtained 11 new draft genomes to improve the understanding of toxin production in these genera. Comparison of secondary metabolite pathways in all available 31 genomes for these three genera suggests that the ability to produce microcystin, anatoxin-a, and saxitoxin is associated with specific subgroups. Each toxin gene cluster was concentrated or even limited to a certain subgroup within the ADA clade. Our results indicate that members of the ADA clade encode a variety of secondary metabolites following the phylogenetic clustering of constituent species. The newly sequenced members of the ADA clade show that phylogenetic separation of planktonic Dolichospermum and benthic Anabaena is not complete. This underscores the importance of taxonomic revision of Anabaena, Dolichospermum and Aphanizomenon genera to reflect current phylogenomic understanding.

ACS Style

Julia Österholm; Rafael V. Popin; David P. Fewer; Kaarina Sivonen. Phylogenomic Analysis of Secondary Metabolism in the Toxic Cyanobacterial Genera Anabaena, Dolichospermum and Aphanizomenon. Toxins 2020, 12, 248 .

AMA Style

Julia Österholm, Rafael V. Popin, David P. Fewer, Kaarina Sivonen. Phylogenomic Analysis of Secondary Metabolism in the Toxic Cyanobacterial Genera Anabaena, Dolichospermum and Aphanizomenon. Toxins. 2020; 12 (4):248.

Chicago/Turabian Style

Julia Österholm; Rafael V. Popin; David P. Fewer; Kaarina Sivonen. 2020. "Phylogenomic Analysis of Secondary Metabolism in the Toxic Cyanobacterial Genera Anabaena, Dolichospermum and Aphanizomenon." Toxins 12, no. 4: 248.

Journal article
Published: 24 December 2019 in Toxins
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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.

ACS Style

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 Style

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 (1):12.

Chicago/Turabian Style

Tania 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.

Review
Published: 06 November 2019 in The FEBS Journal
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Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two-step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre-existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.

ACS Style

David P. Fewer; Mikko Metsä‐Ketelä. A pharmaceutical model for the molecular evolution of microbial natural products. The FEBS Journal 2019, 287, 1429 -1449.

AMA Style

David P. Fewer, Mikko Metsä‐Ketelä. A pharmaceutical model for the molecular evolution of microbial natural products. The FEBS Journal. 2019; 287 (7):1429-1449.

Chicago/Turabian Style

David P. Fewer; Mikko Metsä‐Ketelä. 2019. "A pharmaceutical model for the molecular evolution of microbial natural products." The FEBS Journal 287, no. 7: 1429-1449.

Research article
Published: 01 November 2019 in ACS Chemical Biology
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Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino and carboxy termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clus-ters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus gene clusters encodes two copies of the cyanobactin prenyltransfer-ase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide sub-strate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc sp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyl-transferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxa-zole linear peptides.

ACS Style

Antti Mattila; Rose-Marie Andsten; Mikael Jumppanen; Michele Assante; Jouni Jokela; Matti Wahlsten; Kornelia M. Mikula; Cihad Sigindere; Daniel H. Kwak; Muriel Gugger; Harri Koskela; Kaarina Sivonen; Xinyu Liu; Jari Yli-Kauhaluoma; Hideo Iwaï; David P. Fewer. Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B. ACS Chemical Biology 2019, 14, 2683 -2690.

AMA Style

Antti Mattila, Rose-Marie Andsten, Mikael Jumppanen, Michele Assante, Jouni Jokela, Matti Wahlsten, Kornelia M. Mikula, Cihad Sigindere, Daniel H. Kwak, Muriel Gugger, Harri Koskela, Kaarina Sivonen, Xinyu Liu, Jari Yli-Kauhaluoma, Hideo Iwaï, David P. Fewer. Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B. ACS Chemical Biology. 2019; 14 (12):2683-2690.

Chicago/Turabian Style

Antti Mattila; Rose-Marie Andsten; Mikael Jumppanen; Michele Assante; Jouni Jokela; Matti Wahlsten; Kornelia M. Mikula; Cihad Sigindere; Daniel H. Kwak; Muriel Gugger; Harri Koskela; Kaarina Sivonen; Xinyu Liu; Jari Yli-Kauhaluoma; Hideo Iwaï; David P. Fewer. 2019. "Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B." ACS Chemical Biology 14, no. 12: 2683-2690.

Journal article
Published: 07 May 2019 in Marine Drugs
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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.

ACS Style

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 Style

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 (5):271.

Chicago/Turabian Style

Tânia 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.

Journal article
Published: 15 February 2019 in Applied and Environmental Microbiology
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Herein, we deciphered the most important biosynthetic traits of a prominent group of bioactive lipopeptides. We reveal evidence for initiation of biosynthesis by two alternative starter units hardwired directly in the same gene cluster, eventually resulting in the production of a remarkable range of lipopeptide variants. We identified several unusual tailoring genes potentially involved in modifying the fatty acid chain. Careful characterization of these biosynthetic gene clusters and their diverse products could provide important insight into lipopeptide biosynthesis in prokaryotes. Some of the variants identified exhibit cytotoxic and antifungal properties, and some are associated with a toxigenic biofilm-forming strain. The findings may prove valuable to researchers in the fields of natural product discovery and toxicology.

ACS Style

Jan Mareš; Jan Hájek; Petra Urajová; Andreja Kust; Jouni Jokela; Kumar Saurav; Tomáš Galica; Kateřina Čapková; Antti Mattila; Esa Haapaniemi; Perttu Permi; Ivar Mysterud; Olav M. Skulberg; Jan Karlsen; David P. Fewer; Kaarina Sivonen; Hanne Hjorth Tønnesen; Pavel Hrouzek. Alternative Biosynthetic Starter Units Enhance the Structural Diversity of Cyanobacterial Lipopeptides. Applied and Environmental Microbiology 2019, 85, 1 .

AMA Style

Jan Mareš, Jan Hájek, Petra Urajová, Andreja Kust, Jouni Jokela, Kumar Saurav, Tomáš Galica, Kateřina Čapková, Antti Mattila, Esa Haapaniemi, Perttu Permi, Ivar Mysterud, Olav M. Skulberg, Jan Karlsen, David P. Fewer, Kaarina Sivonen, Hanne Hjorth Tønnesen, Pavel Hrouzek. Alternative Biosynthetic Starter Units Enhance the Structural Diversity of Cyanobacterial Lipopeptides. Applied and Environmental Microbiology. 2019; 85 (4):1.

Chicago/Turabian Style

Jan Mareš; Jan Hájek; Petra Urajová; Andreja Kust; Jouni Jokela; Kumar Saurav; Tomáš Galica; Kateřina Čapková; Antti Mattila; Esa Haapaniemi; Perttu Permi; Ivar Mysterud; Olav M. Skulberg; Jan Karlsen; David P. Fewer; Kaarina Sivonen; Hanne Hjorth Tønnesen; Pavel Hrouzek. 2019. "Alternative Biosynthetic Starter Units Enhance the Structural Diversity of Cyanobacterial Lipopeptides." Applied and Environmental Microbiology 85, no. 4: 1.

Research article
Published: 19 November 2018 in Biochemistry
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Aromatic prenylation is an important step in the biosynthesis of many natural products and leads to an astonishing diversity of chemical structures. Cyanobactin pathways frequently encode aromatic prenyltransferases that catalyze the prenylation of these macrocyclic and linear peptides. Here we characterized the anacyclamide (acy) biosynthetic gene cluster from Anabaena sp. UHCC-0232. Partial reconstitution of the anacyclamide pathway, heterologous expression and in vitro biochemical characterization of the enzyme demonstrate that the AcyF enzyme encoded in this biosynthetic gene cluster is a Trp N-prenyltransferase. Phylogenetic analysis suggests the monophyletic origin and rapid diversification of the cyanobactin prenyltransferase enzymes and the multiple origins of N-1 Trp prenylation in prenylated natural products. The AcyF enzyme displayed high flexibility towards a range of Trp-containing substrates and represents an interesting new tool for biocatalytic applications.

ACS Style

Luca Dalponte; Anirudra Parajuli; Ellen Younger; Antti Mattila; Jouni Jokela; Matti Wahlsten; Niina Leikoski; Kaarina Sivonen; Scott Jarmusch; Wael ElSayed Houssen; David P. Fewer. N-Prenylation of Tryptophan by an Aromatic Prenyltransferase from the Cyanobactin Biosynthetic Pathway. Biochemistry 2018, 57, 6860 -6867.

AMA Style

Luca Dalponte, Anirudra Parajuli, Ellen Younger, Antti Mattila, Jouni Jokela, Matti Wahlsten, Niina Leikoski, Kaarina Sivonen, Scott Jarmusch, Wael ElSayed Houssen, David P. Fewer. N-Prenylation of Tryptophan by an Aromatic Prenyltransferase from the Cyanobactin Biosynthetic Pathway. Biochemistry. 2018; 57 (50):6860-6867.

Chicago/Turabian Style

Luca Dalponte; Anirudra Parajuli; Ellen Younger; Antti Mattila; Jouni Jokela; Matti Wahlsten; Niina Leikoski; Kaarina Sivonen; Scott Jarmusch; Wael ElSayed Houssen; David P. Fewer. 2018. "N-Prenylation of Tryptophan by an Aromatic Prenyltransferase from the Cyanobactin Biosynthetic Pathway." Biochemistry 57, no. 50: 6860-6867.

Journal article
Published: 28 September 2018 in Scientific Reports
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Cyanobactins are a family of linear and cyclic peptides produced through the post-translational modification of short precursor peptides. A mass spectrometry-based screening of potential cyanobactin producers led to the discovery of a new prenylated member of this family of compounds, sphaerocyclamide (1), from Sphaerospermopsis sp. LEGE 00249. The sphaerocyclamide biosynthetic gene cluster (sph) encoding the novel macrocyclic prenylated cyanobactin, was sequenced. Heterologous expression of the sph gene cluster in Escherichia coli confirmed the connection between genomic and mass spectrometric data. Unambiguous establishment of the orientation and site of prenylation required the full structural elucidation of 1 using Nuclear Magnetic Resonance (NMR), which demonstrated that a forward prenylation occurred on the tyrosine residue. Compound 1 was tested in pharmacologically or ecologically relevant biological assays and revealed moderate antimicrobial activity towards the fouling bacterium Halomonas aquamarina CECT 5000.

ACS Style

Joana Martins; Niina Leikoski; Matti Wahlsten; Joana Azevedo; Jorge Antunes; Jouni Jokela; Kaarina Sivonen; Vitor Vasconcelos; David P. Fewer; Pedro N. Leão. Sphaerocyclamide, a prenylated cyanobactin from the cyanobacterium Sphaerospermopsis sp. LEGE 00249. Scientific Reports 2018, 8, 1 -9.

AMA Style

Joana Martins, Niina Leikoski, Matti Wahlsten, Joana Azevedo, Jorge Antunes, Jouni Jokela, Kaarina Sivonen, Vitor Vasconcelos, David P. Fewer, Pedro N. Leão. Sphaerocyclamide, a prenylated cyanobactin from the cyanobacterium Sphaerospermopsis sp. LEGE 00249. Scientific Reports. 2018; 8 (1):1-9.

Chicago/Turabian Style

Joana Martins; Niina Leikoski; Matti Wahlsten; Joana Azevedo; Jorge Antunes; Jouni Jokela; Kaarina Sivonen; Vitor Vasconcelos; David P. Fewer; Pedro N. Leão. 2018. "Sphaerocyclamide, a prenylated cyanobactin from the cyanobacterium Sphaerospermopsis sp. LEGE 00249." Scientific Reports 8, no. 1: 1-9.

Meeting report
Published: 01 July 2018 in Cancer Chemistry
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Trypsin-3 is a highly active protease that has recently been identified as a potential therapeutic target for the reduction of tumor growth and metastasis in prostate, breast and pancreatic cancers. Current trypsin inhibitors typically inhibit a broad range of different trypsin-like enzymes. Thus, novel approaches to identify trypsin-3 selective inhibitors are needed. Cyanobacteria produce a vast diversity of natural products with complex chemical structures many of which are potent protease inhibitors. We screened extracts of 140 cyanobacteria strains and discovered numerous strains showing selectivity towards trypsin-2 and -3 inhibition. We isolated a complex glycopeptide from one of these strains, which selectively inhibited human trypsin-2 and -3 with IC50 values of about 100 nM, while trypsin-1 was not inhibited. Importantly, we also found that this peptide inhibited invasion of aggressive and metastatic PC-3M prostate cancer cells though ECM preparation, while it did not affect the proliferation of the cells. Our results suggest that microbial natural products may offer a viable alternative source of potent and selective trypsin-3 inhibitors. Such inhibitors may be suitable, after further development, for targeting the mechanisms associated with the invasion and metastatic dissemination of cancer cells, i.e., for treatment of aggressive cancers. Citation Format: Hannu Koistinen, Matti Wahlsten, Muhammad N. Ahmed, Kaarina Sivonen, Matthias Nees, Ulf-Håkan Stenman, David P. Fewer. Cyanobacterial trypsin-3 inhibitor inhibits prostate cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2679.

ACS Style

Hannu Koistinen; Matti Wahlsten; Muhammad N. Ahmed; Kaarina Sivonen; Matthias Nees; Ulf-Håkan Stenman; David P. Fewer. Abstract 2679: Cyanobacterial trypsin-3 inhibitor inhibits prostate cancer cell invasion. Cancer Chemistry 2018, 78, 2679 -2679.

AMA Style

Hannu Koistinen, Matti Wahlsten, Muhammad N. Ahmed, Kaarina Sivonen, Matthias Nees, Ulf-Håkan Stenman, David P. Fewer. Abstract 2679: Cyanobacterial trypsin-3 inhibitor inhibits prostate cancer cell invasion. Cancer Chemistry. 2018; 78 ():2679-2679.

Chicago/Turabian Style

Hannu Koistinen; Matti Wahlsten; Muhammad N. Ahmed; Kaarina Sivonen; Matthias Nees; Ulf-Håkan Stenman; David P. Fewer. 2018. "Abstract 2679: Cyanobacterial trypsin-3 inhibitor inhibits prostate cancer cell invasion." Cancer Chemistry 78, no. : 2679-2679.

Research article
Published: 23 March 2018 in ACS Chemical Biology
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The pederin family includes a number of bioactive compounds isolated from symbiotic organisms of diverse evolutionary origin. Pederin is linked to beetle-induced dermatitis in humans and pederin family members possess potent antitumor activity caused by selective inhibition of the eukaryotic ribosome. Their biosynthesis is accomplished by a polyketide/non-ribosomal peptide synthetase machinery employing an unusual trans-acyltransferase mechanism. Here we report a novel pederin type compound, cusperin, from the free-living cyanobacterium Cuspidothrix issatschenkoi (earlier Aphanizomenon). The chemical structure of cusperin is similar to that of nosperin recently isolated from the lichen cyanobiont Nostoc sharing the tehrahydropyran moiety and major part of the linear backbone. However, the cusperin molecule is extended by a glycine residue and lacks one hydroxyl substituent. Pederins were previously thought to be exclusive to symbiotic relationships. However, C. issatschenkoi is a non-symbiotic planktonic organism and a frequent component of toxic water blooms. Cusperin is devoid of the cytotoxic activity reported for other pederin family members. Hence, our findings raise questions about the role of pederin analogues in cyanobacteria and broaden the knowledge of ecological distribution of this group of polyketides.

ACS Style

Andreja Kust; Jan Mareš; Jouni Jokela; Petra Urajová; Jan Hájek; Kumar Saurav; Kateřina Voráčová; David P. Fewer; Esa Haapaniemi; Perttu Permi; Klára Řeháková; Kaarina Sivonen; Pavel Hrouzek. Discovery of a Pederin Family Compound in a Nonsymbiotic Bloom-Forming Cyanobacterium. ACS Chemical Biology 2018, 13, 1123 -1129.

AMA Style

Andreja Kust, Jan Mareš, Jouni Jokela, Petra Urajová, Jan Hájek, Kumar Saurav, Kateřina Voráčová, David P. Fewer, Esa Haapaniemi, Perttu Permi, Klára Řeháková, Kaarina Sivonen, Pavel Hrouzek. Discovery of a Pederin Family Compound in a Nonsymbiotic Bloom-Forming Cyanobacterium. ACS Chemical Biology. 2018; 13 (5):1123-1129.

Chicago/Turabian Style

Andreja Kust; Jan Mareš; Jouni Jokela; Petra Urajová; Jan Hájek; Kumar Saurav; Kateřina Voráčová; David P. Fewer; Esa Haapaniemi; Perttu Permi; Klára Řeháková; Kaarina Sivonen; Pavel Hrouzek. 2018. "Discovery of a Pederin Family Compound in a Nonsymbiotic Bloom-Forming Cyanobacterium." ACS Chemical Biology 13, no. 5: 1123-1129.

Journal article
Published: 14 February 2018 in The ISME Journal
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Nodularia spumigena is a nitrogen-fixing cyanobacterium that forms toxic blooms in the Baltic Sea each summer and the availability of phosphorous is an important factor limiting the formation of these blooms. Bioinformatic analysis identified a phosphonate degrading (phn) gene cluster in the genome of N. spumigena suggesting that this bacterium may use phosphonates as a phosphorus source. Our results show that strains of N. spumigena could grow in medium containing methylphosphonic acid (MPn) as the sole source of phosphorous and released methane when growing in medium containing MPn. We analyzed the total transcriptomes of N. spumigena UHCC 0039 grown using MPn and compared them with cultures growing in Pi-replete medium. The phnJ, phosphonate lyase gene, was upregulated when MPn was the sole source of phosphorus, suggesting that the expression of this gene could be used to indicate the presence of bioavailable phosphonates. Otherwise, growth on MPn resulted in only a minor reconstruction of the transcriptome and enabled good growth. However, N. spumigena strains were not able to utilize any of the anthropogenic phosphonates tested. The phosphonate utilizing pathway may offer N. spumigena a competitive advantage in the Pi-limited cyanobacterial blooms of the Baltic Sea.

ACS Style

Jonna E. Teikari; David P. Fewer; Rashmi Shrestha; Shengwei Hou; Niina Leikoski; Minna Mäkelä; Asko Simojoki; Wolfgang R. Hess; Kaarina Sivonen. Strains of the toxic and bloom-forming Nodularia spumigena (cyanobacteria) can degrade methylphosphonate and release methane. The ISME Journal 2018, 12, 1619 -1630.

AMA Style

Jonna E. Teikari, David P. Fewer, Rashmi Shrestha, Shengwei Hou, Niina Leikoski, Minna Mäkelä, Asko Simojoki, Wolfgang R. Hess, Kaarina Sivonen. Strains of the toxic and bloom-forming Nodularia spumigena (cyanobacteria) can degrade methylphosphonate and release methane. The ISME Journal. 2018; 12 (6):1619-1630.

Chicago/Turabian Style

Jonna E. Teikari; David P. Fewer; Rashmi Shrestha; Shengwei Hou; Niina Leikoski; Minna Mäkelä; Asko Simojoki; Wolfgang R. Hess; Kaarina Sivonen. 2018. "Strains of the toxic and bloom-forming Nodularia spumigena (cyanobacteria) can degrade methylphosphonate and release methane." The ISME Journal 12, no. 6: 1619-1630.

Original research article
Published: 09 October 2017 in Frontiers in Microbiology
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Nostoc is cyanobacterial genus, common in soils and a prolific producer of natural products. This research project aimed to explore Brazilian cyanobacteria for new bioactive compounds and their characterization. Here we report the production of hepatotoxins and new protease inhibitors from benthic Nostoc sp. CENA543 isolated from small, shallow, saline-alkaline lake in the Nhecolândia, Pantanal wetland area in Brazil. Nostoc sp. CENA543 produces exceptionally high amounts of nodularin-R. This is the first free-living Nostoc found that produce nodularin at comparable levels as the toxic, bloom-forming, Nodularia spumigena. We also found and characterized pseudospumigins A-F, which are a novel family of linear tetrapeptides. Pseudospumigins are structurally related to linear tetrapeptide spumigins and aeruginosins both present in N. spumigena but differ in respect to their diagnostic amino acid which is Ile/Leu/Val in pseudospumigins, Pro/mPro in spumigins and Choi in aeruginosins. The pseudospumigin gene cluster is more similar to the spumigin biosynthetic gene cluster than the aeruginosin gene cluster. Pseudospumigin A inhibited trypsin (IC50 4.5 μM after 1 h) in a similar manner as spumigin E from N. spumigena but was almost two orders of magnitude less potent. This study identifies another location and environment where the hepatotoxic nodularin has the potential to cause deaths of eukaryotic organisms.

ACS Style

Jouni Jokela; Lassi Matti Petteri Heinilä; Tânia K. Shishido; Matti Wahlsten; David Fewer; Marli Fiore; Hao Wang; Esa Haapaniemi; Perttu Permi; Kaarina Sivonen. Production of High Amounts of Hepatotoxin Nodularin and New Protease Inhibitors Pseudospumigins by the Brazilian Benthic Nostoc sp. CENA543. Frontiers in Microbiology 2017, 8, 1963 .

AMA Style

Jouni Jokela, Lassi Matti Petteri Heinilä, Tânia K. Shishido, Matti Wahlsten, David Fewer, Marli Fiore, Hao Wang, Esa Haapaniemi, Perttu Permi, Kaarina Sivonen. Production of High Amounts of Hepatotoxin Nodularin and New Protease Inhibitors Pseudospumigins by the Brazilian Benthic Nostoc sp. CENA543. Frontiers in Microbiology. 2017; 8 ():1963.

Chicago/Turabian Style

Jouni Jokela; Lassi Matti Petteri Heinilä; Tânia K. Shishido; Matti Wahlsten; David Fewer; Marli Fiore; Hao Wang; Esa Haapaniemi; Perttu Permi; Kaarina Sivonen. 2017. "Production of High Amounts of Hepatotoxin Nodularin and New Protease Inhibitors Pseudospumigins by the Brazilian Benthic Nostoc sp. CENA543." Frontiers in Microbiology 8, no. : 1963.

Research article
Published: 29 September 2017 in ACS Chemical Biology
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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.

ACS Style

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 Style

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 (11):2746-2755.

Chicago/Turabian Style

Tânia 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.