@article{DehmKrumbholzBaunachetal.2019, author = {Dehm, Daniel and Krumbholz, Julia and Baunach, Martin and Wiebach, Vincent and Hinrichs, Katrin and Guljamow, Arthur and Tabuchi, Takeshi and Jenke-Kodama, Holger and S{\"u}ssmuth, Roderich D. and Dittmann-Th{\"u}nemann, Elke}, title = {Unlocking the spatial control of secondary metabolism uncovers hidden natural product diversity in nostoc punctiforme}, series = {ACS chemical biology}, volume = {14}, journal = {ACS chemical biology}, number = {6}, publisher = {American Chemical Society}, address = {Washington}, issn = {1554-8929}, doi = {10.1021/acschembio.9b00240}, pages = {1271 -- 1279}, year = {2019}, abstract = {Filamentous cyanobacteria belong to the most prolific producers of structurally unique and biologically active natural products, yet the majority of biosynthetic gene clusters predicted for these multicellular collectives are currently orphan. Here, we present a systems analysis of secondary metabolite gene expression in the model strain Nostoc punctiforme PCC73102 using RNA-seq and fluorescence reporter analysis. Our data demonstrate that the majority of the cryptic gene clusters are not silent but are expressed with regular or sporadic pattern. Cultivation of N. punctiforme using high-density fermentation overrules the spatial control and leads to a pronounced upregulation of more than 50\% of biosynthetic gene clusters. Our data suggest that a combination of autocrine factors, a high CO2 level, and high light account for the upregulation of individual pathways. Our overarching study not only sheds light on the strategies of filamentous cyanobacteria to share the enormous metabolic burden connected with the production of specialized molecules but provides an avenue for the genome-based discovery of natural products in multicellular cyanobacteria as exemplified by the discovery of highly unusual variants of the tricyclic peptide microviridin.}, language = {en} } @book{DittmannThuenemann2010, author = {Dittmann-Th{\"u}nemann, Elke}, title = {Toxische Cyanobakterien auf dem Vormarsch : {\"U}berlebensk{\"u}nstler und Meister der Naturstoffsynthese : Antrittsvorlesung 2010-06-16}, publisher = {Univ.-Bibl.}, address = {Potsdam}, year = {2010}, language = {de} } @article{VossBolhuisFeweretal.2013, author = {Voss, Bj{\"o}rn and Bolhuis, Henk and Fewer, David P. and Kopf, Matthias and M{\"o}ke, Fred and Haas, Fabian and El-Shehawy, Rehab and Hayes, Paul and Bergman, Birgitta and Sivonen, Kaarina and Dittmann-Th{\"u}nemann, Elke and Scanlan, Dave J. and Hagemann, Martin and Stal, Lucas J. and Hess, Wolfgang R.}, title = {Insights into the physiology and ecology of the brackish-water-adapted cyanobacterium nodularia spumigena CCY9414 based on a genome-transcriptome analysis}, series = {PLoS one}, volume = {8}, journal = {PLoS one}, number = {3}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0060224}, pages = {22}, year = {2013}, abstract = {Nodularia spumigena is a filamentous diazotrophic cyanobacterium that dominates the annual late summer cyanobacterial blooms in the Baltic Sea. But N. spumigena also is common in brackish water bodies worldwide, suggesting special adaptation allowing it to thrive at moderate salinities. A draft genome analysis of N. spumigena sp. CCY9414 yielded a single scaffold of 5,462,271 nucleotides in length on which genes for 5,294 proteins were annotated. A subsequent strand-specific transcriptome analysis identified more than 6,000 putative transcriptional start sites (TSS). Orphan TSSs located in intergenic regions led us to predict 764 non-coding RNAs, among them 70 copies of a possible retrotransposon and several potential RNA regulators, some of which are also present in other N2-fixing cyanobacteria. Approximately 4\% of the total coding capacity is devoted to the production of secondary metabolites, among them the potent hepatotoxin nodularin, the linear spumigin and the cyclic nodulapeptin. The transcriptional complexity associated with genes involved in nitrogen fixation and heterocyst differentiation is considerably smaller compared to other Nostocales. In contrast, sophisticated systems exist for the uptake and assimilation of iron and phosphorus compounds, for the synthesis of compatible solutes, and for the formation of gas vesicles, required for the active control of buoyancy. Hence, the annotation and interpretation of this sequence provides a vast array of clues into the genomic underpinnings of the physiology of this cyanobacterium and indicates in particular a competitive edge of N. spumigena in nutrient-limited brackish water ecosystems.}, language = {en} } @article{MeissnerFastnerDittmannThuenemann2013, author = {Meissner, Sven and Fastner, Jutta and Dittmann-Th{\"u}nemann, Elke}, title = {Microcystin production revisited conjugate formation makes a major contribution}, series = {Environmental microbiology}, volume = {15}, journal = {Environmental microbiology}, number = {6}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1462-2912}, doi = {10.1111/1462-2920.12072}, pages = {1810 -- 1820}, year = {2013}, abstract = {The impact of environmental stimuli on the production of the widespread cyanobacterial hepatotoxin microcystin (MC) is under debate. Whereas transcriptional studies of the biosynthetic genes suggest a clear influence of light conditions on toxin production the data for the metabolite itself are inconsistent and highly strain-specific. Here, we have reassessed the MC content by using two immunological detection techniques that allow a parallel quantification of MC in the methanolic extracts and the residual pellet fraction that contains high molecular weight proteins. Our results show a significant proportion of MC in the protein bound fraction in strains of Microcystis and Planktothrix and of the related toxin nodularin (NOD) in Nodularia. Moreover, we could show a very strong increase of MC after high light illumination in the protein fraction contributing to a significant overall increase in MC production under these conditions that is not seen in extracts analysed by LC-MS and ELISA. The fact that a considerable portion of MC is neglected with current analysis techniques was also confirmed for selected field samples. Immunofluorescence studies suggest strain-specific differences in the amount of MC conjugate formation.}, language = {en} } @article{ZiemertIshidaWeizetal.2010, author = {Ziemert, Nadine and Ishida, Keishi and Weiz, Annika and Hertweck, Christian and Dittmann-Th{\"u}nemann, Elke}, title = {Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides}, issn = {0099-2240}, doi = {10.1128/AEM.02858-09}, year = {2010}, abstract = {Microviridins are ribosomally synthesized tricyclic depsipeptides produced by different genera of cyanobacteria. The prevalence of the microviridin gene clusters and the natural diversity of microviridin precursor sequences are currently unknown. Screening of laboratory strains and field samples of the bloom-forming freshwater cyanobacterium Microcystis via PCR revealed global occurrence of the microviridin pathway and an unexpected natural variety. We could detect 15 new variants of the precursor gene mdnA encoding microviridin backbones that differ in up to 4 amino acid positions from known isoforms of the peptide. The survey not only provides insights into the versatility of the biosynthetic enzymes in a closely related group of cyanobacteria, but also facilitates the discovery and characterization of cryptic microviridin variants. This is demonstrated for microviridin L in Microcystis aeruginosa strain NIES843 and heterologously produced variants.}, language = {en} } @misc{NeilanPearsonMuenchhoffetal.2013, author = {Neilan, Brett A. and Pearson, Leanne A. and M{\"u}nchhoff, Julia and Moffitt, Michelle C. and Dittmann-Th{\"u}nemann, Elke}, title = {Environmental conditions that influence toxin biosynthesis in cyanobacteria}, series = {Environmental microbiology}, volume = {15}, journal = {Environmental microbiology}, number = {5}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1462-2912}, doi = {10.1111/j.1462-2920.2012.02729.x}, pages = {1239 -- 1253}, year = {2013}, abstract = {Over the past 15 years, the genetic basis for production of many cyanobacterial bioactive compounds has been described. This knowledge has enabled investigations into the environmental factors that regulate the production of these toxins at the molecular level. Such molecular or systems level studies are also likely to reveal the physiological role of the toxin and contribute to effective water resource management. This review focuses on the environmental regulation of some of the most relevant cyanotoxins, namely the microcystins, nodularin, cylindrospermopsin, saxitoxins, anatoxins and jamaicamides.}, language = {en} } @article{FerirVermeireHuskensetal.2011, author = {Ferir, Geoffrey and Vermeire, Kurt and Huskens, Dana and Balzarini, Jan and Van Damme, Els J. M. and Kehr, Jan-Christoph and Dittmann-Th{\"u}nemann, Elke and Swanson, Michael D. and Markovitz, David M. and Schols, Dominique}, title = {Synergistic in vitro anti-HIV type 1 activity of tenofovir with carbohydrate-binding agents (CBAs)}, series = {Antiviral research}, volume = {90}, journal = {Antiviral research}, number = {3}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0166-3542}, doi = {10.1016/j.antiviral.2011.03.188}, pages = {200 -- 204}, year = {2011}, abstract = {Tenofovir, a well-known and highly prescribed anti-HIV-1 drug for the treatment of HIV/AIDS infections, has recently also shown its effectiveness as a potential microbicide drug in the prevention of HIV transmission. Here, we evaluated the combination of tenofovir with various members of the class of carbohydrate-binding agents (CBAs) targeting the glycans on the viral envelope gp120 for their anti-HIV efficacy. The tenofovir/CBA combinations predominantly showed synergistic antiviral activity using the median effect principle. These findings illustrate that combination of tenofovir with CBAs may increase the antiviral potency of the individual drugs and reducing the risk on potential side-effects.}, language = {en} } @article{MeissnerSteinhauserDittmannThuenemann2015, author = {Meissner, Sven and Steinhauser, Dirk and Dittmann-Th{\"u}nemann, Elke}, title = {Metabolomic analysis indicates a pivotal role of the hepatotoxin microcystin in high light adaptation of Microcystis}, series = {Environmental microbiology}, volume = {17}, journal = {Environmental microbiology}, number = {5}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1462-2912}, doi = {10.1111/1462-2920.12565}, pages = {1497 -- 1509}, year = {2015}, abstract = {Microcystis is a freshwater cyanobacterium frequently forming nuisance blooms in the summer months. The genus belongs to the predominant producers of the potent hepatotoxin microcystin. The success of Microcystis and its remarkable resistance to high light conditions are not well understood. Here, we have compared the metabolic response of Microcystis aeruginosaPCC7806, its microcystin-deficient mcyB mutant (Mut) and the cyanobacterial model organism SynechocystisPCC6803 to high light exposure of 250molphotonsm(-2)s(-1) using GC/MS-based metabolomics. Microcystis wild type and Mut show pronounced differences in their metabolic reprogramming upon high light. Seventeen percent of the detected metabolites showed significant differences between the two genotypes after high light exposure. Whereas the microcystin-producing wild type shows a faster accumulation of glycolate upon high light illumination, loss of microcystin leads to an accumulation of general stress markers such as trehalose and sucrose. The study further uncovers differences in the high light adaptation of the bloom-forming cyanobacterium Microcystis and the model cyanobacterium Synechocystis. Most notably, Microcystis invests more into carbon reserves such as glycogen after high light exposure. Our data shed new light on the lifestyle of bloom-forming cyanobacteria, the role of the widespread toxin microcystin and the metabolic diversity of cyanobacteria.}, language = {en} } @article{HuVoellerSussmuthetal.2015, author = {Hu, Chenlin and V{\"o}ller, Ginka and Sussmuth, Roderich and Dittmann-Th{\"u}nemann, Elke and Kehr, Jan-Christoph}, title = {Functional assessment of mycosporine-like amino acids in Microcystis aeruginosa strain PCC 7806}, series = {Environmental microbiology}, volume = {17}, journal = {Environmental microbiology}, number = {5}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1462-2912}, doi = {10.1111/1462-2920.12577}, pages = {1548 -- 1559}, year = {2015}, abstract = {The biological role of the widespread mycosporine-like amino acids (MAAs) in cyanobacteria is under debate. Here, we have constructed and characterized two mutants impaired in MAA biosynthesis in the bloom-forming cyanobacterium Microcystis aeruginosaPCC 7806. We could identify shinorine as the sole MAA type of the strain, which is exclusively located in the extracellular matrix. Bioinformatic studies as wells as polymerase chain reaction screening revealed that the ability to produce MAAs is sporadically distributed within the genus. Growth experiments and reactive oxygen species quantification with wild-type and mutant strains did not support a role of shinorine in protection against UV or other stress conditions in M.aeruginosaPCC 7806. The shinorine content per dry weight of cells as well as transcription of the mys gene cluster was not significantly elevated in response to UV-A, UV-B or any other stress condition tested. Remarkably, both mutants exhibited pronounced morphological changes compared with the wild type. We observed an increased accumulation and an enhanced hydrophobicity of the extracellular matrix. Our study suggests that MAAs in Microcystis play a negligible role in protection against UV radiation but might be a strain-specific trait involved in extracellular matrix formation and cell-cell interaction.}, language = {en} } @misc{KehrPicchiDittmannThuenemann2011, author = {Kehr, Jan-Christoph and Picchi, Douglas Gatte and Dittmann-Th{\"u}nemann, Elke}, title = {Natural product biosyntheses in cyanobacteria a treasure trove of unique enzymes}, series = {Beilstein journal of organic chemistry}, volume = {7}, journal = {Beilstein journal of organic chemistry}, number = {2}, publisher = {Beilstein-Institut zur F{\"o}rderung der Chemischen Wissenschaften}, address = {Frankfurt, Main}, issn = {1860-5397}, doi = {10.3762/bjoc.7.191}, pages = {1622 -- 1635}, year = {2011}, abstract = {Cyanobacteria are prolific producers of natural products. Investigations into the biochemistry responsible for the formation of these compounds have revealed fascinating mechanisms that are not, or only rarely, found in other microorganisms. In this article, we survey the biosynthetic pathways of cyanobacteria isolated from freshwater, marine and terrestrial habitats. We especially emphasize modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways and highlight the unique enzyme mechanisms that were elucidated or can be anticipated for the individual products. We further include ribosomal natural products and UV-absorbing pigments from cyanobacteria. Mechanistic insights obtained from the biochemical studies of cyanobacterial pathways can inspire the development of concepts for the design of bioactive compounds by synthetic-biology approaches in the future.}, language = {en} } @article{WeizIshidaMakoweretal.2011, author = {Weiz, Annika R. and Ishida, Keishi and Makower, Katharina and Ziemert, Nadine and Hertweck, Christian and Dittmann-Th{\"u}nemann, Elke}, title = {Leader Peptide and a Membrane Protein Scaffold Guide the Biosynthesis of the Tricyclic Peptide Microviridin}, series = {Chemistry \& biology}, volume = {18}, journal = {Chemistry \& biology}, number = {11}, publisher = {Cell Press}, address = {Cambridge}, issn = {1074-5521}, doi = {10.1016/j.chembiol.2011.09.011}, pages = {1413 -- 1421}, year = {2011}, abstract = {Microviridins are unique protease inhibitors from bloom-forming cyanobacteria that have both ecological and pharmacological relevance. Their peptide backbones are produced ribosomally, and ATP grasp ligases introduce omega-ester and omega-amide bonds to yield rare cage-like structures. Bioinformatic analysis of the microviridin biosynthesis gene cluster suggests a novel type of processing machinery, which could rationalize the challenging in vivo/in vitro reconstitution of the pathway. In this work, we report the establishment of a minimal expression system for microviridins. Through bioinformatics and mutational analysis of the MdnA leader peptide we identified and characterized a strictly conserved binding motif that is specific for microviridin ligases. Furthermore, we showed that the ABC transporter MdnE is crucial for cyclization and processing of microviridins and demonstrated that MdnE is essential for stability of the microviridin biosynthesis complex.}, language = {en} } @article{GattePicchiWeizIshidaetal.2014, author = {Gatte-Picchi, Douglas and Weiz, Annika and Ishida, Keishi and Hertweck, Christian and Dittmann-Th{\"u}nemann, Elke}, title = {Functional analysis of environmental DNA-derived microviridins provides new insights into the diversity of the tricyclic peptide family}, series = {Applied and environmental microbiology}, volume = {80}, journal = {Applied and environmental microbiology}, number = {4}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0099-2240}, doi = {10.1128/AEM.03502-13}, pages = {1380 -- 1387}, year = {2014}, abstract = {Microviridins represent a unique family of ribosomally synthesized cage-like depsipeptides from cyanobacteria with potent protease-inhibitory activities. The natural diversity of these peptides is largely unexplored. Here, we describe two methodologies that were developed to functionally characterize cryptic microviridin gene clusters from metagenomic DNA. Environmental samples were collected and enriched from cyanobacterial freshwater blooms of different geographical origins containing predominantly Microcystis sp. Microviridins were produced either directly from fosmid clones or after insertion of environmental DNA-derived gene cassettes into a minimal expression platform in Escherichia coli. Three novel microviridin variants were isolated and tested against different serine-type proteases. The comparison of the bioactivity profiles of the new congeners allows deduction of further structure-function relationships for microviridins. Moreover, this study provides new insights into microviridin processing and gene cluster organization.}, language = {en} } @article{ZilligesKehrMeissneretal.2011, author = {Zilliges, Yvonne and Kehr, Jan-Christoph and Meissner, Sven and Ishida, Keishi and Mikkat, Stefan and Hagemann, Martin and Kaplan, Aaron and B{\"o}rner, Thomas and Dittmann-Th{\"u}nemann, Elke}, title = {The cyanobacterial hepatotoxin microcystin binds to proteins and increases the fitness of microcystis under oxidative stress conditions}, series = {PLoS one}, volume = {6}, journal = {PLoS one}, number = {3}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0017615}, pages = {11}, year = {2011}, abstract = {Microcystins are cyanobacterial toxins that represent a serious threat to drinking water and recreational lakes worldwide. Here, we show that microcystin fulfils an important function within cells of its natural producer Microcystis. The microcystin deficient mutant Delta mcyB showed significant changes in the accumulation of proteins, including several enzymes of the Calvin cycle, phycobiliproteins and two NADPH-dependent reductases. We have discovered that microcystin binds to a number of these proteins in vivo and that the binding is strongly enhanced under high light and oxidative stress conditions. The nature of this binding was studied using extracts of a microcystin-deficient mutant in vitro. The data obtained provided clear evidence for a covalent interaction of the toxin with cysteine residues of proteins. A detailed investigation of one of the binding partners, the large subunit of RubisCO showed a lower susceptibility to proteases in the presence of microcystin in the wild type. Finally, the mutant defective in microcystin production exhibited a clearly increased sensitivity under high light conditions and after hydrogen peroxide treatment. Taken together, our data suggest a protein-modulating role for microcystin within the producing cell, which represents a new addition to the catalogue of functions that have been discussed for microbial secondary metabolites.}, language = {en} } @misc{DittmannThuenemannGuggerSivonenetal.2015, author = {Dittmann-Th{\"u}nemann, Elke and Gugger, Muriel and Sivonen, Kaarina and Fewer, David P.}, title = {Natural Product Biosynthetic Diversity and Comparative Genomics of the Cyanobacteria}, series = {Trends in microbiology}, volume = {23}, journal = {Trends in microbiology}, number = {10}, publisher = {Elsevier}, address = {Oxford}, issn = {0966-842X}, doi = {10.1016/j.tim.2015.07.008}, pages = {642 -- 652}, year = {2015}, abstract = {Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with intricate chemical structures and potent biological activities. The bulk of these natural products are known from just a handful of genera. Recent efforts have elucidated the mechanisms underpinning the biosynthesis of a diverse array of natural products from cyanobacteria. Many of the biosynthetic mechanisms are unique to cyanobacteria or rarely described from other organisms. Advances in genome sequence technology have precipitated a deluge of genome sequences for cyanobacteria. This makes it possible to link known natural products to biosynthetic gene clusters but also accelerates the discovery of new natural products through genome mining. These studies demonstrate that cyanobacteria encode a huge variety of cryptic gene clusters for the production of natural products, and the known chemical diversity is likely to be just a fraction of the true biosynthetic capabilities of this fascinating and ancient group of organisms.}, language = {en} } @unpublished{KehrDittmannThuenemann2015, author = {Kehr, Jan-Christoph and Dittmann-Th{\"u}nemann, Elke}, title = {Protective tunicate endosymbiont with extreme genome reduction}, series = {Environmental microbiology}, volume = {17}, journal = {Environmental microbiology}, number = {10}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1462-2912}, doi = {10.1111/1462-2920.12941}, pages = {3430 -- 3432}, year = {2015}, language = {en} } @misc{DittmannThuenemannFewerNeilan2013, author = {Dittmann-Th{\"u}nemann, Elke and Fewer, David P. and Neilan, Brett A.}, title = {Cyanobacterial toxins biosynthetic routes and evolutionary roots}, series = {FEMS microbiology reviews}, volume = {37}, journal = {FEMS microbiology reviews}, number = {1}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {0168-6445}, doi = {10.1111/j.1574-6976.2012.12000.x}, pages = {23 -- 43}, year = {2013}, abstract = {Cyanobacteria produce an unparalleled variety of toxins that can cause severe health problems or even death in humans, and wild or domestic animals. In the last decade, biosynthetic pathways have been assigned to the majority of the known toxin families. This review summarizes current knowledge about the enzymatic basis for the production of the hepatotoxins microcystin and nodularin, the cytotoxin cylindrospermopsin, the neurotoxins anatoxin and saxitoxin, and the dermatotoxin lyngbyatoxin. Elucidation of the biosynthetic pathways of the toxins has paved the way for the development of molecular techniques for the detection and quantification of the producing cyanobacteria in different environments. Phylogenetic analyses of related clusters from a large number of strains has also allowed for the reconstruction of the evolutionary scenarios that have led to the emergence, diversification, and loss of such gene clusters in different strains and genera of cyanobacteria. Advances in the understanding of toxin biosynthesis and evolution have provided new methods for drinking-water quality control and may inspire the development of techniques for the management of bloom formation in the future.}, language = {en} } @misc{ArnisonBibbBierbaumetal.2013, author = {Arnison, Paul G. and Bibb, Mervyn J. and Bierbaum, Gabriele and Bowers, Albert A. and Bugni, Tim S. and Bulaj, Grzegorz and Camarero, Julio A. and Campopiano, Dominic J. and Challis, Gregory L. and Clardy, Jon and Cotter, Paul D. and Craik, David J. and Dawson, Michael and Dittmann-Th{\"u}nemann, Elke and Donadio, Stefano and Dorrestein, Pieter C. and Entian, Karl-Dieter and Fischbach, Michael A. and Garavelli, John S. and Goeransson, Ulf and Gruber, Christian W. and Haft, Daniel H. and Hemscheidt, Thomas K. and Hertweck, Christian and Hill, Colin and Horswill, Alexander R. and Jaspars, Marcel and Kelly, Wendy L. and Klinman, Judith P. and Kuipers, Oscar P. and Link, A. James and Liu, Wen and Marahiel, Mohamed A. and Mitchell, Douglas A. and Moll, Gert N. and Moore, Bradley S. and Mueller, Rolf and Nair, Satish K. and Nes, Ingolf F. and Norris, Gillian E. and Olivera, Baldomero M. and Onaka, Hiroyasu and Patchett, Mark L. and Piel, J{\"o}rn and Reaney, Martin J. T. and Rebuffat, Sylvie and Ross, R. Paul and Sahl, Hans-Georg and Schmidt, Eric W. and Selsted, Michael E. and Severinov, Konstantin and Shen, Ben and Sivonen, Kaarina and Smith, Leif and Stein, Torsten and Suessmuth, Roderich D. and Tagg, John R. and Tang, Gong-Li and Truman, Andrew W. and Vederas, John C. and Walsh, Christopher T. and Walton, Jonathan D. and Wenzel, Silke C. and Willey, Joanne M. and van der Donk, Wilfred A.}, title = {Ribosomally synthesized and post-translationally modified peptide natural products overview and recommendations for a universal nomenclature}, series = {Natural product reports : a journal of current developments in bio-organic chemistry}, volume = {30}, journal = {Natural product reports : a journal of current developments in bio-organic chemistry}, number = {1}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {0265-0568}, doi = {10.1039/c2np20085f}, pages = {108 -- 160}, year = {2013}, abstract = {This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.}, language = {en} } @misc{WelkerDittmannThuenemannvonDoehren2012, author = {Welker, Martin and Dittmann-Th{\"u}nemann, Elke and von Doehren, Hans}, title = {Cyanobacteria as a source of natural products}, series = {Methods in enzymology}, volume = {517}, journal = {Methods in enzymology}, number = {1}, editor = {Hopwood, DA}, publisher = {Elsevier}, address = {San Diego}, isbn = {978-0-12-404634-4}, issn = {0076-6879}, doi = {10.1016/B978-0-12-404634-4.00002-4}, pages = {23 -- 46}, year = {2012}, abstract = {Cyanobacteria or blue-green algae from various environments have been recognized as sources of a variety of bioactive metabolites. Strategies of strain isolation from aquatic habitats, and cultivation and harvesting for metabolite production are described. Strategies for screening of compounds are discussed, including their direct MALDI-TOF mass spectrometric detection in whole cells. Genetic approaches including genomic mining, mutagenesis including transcriptional activation, heterologous expression, and in vitro. reconstitution of pathways are presented.}, language = {en} } @article{GuljamowDelissenBaumannetal.2012, author = {Guljamow, Arthur and Delissen, Friedmar and Baumann, Otto and Thuenemann, Andreas F. and Dittmann-Th{\"u}nemann, Elke}, title = {Unique properties of eukaryote-type actin and profilin horizontally transferred to cyanobacteria}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {1}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0029926}, pages = {221 -- 231}, year = {2012}, abstract = {A eukaryote-type actin and its binding protein profilin encoded on a genomic island in the cyanobacterium Microcystis aeruginosa PCC 7806 co-localize to form a hollow, spherical enclosure occupying a considerable intracellular space as shown by in vivo fluorescence microscopy. Biochemical and biophysical characterization reveals key differences between these proteins and their eukaryotic homologs. Small-angle X-ray scattering shows that the actin assembles into elongated, filamentous polymers which can be visualized microscopically with fluorescent phalloidin. Whereas rabbit actin forms thin cylindrical filaments about 100 mu m in length, cyanobacterial actin polymers resemble a ribbon, arrest polymerization at 510 lam and tend to form irregular multi-strand assemblies. While eukaryotic profilin is a specific actin monomer binding protein, cyanobacterial profilin shows the unprecedented property of decorating actin filaments. Electron micrographs show that cyanobacterial profilin stimulates actin filament bundling and stabilizes their lateral alignment into heteropolymeric sheets from which the observed hollow enclosure may be formed. We hypothesize that adaptation to the confined space of a bacterial cell devoid of binding proteins usually regulating actin polymerization in eukaryotes has driven the co-evolution of cyanobacterial actin and profilin, giving rise to an intracellular entity.}, language = {en} } @article{LiaimerJenkeKodamaIshidaetal.2011, author = {Liaimer, Anton and Jenke-Kodama, Holger and Ishida, Keishi and Hinrichs, Katrin and Stangeland, Janne and Hertweck, Christian and Dittmann-Th{\"u}nemann, Elke}, title = {A polyketide interferes with cellular differentiation in the symbiotic cyanobacterium Nostoc punctiforme}, series = {Environmental microbiology reports}, volume = {3}, journal = {Environmental microbiology reports}, number = {5}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {1758-2229}, doi = {10.1111/j.1758-2229.2011.00258.x}, pages = {550 -- 558}, year = {2011}, abstract = {Nostoc punctiforme is a filamentous cyanobacterium capable of forming symbiotic associations with a wide range of plants. The strain exhibits extensive phenotypic characteristics and can differentiate three mutually exclusive cell types: nitrogen-fixing heterocysts, motile hormogonia and spore-like akinetes. Here, we provide evidence for a crucial role of an extracellular metabolite in balancing cellular differentiation. Insertional mutagenesis of a gene of the polyketide synthase gene cluster pks2 led to the accumulation of short filaments carrying mostly terminal heterocysts under diazotrophic conditions. The mutant has a strong tendency to form biofilms on solid surfaces as well as in liquid culture. The pks2-strain keeps forming hormogonia over the entire growth curve and shows an early onset of akinete formation. We could isolate two fractions of the wildtype supernatant that could restore the capability to form long filaments with intercalary heterocysts. Growth of the mutant cells in the neighbourhood of wild-type cells on plates led to a reciprocal influence and a partial reconstruction of wild-type and mutant phenotype respectively. We postulate that extracellular metabolites of Nostoc punctiforme act as life cycle governing factors (LCGFs) and that the ratio between distinct factors may guide the differentiation into different life stages.}, language = {en} } @article{WeizIshidaQuittereretal.2014, author = {Weiz, Annika R. and Ishida, Keishi and Quitterer, Felix and Meyer, Sabine and Kehr, Jan-Christoph and Mueller, Kristian M. and Groll, Michael and Hertweck, Christian and Dittmann-Th{\"u}nemann, Elke}, title = {Harnessing the evolvability of tricyclic microviridins to dissect protease-inhibitor interactions}, series = {Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker ; International edition}, volume = {53}, journal = {Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker ; International edition}, number = {14}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1433-7851}, doi = {10.1002/anie.201309721}, pages = {3735 -- 3738}, year = {2014}, abstract = {Understanding and controlling proteolysis is an important goal in therapeutic chemistry. Among the natural products specifically inhibiting proteases microviridins are particularly noteworthy. Microviridins are ribosomally produced and posttranslationally modified peptides that are processed into a unique, cagelike architecture. Here, we report a combined rational and random mutagenesis approach that provides fundamental insights into selectivity-conferring moieties of microviridins. The potent variant microviridin J was co-crystallized with trypsin, and for the first time the three-dimensional structure of microviridins was determined and the mode of inhibition revealed.}, language = {en} } @article{HarelWeissDanieletal.2012, author = {Harel, Moshe and Weiss, Gad and Daniel, Einat and Wilenz, Avraham and Hadas, Ora and Sukenik, Assaf and Sedmak, Bojan and Dittmann-Th{\"u}nemann, Elke and Braun, Sergei and Kaplan, Aaron}, title = {Casting a net fibres produced by Microcystis sp in field and laboratory populations}, series = {Environmental microbiology reports}, volume = {4}, journal = {Environmental microbiology reports}, number = {3}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {1758-2229}, doi = {10.1111/j.1758-2229.2012.00339.x}, pages = {342 -- 349}, year = {2012}, abstract = {The reasons for the apparent dominance of the toxic cyanobacterium Microcystis sp., reflected by its massive blooms in many fresh water bodies, are poorly understood. We show that in addition to a large array of secondary metabolites, some of which are toxic to eukaryotes, Microcystis sp. secretes large amounts of fibrous exopolysaccharides that form extremely long fibres several millimetres in length. This phenomenon was detected in field and laboratory cultures of various Microcystis strains. In addition, we have identified and characterized three of the proteins associated with the fibres and the genes encoding them in Microcystis sp. PCC 7806 but were unable to completely delete them from its genome. Phylogenetic analysis of the most abundant one, designated IPF-469, showed its presence only in cyanobacteria. Its closest relatives were detected in Synechocystis sp. PCC 6803 and in Cyanothece sp. strains; in the latter the genomic organization of the IPF-469 was highly conserved. IPF-469 and the other two proteins identified here, a haloperoxidase and a haemolysin-type calcium-binding protein, may be part of the fibres secretion pathway. The biological role of the fibres in Microcystis sp. is discussed.}, language = {en} } @misc{KaplanHarelKaplanLevyetal.2012, author = {Kaplan, Aaron and Harel, Moshe and Kaplan-Levy, Ruth N. and Hadas, Ora and Sukenik, Assaf and Dittmann-Th{\"u}nemann, Elke}, title = {The languages spoken in the water body (or the biological role of cyanobacterial toxins)}, series = {Frontiers in microbiology}, volume = {3}, journal = {Frontiers in microbiology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-302X}, doi = {10.3389/fmicb.2012.00138}, pages = {11}, year = {2012}, abstract = {Although intensification of toxic cyanobacterial blooms over the last decade is a matter of growing concern due to bloom impact on water quality, the biological role of most of the toxins produced is not known. In this critical review we focus primarily on the biological role of two toxins, microcystins and cylindrospermopsin, in inter- and intra-species communication and in nutrient acquisition. We examine the experimental evidence supporting some of the dogmas in the field and raise several open questions to be dealt with in future research. We do not discuss the health and environmental implications of toxin presence in the water body.}, language = {en} } @misc{LiaimerJensenDittmannThuenemann2016, author = {Liaimer, Anton and Jensen, John B. and Dittmann-Th{\"u}nemann, Elke}, title = {A genetic and chemical perspective on symbiotic recruitment of cyanobacteria of the genus Nostoc into the host plant Blasia pusilla L.}, series = {Frontiers in microbiology}, journal = {Frontiers in microbiology}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-407179}, pages = {16}, year = {2016}, abstract = {Liverwort Blasia pusilla L. recruits soil nitrogen-fixing cyanobacteria of genus Nostoc as symbiotic partners. In this work we compared Nostoc community composition inside the plants and in the soil around them from two distant locations in Northern Norway. STRR fingerprinting and 16S rDNA phylogeny reconstruction showed a remarkable local diversity among isolates assigned to several Nostoc clades. An extensive web of negative allelopathic interactions was recorded at an agricultural site, but not at the undisturbed natural site. The cell extracts of the cyanobacteria did not show antimicrobial activities, but four isolates were shown to be cytotoxic to human cells. The secondary metabolite profiles of the isolates were mapped by MALDI-TOF MS, and the most prominent ions were further analyzed by Q-TOF for MS/MS aided identification. Symbiotic isolates produced a great variety of small peptide-like substances, most of which lack any record in the databases. Among identified compounds we found microcystin and nodularin variants toxic to eukaryotic cells. Microcystin producing chemotypes were dominating as symbiotic recruits but not in the free-living community. In addition, we were able to identify several novel aeruginosins and banyaside-like compounds, as well as nostocyclopeptides and nosperin.}, language = {en} } @article{MakowerSchuurmansGrothetal.2015, author = {Makower, A. Katharina and Schuurmans, J. Merijn and Groth, Detlef and Zilliges, Yvonne and Matthijs, Hans C. P. and Dittmann-Th{\"u}nemann, Elke}, title = {Transcriptomics-Aided dissection of the intracellular and extracellular roles of microcystin in microcystis aeruginosa PCC 7806}, series = {Applied and environmental microbiology}, volume = {81}, journal = {Applied and environmental microbiology}, number = {2}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0099-2240}, doi = {10.1128/AEM.02601-14}, pages = {544 -- 554}, year = {2015}, abstract = {Recent studies have provided evidence for both intracellular and extracellular roles of the potent hepatotoxin microcystin (MC) in the bloom-forming cyanobacterium Microcystis. Here, we surveyed transcriptomes of the wild-type strain M. aeruginosa PCC 7806 and the microcystin-deficient Delta mcyB mutant under low light conditions with and without the addition of external MC of the LR variant (MC-LR). Transcriptomic data acquired by microarray and quantitative PCR revealed substantial differences in the relative expression of genes of the central intermediary metabolism, photosynthesis, and energy metabolism. In particular, the data provide evidence for a lower photosystem I (PSI)-to-photosystem II (PSII) ratio and a more pronounced carbon limitation in the microcystin-deficient mutant. Interestingly, only 6\% of the transcriptional differences could be complemented by external microcystin-LR addition. This MC signaling effect was seen exclusively for genes of the secondary metabolism category. The orphan polyketide synthase gene cluster IPF38-51 was specifically downregulated in response to external MC-LR under low light. Our data suggest a hierarchical and light-dependent cross talk of secondary metabolites and support both an intracellular and an extracellular role of MC in Microcystis.}, language = {en} } @misc{KehrDittmannThuenemann2015, author = {Kehr, Jan-Christoph and Dittmann-Th{\"u}nemann, Elke}, title = {Biosynthesis and function of extracellular glycans in cyanobacteria}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-400121}, pages = {17}, year = {2015}, abstract = {The cell surface of cyanobacteria is covered with glycans that confer versatility and adaptability to a multitude of environmental factors. The complex carbohydrates act as barriers against different types of stress and play a role in intra- as well as inter-species interactions. In this review, we summarize the current knowledge of the chemical composition, biosynthesis and biological function of exo- and lipo-polysaccharides from cyanobacteria and give an overview of sugar-binding lectins characterized from cyanobacteria. We discuss similarities with well-studied enterobacterial systems and highlight the unique features of cyanobacteria. We pay special attention to colony formation and EPS biosynthesis in the bloom-forming cyanobacterium, Microcystis aeruginosa.}, language = {en} } @article{BaunachChowdhuryStallforthetal.2021, author = {Baunach, Martin and Chowdhury, Somak and Stallforth, Pierre and Dittmann-Th{\"u}nemann, Elke}, title = {The landscape of recombination events that create nonribosomal peptide diversity}, series = {Molecular biology and evolution : MBE}, volume = {38}, journal = {Molecular biology and evolution : MBE}, number = {5}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0737-4038}, doi = {10.1093/molbev/msab015}, pages = {2116 -- 2130}, year = {2021}, abstract = {Nonribosomal peptides (NRP) are crucial molecular mediators in microbial ecology and provide indispensable drugs. Nevertheless, the evolution of the flexible biosynthetic machineries that correlates with the stunning structural diversity of NRPs is poorly understood. Here, we show that recombination is a key driver in the evolution of bacterial NRP synthetase (NRPS) genes across distant bacterial phyla, which has guided structural diversification in a plethora of NRP families by extensive mixing andmatching of biosynthesis genes. The systematic dissection of a large number of individual recombination events did not only unveil a striking plurality in the nature and origin of the exchange units but allowed the deduction of overarching principles that enable the efficient exchange of adenylation (A) domain substrates while keeping the functionality of the dynamic multienzyme complexes. In the majority of cases, recombination events have targeted variable portions of the A(core) domains, yet domain interfaces and the flexible A(sub) domain remained untapped. Our results strongly contradict the widespread assumption that adenylation and condensation (C) domains coevolve and significantly challenge the attributed role of C domains as stringent selectivity filter during NRP synthesis. Moreover, they teach valuable lessons on the choice of natural exchange units in the evolution of NRPS diversity, which may guide future engineering approaches.}, language = {en} }