TY - JOUR A1 - Baunach, Martin A1 - Chowdhury, Somak A1 - Stallforth, Pierre A1 - Dittmann-Thünemann, Elke T1 - The landscape of recombination events that create nonribosomal peptide diversity JF - Molecular biology and evolution : MBE N2 - 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. KW - evolution KW - recombination KW - structural diversity KW - natural products KW - nonribosomal peptide synthetases KW - microbial ecology Y1 - 2021 U6 - https://doi.org/10.1093/molbev/msab015 SN - 0737-4038 SN - 1537-1719 VL - 38 IS - 5 SP - 2116 EP - 2130 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Dehm, Daniel A1 - Krumbholz, Julia A1 - Baunach, Martin A1 - Wiebach, Vincent A1 - Hinrichs, Katrin A1 - Guljamow, Arthur A1 - Tabuchi, Takeshi A1 - Jenke-Kodama, Holger A1 - Süssmuth, Roderich D. A1 - Dittmann-Thünemann, Elke T1 - Unlocking the spatial control of secondary metabolism uncovers hidden natural product diversity in nostoc punctiforme JF - ACS chemical biology N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1021/acschembio.9b00240 SN - 1554-8929 SN - 1554-8937 VL - 14 IS - 6 SP - 1271 EP - 1279 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Ferir, Geoffrey A1 - Vermeire, Kurt A1 - Huskens, Dana A1 - Balzarini, Jan A1 - Van Damme, Els J. M. A1 - Kehr, Jan-Christoph A1 - Dittmann-Thünemann, Elke A1 - Swanson, Michael D. A1 - Markovitz, David M. A1 - Schols, Dominique T1 - Synergistic in vitro anti-HIV type 1 activity of tenofovir with carbohydrate-binding agents (CBAs) JF - Antiviral research N2 - 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. KW - Tenofovir KW - Carbohydrate-binding agents KW - HIV KW - Synergy KW - Microbicide Y1 - 2011 U6 - https://doi.org/10.1016/j.antiviral.2011.03.188 SN - 0166-3542 VL - 90 IS - 3 SP - 200 EP - 204 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Gatte-Picchi, Douglas A1 - Weiz, Annika A1 - Ishida, Keishi A1 - Hertweck, Christian A1 - Dittmann-Thünemann, Elke T1 - Functional analysis of environmental DNA-derived microviridins provides new insights into the diversity of the tricyclic peptide family JF - Applied and environmental microbiology N2 - 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. Y1 - 2014 U6 - https://doi.org/10.1128/AEM.03502-13 SN - 0099-2240 SN - 1098-5336 VL - 80 IS - 4 SP - 1380 EP - 1387 PB - American Society for Microbiology CY - Washington ER - TY - JOUR A1 - Guljamow, Arthur A1 - Delissen, Friedmar A1 - Baumann, Otto A1 - Thuenemann, Andreas F. A1 - Dittmann-Thünemann, Elke T1 - Unique properties of eukaryote-type actin and profilin horizontally transferred to cyanobacteria JF - PLoS one N2 - 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. Y1 - 2012 U6 - https://doi.org/10.1371/journal.pone.0029926 SN - 1932-6203 VL - 7 IS - 1 SP - 221 EP - 231 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Harel, Moshe A1 - Weiss, Gad A1 - Daniel, Einat A1 - Wilenz, Avraham A1 - Hadas, Ora A1 - Sukenik, Assaf A1 - Sedmak, Bojan A1 - Dittmann-Thünemann, Elke A1 - Braun, Sergei A1 - Kaplan, Aaron T1 - Casting a net fibres produced by Microcystis sp in field and laboratory populations JF - Environmental microbiology reports N2 - 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. Y1 - 2012 U6 - https://doi.org/10.1111/j.1758-2229.2012.00339.x SN - 1758-2229 VL - 4 IS - 3 SP - 342 EP - 349 PB - Wiley-Blackwell CY - Malden ER - TY - JOUR A1 - Hu, Chenlin A1 - Völler, Ginka A1 - Sussmuth, Roderich A1 - Dittmann-Thünemann, Elke A1 - Kehr, Jan-Christoph T1 - Functional assessment of mycosporine-like amino acids in Microcystis aeruginosa strain PCC 7806 JF - Environmental microbiology N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1111/1462-2920.12577 SN - 1462-2912 SN - 1462-2920 VL - 17 IS - 5 SP - 1548 EP - 1559 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Liaimer, Anton A1 - Jenke-Kodama, Holger A1 - Ishida, Keishi A1 - Hinrichs, Katrin A1 - Stangeland, Janne A1 - Hertweck, Christian A1 - Dittmann-Thünemann, Elke T1 - A polyketide interferes with cellular differentiation in the symbiotic cyanobacterium Nostoc punctiforme JF - Environmental microbiology reports N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1111/j.1758-2229.2011.00258.x SN - 1758-2229 VL - 3 IS - 5 SP - 550 EP - 558 PB - Wiley-Blackwell CY - Malden ER - TY - JOUR A1 - Makower, A. Katharina A1 - Schuurmans, J. Merijn A1 - Groth, Detlef A1 - Zilliges, Yvonne A1 - Matthijs, Hans C. P. A1 - Dittmann-Thünemann, Elke T1 - Transcriptomics-Aided dissection of the intracellular and extracellular roles of microcystin in microcystis aeruginosa PCC 7806 JF - Applied and environmental microbiology N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1128/AEM.02601-14 SN - 0099-2240 SN - 1098-5336 VL - 81 IS - 2 SP - 544 EP - 554 PB - American Society for Microbiology CY - Washington ER - TY - JOUR A1 - Meissner, Sven A1 - Fastner, Jutta A1 - Dittmann-Thünemann, Elke T1 - Microcystin production revisited conjugate formation makes a major contribution JF - Environmental microbiology N2 - 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. Y1 - 2013 U6 - https://doi.org/10.1111/1462-2920.12072 SN - 1462-2912 VL - 15 IS - 6 SP - 1810 EP - 1820 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Meissner, Sven A1 - Steinhauser, Dirk A1 - Dittmann-Thünemann, Elke T1 - Metabolomic analysis indicates a pivotal role of the hepatotoxin microcystin in high light adaptation of Microcystis JF - Environmental microbiology N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1111/1462-2920.12565 SN - 1462-2912 SN - 1462-2920 VL - 17 IS - 5 SP - 1497 EP - 1509 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Voss, Björn A1 - Bolhuis, Henk A1 - Fewer, David P. A1 - Kopf, Matthias A1 - Möke, Fred A1 - Haas, Fabian A1 - El-Shehawy, Rehab A1 - Hayes, Paul A1 - Bergman, Birgitta A1 - Sivonen, Kaarina A1 - Dittmann-Thünemann, Elke A1 - Scanlan, Dave J. A1 - Hagemann, Martin A1 - Stal, Lucas J. A1 - Hess, Wolfgang R. T1 - Insights into the physiology and ecology of the brackish-water-adapted cyanobacterium nodularia spumigena CCY9414 based on a genome-transcriptome analysis JF - PLoS one N2 - 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. Y1 - 2013 U6 - https://doi.org/10.1371/journal.pone.0060224 SN - 1932-6203 VL - 8 IS - 3 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Weiz, Annika R. A1 - Ishida, Keishi A1 - Makower, Katharina A1 - Ziemert, Nadine A1 - Hertweck, Christian A1 - Dittmann-Thünemann, Elke T1 - Leader Peptide and a Membrane Protein Scaffold Guide the Biosynthesis of the Tricyclic Peptide Microviridin JF - Chemistry & biology N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1016/j.chembiol.2011.09.011 SN - 1074-5521 VL - 18 IS - 11 SP - 1413 EP - 1421 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Weiz, Annika R. A1 - Ishida, Keishi A1 - Quitterer, Felix A1 - Meyer, Sabine A1 - Kehr, Jan-Christoph A1 - Mueller, Kristian M. A1 - Groll, Michael A1 - Hertweck, Christian A1 - Dittmann-Thünemann, Elke T1 - Harnessing the evolvability of tricyclic microviridins to dissect protease-inhibitor interactions JF - Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker ; International edition N2 - 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. KW - cyanobacteria KW - peptide engineering KW - protease inhibitors KW - RiPPs KW - structure elucidation Y1 - 2014 U6 - https://doi.org/10.1002/anie.201309721 SN - 1433-7851 SN - 1521-3773 VL - 53 IS - 14 SP - 3735 EP - 3738 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Ziemert, Nadine A1 - Ishida, Keishi A1 - Weiz, Annika A1 - Hertweck, Christian A1 - Dittmann-Thünemann, Elke T1 - Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides N2 - 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. Y1 - 2010 UR - http://aem.asm.org/ U6 - https://doi.org/10.1128/AEM.02858-09 SN - 0099-2240 ER - TY - JOUR A1 - Zilliges, Yvonne A1 - Kehr, Jan-Christoph A1 - Meissner, Sven A1 - Ishida, Keishi A1 - Mikkat, Stefan A1 - Hagemann, Martin A1 - Kaplan, Aaron A1 - Börner, Thomas A1 - Dittmann-Thünemann, Elke T1 - The cyanobacterial hepatotoxin microcystin binds to proteins and increases the fitness of microcystis under oxidative stress conditions JF - PLoS one N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0017615 SN - 1932-6203 VL - 6 IS - 3 PB - PLoS CY - San Fransisco ER -