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Laxaphycins are a family of cyclic lipopeptides with synergistic antifungal and antiproliferative activities.
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 StyleLassi 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 StyleLassi 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.
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. 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.
Lassi Matti Petteri Heinilä; David P. Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Anna Jortikka; Kaarina Sivonen. Shared PKS Module in Biosynthesis of Synergistic Laxaphycins. Frontiers in Microbiology 2020, 11, 1 .
AMA StyleLassi Matti Petteri Heinilä, David P. Fewer, Jouni Kalevi Jokela, Matti Wahlsten, Anna Jortikka, Kaarina Sivonen. Shared PKS Module in Biosynthesis of Synergistic Laxaphycins. Frontiers in Microbiology. 2020; 11 ():1.
Chicago/Turabian StyleLassi Matti Petteri Heinilä; David P. Fewer; Jouni Kalevi Jokela; Matti Wahlsten; Anna Jortikka; Kaarina Sivonen. 2020. "Shared PKS Module in Biosynthesis of Synergistic Laxaphycins." Frontiers in Microbiology 11, no. : 1.
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.
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 StyleMartin 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 StyleMartin 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.
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.
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.
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 StyleAntti 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 StyleAntti 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.
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 acid, 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.
Anu Humisto; Jouni Jokela; Knut Teigen; Matti Wahlsten; Perttu Permi; Kaarina Sivonen; Lars Herfindal. Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes 2019, 1861, 1510 -1521.
AMA StyleAnu Humisto, Jouni Jokela, Knut Teigen, Matti Wahlsten, Perttu Permi, Kaarina Sivonen, Lars Herfindal. Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2019; 1861 (8):1510-1521.
Chicago/Turabian StyleAnu Humisto; Jouni Jokela; Knut Teigen; Matti Wahlsten; Perttu Permi; Kaarina Sivonen; Lars Herfindal. 2019. "Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes." Biochimica et Biophysica Acta (BBA) - Biomembranes 1861, no. 8: 1510-1521.
Cyanobacteria have a worldwide distribution in the terrestrial habitats, occurring predominantly on the surface of the soils, stones, rocks, and trees, practically in moist, neutral or alkaline aeries. The unique natural and bioactive compounds from cyanobacteria with various biological activities and an extensive range of chemical classes have a significant capability for expansion of the pharmaceuticals and other biomedical purposes. Regardless of the progresses in our knowledge on cyanobacteria, however, cyanobacteria are still viewed as an unexplored source of potential drugs. In this study presence of bioactive compounds among the cyanobacteria culture collection of Iran, where a wide variety of strains can be found, was investigated. We explored one Nostoc strain isolated from rice fields in Golestan province of northern Iran for searching for novel products. The chemical construction of the new bioactive compound was clarified by application of liquid chromatography-mass spectrometer (LC-MS) and Marfey's analysis of the degradation products. We found a novel peptide aldehyde compound from a hydrophilic extract of the Nostoc sp. Bahar_M, which is composed of the three subunits, 2-hydroxy-4-(4-hydroxyphenyl) butanoic acid (Hhpba), L-Ile, and L-argininal. According to the structural information, we predicted that the novel peptide-aldehyde compound probably to be trypsin inhibitors. Results demonstrated that terrestrial cyanobacteria are a promissing resource of bioactive natural products.
Bahareh Nowruzi; Matti Wahlsten; Jouni Jokela; Taher Nejad Sattari; Juoni Jokela. A Report on Finding a New Peptide Aldehyde from Cyanobacterium Nostoc sp. Bahar M by LC-MS and Marfey's Analysis. Iranian Journal of Biotechnology 2019, 17, e1853 -78.
AMA StyleBahareh Nowruzi, Matti Wahlsten, Jouni Jokela, Taher Nejad Sattari, Juoni Jokela. A Report on Finding a New Peptide Aldehyde from Cyanobacterium Nostoc sp. Bahar M by LC-MS and Marfey's Analysis. Iranian Journal of Biotechnology. 2019; 17 (2):e1853-78.
Chicago/Turabian StyleBahareh Nowruzi; Matti Wahlsten; Jouni Jokela; Taher Nejad Sattari; Juoni Jokela. 2019. "A Report on Finding a New Peptide Aldehyde from Cyanobacterium Nostoc sp. Bahar M by LC-MS and Marfey's Analysis." Iranian Journal of Biotechnology 17, no. 2: e1853-78.
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.
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.
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 StyleJan 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 StyleJan 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.
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.
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 StyleLuca 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 StyleLuca 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.
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.
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 StyleJoana 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 StyleJoana 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.
Recent works provide evidence of the prebiotic potential of arabinoxylan-derived oligosaccharides (A)XOS. In this study, we developed a structural analysis for cereal-derived (A)XOS by negative ionization HILIC-MS/MS. Initially, we assessed twelve (A)XOS samples of known structures with different linkage positions and branching points by direct-infusion negative ESI-MSn. We subsequently developed the negative ion HILIC-MS/MS with a post-column addition of ammonium chloride. The selected (A)XOS represented both linear (arabinofuranosyl residue linked to the non-reducing end of xylooligosaccharide) and branched structures. Each (A)XOS sample produced a specific spectrum in negative ion ESI-MSn. By analyzing cross-ring fragment ions, we determined the linkage positions of linear (A)XOS. The presence or absence of diagnostic ions in the MS3 allowed us to detect different branches (O-2- or/and O-3-linked arabinofuranosyl with/or without O-4-linked xylopyranosyl at the non-reducing end). Furthermore, we could identify all analyzed samples by HILIC-MS/MS, based on the formed spectral library and chromatographic retention times.
Minna Juvonen; Markus Kotiranta; Jouni Jokela; Päivi Tuomainen; Maija Tenkanen. Identification and structural analysis of cereal arabinoxylan-derived oligosaccharides by negative ionization HILIC-MS/MS. Food Chemistry 2018, 275, 176 -185.
AMA StyleMinna Juvonen, Markus Kotiranta, Jouni Jokela, Päivi Tuomainen, Maija Tenkanen. Identification and structural analysis of cereal arabinoxylan-derived oligosaccharides by negative ionization HILIC-MS/MS. Food Chemistry. 2018; 275 ():176-185.
Chicago/Turabian StyleMinna Juvonen; Markus Kotiranta; Jouni Jokela; Päivi Tuomainen; Maija Tenkanen. 2018. "Identification and structural analysis of cereal arabinoxylan-derived oligosaccharides by negative ionization HILIC-MS/MS." Food Chemistry 275, no. : 176-185.
Prenylation is a widespread modification that improves the biological activities of secondary metabolites. This reaction also represents a key modification step in biosyntheses of cyanobactins, a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) produced by cyanobacteria. In cyanobactins, amino acids are commonly isoprenylated by ABBA prenyltransferases that use C5 donors. Notably, mass spectral analysis of piricyclamides from a fresh-water cyanobacterium suggested that they may instead have a C10 geranyl group. Here we characterize a novel geranyltransferase involved in piricyclamide biosynthesis. Using the purified enzyme, we show that the enzyme PirF catalyzes Tyr O-geranylation, which is an unprecedented post-translational modification. In addition, the combination of enzymology and analytical chemistry revealed the structure of the final natural product, piricyclamide 7005E1, and the regioselectivity of PirF, which has potential as a synthetic biological tool providing drug-like properties to diverse small molecules.
Maho Morita; Yue Hao; Jouni K. Jokela; Debosmita Sardar; Zhenjian Lin; Kaarina Sivonen; Satish K. Nair; Eric W. Schmidt. Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis. Journal of the American Chemical Society 2018, 140, 6044 -6048.
AMA StyleMaho Morita, Yue Hao, Jouni K. Jokela, Debosmita Sardar, Zhenjian Lin, Kaarina Sivonen, Satish K. Nair, Eric W. Schmidt. Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis. Journal of the American Chemical Society. 2018; 140 (19):6044-6048.
Chicago/Turabian StyleMaho Morita; Yue Hao; Jouni K. Jokela; Debosmita Sardar; Zhenjian Lin; Kaarina Sivonen; Satish K. Nair; Eric W. Schmidt. 2018. "Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis." Journal of the American Chemical Society 140, no. 19: 6044-6048.
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.
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 StyleAndreja 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 StyleAndreja 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.
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.
Anu Humisto; Jouni Jokela; Liwei Liu; Matti Wahlsten; Hao Wang; Perttu Permi; João Paulo Machado; Agostinho Antunes; David P. Fewer; Kaarina Sivonen. The Swinholide Biosynthesis Gene Cluster from a Terrestrial Cyanobacterium, Nostoc sp. Strain UHCC 0450. Applied and Environmental Microbiology 2018, 84, e02321-17 .
AMA StyleAnu Humisto, Jouni Jokela, Liwei Liu, Matti Wahlsten, Hao Wang, Perttu Permi, João Paulo Machado, Agostinho Antunes, David P. Fewer, Kaarina Sivonen. The Swinholide Biosynthesis Gene Cluster from a Terrestrial Cyanobacterium, Nostoc sp. Strain UHCC 0450. Applied and Environmental Microbiology. 2018; 84 (3):e02321-17.
Chicago/Turabian StyleAnu Humisto; Jouni Jokela; Liwei Liu; Matti Wahlsten; Hao Wang; Perttu Permi; João Paulo Machado; Agostinho Antunes; David P. Fewer; Kaarina Sivonen. 2018. "The Swinholide Biosynthesis Gene Cluster from a Terrestrial Cyanobacterium, Nostoc sp. Strain UHCC 0450." Applied and Environmental Microbiology 84, no. 3: e02321-17.
Microcystins (MCs) are serine/threonine phosphatase inhibitors synthesized by several members of the phylum Cyanobacteria. Mining the draft genome sequence of the nostocalean MC-producing Fischerella sp. strain CENA161 led to the identification of three contigs containing mcy genes. Subsequent PCR and Sanger sequencing allowed the assembling of its complete biosynthetic mcy gene cluster with 55,016 bases in length. The cluster encoding ten genes (mcyA-J) with a central bidirectional promoter was organized in a similar manner as found in other genera of nostocalean cyanobacteria. However, the nucleotide sequence of the mcy gene cluster of Fischerella sp. CENA161 showed significant differences from all the other MC-producing cyanobacterial genera, sharing only 85.2 to 78.2% identities. Potential MC variants produced by Fischerella sp. CENA161 were predicted by the analysis of the adenylation domain binding pockets and further investigated by LC-MS/MS analysis. To our knowledge, this study presents the first complete mcy cluster characterization from a strain of the genus Fischerella, providing new insight into the distribution and evolution of MCs in the phylum Cyanobacteria.
Karina Heck; Danillo O. Alvarenga; Tania K. Shishido; Alessandro De Mello Varani; Felipe A. Dörr; Ernani Pinto; Leo Rouhiainen; Jouni Jokela; Kaarina Sivonen; Marli F. Fiore. Biosynthesis of microcystin hepatotoxins in the cyanobacterial genus Fischerella. Toxicon 2018, 141, 43 -50.
AMA StyleKarina Heck, Danillo O. Alvarenga, Tania K. Shishido, Alessandro De Mello Varani, Felipe A. Dörr, Ernani Pinto, Leo Rouhiainen, Jouni Jokela, Kaarina Sivonen, Marli F. Fiore. Biosynthesis of microcystin hepatotoxins in the cyanobacterial genus Fischerella. Toxicon. 2018; 141 ():43-50.
Chicago/Turabian StyleKarina Heck; Danillo O. Alvarenga; Tania K. Shishido; Alessandro De Mello Varani; Felipe A. Dörr; Ernani Pinto; Leo Rouhiainen; Jouni Jokela; Kaarina Sivonen; Marli F. Fiore. 2018. "Biosynthesis of microcystin hepatotoxins in the cyanobacterial genus Fischerella." Toxicon 141, no. : 43-50.
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.
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 StyleJouni 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 StyleJouni 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.
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.
The cyanobactin macrocyclase (OscGmac) has high substrate promiscuity and can be used for making libraries of highly diverse cyclic peptides.
Cristina N. Alexandru-Crivac; Christian Umeobika; Niina Leikoski; Jouni Jokela; Kirstie A. Rickaby; André M. Grilo; Peter Sjö; Alleyn T. Plowright; Mohannad Idress; Eike Siebs; Ada Nneoyi-Egbe; Matti Wahlsten; Kaarina Sivonen; Marcel Jaspars; Laurent Trembleau; David P. Fewer; Wael E. Houssen. Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants. Chemical Communications 2017, 53, 10656 -10659.
AMA StyleCristina N. Alexandru-Crivac, Christian Umeobika, Niina Leikoski, Jouni Jokela, Kirstie A. Rickaby, André M. Grilo, Peter Sjö, Alleyn T. Plowright, Mohannad Idress, Eike Siebs, Ada Nneoyi-Egbe, Matti Wahlsten, Kaarina Sivonen, Marcel Jaspars, Laurent Trembleau, David P. Fewer, Wael E. Houssen. Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants. Chemical Communications. 2017; 53 (77):10656-10659.
Chicago/Turabian StyleCristina N. Alexandru-Crivac; Christian Umeobika; Niina Leikoski; Jouni Jokela; Kirstie A. Rickaby; André M. Grilo; Peter Sjö; Alleyn T. Plowright; Mohannad Idress; Eike Siebs; Ada Nneoyi-Egbe; Matti Wahlsten; Kaarina Sivonen; Marcel Jaspars; Laurent Trembleau; David P. Fewer; Wael E. Houssen. 2017. "Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants." Chemical Communications 53, no. 77: 10656-10659.
Cyanobacteria produce a wide range of natural products with antifungal bioactivity. The cyclic glycosylated lipopeptides of the hassallidin family have potent antifungal activity and display a great degree of chemical diversity. Here, we report the discovery of a hassallidin biosynthetic gene cluster from the filamentous cyanobacterium Planktothrix serta PCC 8927. The hassallidin gene cluster showed heavy rearrangement and marks of genomic plasticity. Nucleotide bias, differences in GC content, and phylogenetic incongruence suggested the acquisition of the hassallidin biosynthetic gene cluster in Planktothrix serta PCC 8927 by horizontal gene transfer. Chemical analyses by liquid chromatography and mass spectrometry demonstrated that this strain produced hassallidin E, a new glycosylated hassallidin variant. Hassallidin E was the only structural variant produced by Planktothrix serta PCC 8927 in all tested conditions. Further evaluated on human pathogenic fungi, hassallidin E showed an antifungal bioactivity. Hassallidin production levels correlated with nitrogen availability, in the only nitrogen-fixing Planktothrix described so far. Our results provide insights into the distribution and chemical diversity of cyanobacterial antifungal compounds as well as raise questions on their ecological relevance.
Claire Pancrace; Jouni Jokela; Nathalie Sassoon; Christelle Ganneau; Marie Desnos-Ollivier; Matti Wahlsten; Anu Humisto; Alexandra Calteau; Sylvie Bay; David P. Fewer; Kaarina Sivonen; Muriel Gugger. Rearranged Biosynthetic Gene Cluster and Synthesis of Hassallidin E in Planktothrix serta PCC 8927. ACS Chemical Biology 2017, 12, 1796 -1804.
AMA StyleClaire Pancrace, Jouni Jokela, Nathalie Sassoon, Christelle Ganneau, Marie Desnos-Ollivier, Matti Wahlsten, Anu Humisto, Alexandra Calteau, Sylvie Bay, David P. Fewer, Kaarina Sivonen, Muriel Gugger. Rearranged Biosynthetic Gene Cluster and Synthesis of Hassallidin E in Planktothrix serta PCC 8927. ACS Chemical Biology. 2017; 12 (7):1796-1804.
Chicago/Turabian StyleClaire Pancrace; Jouni Jokela; Nathalie Sassoon; Christelle Ganneau; Marie Desnos-Ollivier; Matti Wahlsten; Anu Humisto; Alexandra Calteau; Sylvie Bay; David P. Fewer; Kaarina Sivonen; Muriel Gugger. 2017. "Rearranged Biosynthetic Gene Cluster and Synthesis of Hassallidin E in Planktothrix serta PCC 8927." ACS Chemical Biology 12, no. 7: 1796-1804.