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 - Kehr, Jan-Christoph A1 - Picchi, Douglas Gatte A1 - Dittmann-Thünemann, Elke T1 - Natural product biosyntheses in cyanobacteria a treasure trove of unique enzymes JF - Beilstein journal of organic chemistry N2 - 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. KW - cyanobacteria KW - natural products KW - NRPS KW - PKS KW - ribosomal peptides Y1 - 2011 U6 - https://doi.org/10.3762/bjoc.7.191 SN - 1860-5397 VL - 7 IS - 2 SP - 1622 EP - 1635 PB - Beilstein-Institut zur Förderung der Chemischen Wissenschaften CY - Frankfurt, Main 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 - 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 - 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 - INPR A1 - Kehr, Jan-Christoph A1 - Dittmann-Thünemann, Elke T1 - Protective tunicate endosymbiont with extreme genome reduction T2 - Environmental microbiology Y1 - 2015 U6 - https://doi.org/10.1111/1462-2920.12941 SN - 1462-2912 SN - 1462-2920 VL - 17 IS - 10 SP - 3430 EP - 3432 PB - Wiley-Blackwell CY - Hoboken ER - TY - GEN A1 - Kehr, Jan-Christoph A1 - Dittmann-Thünemann, Elke T1 - Biosynthesis and function of extracellular glycans in cyanobacteria N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 346 KW - cyanobacteria KW - exopolysaccharides KW - lipopolysaccharides KW - colony formation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400121 ER - TY - JOUR A1 - Meyer, Sabine A1 - Mainz, Andi A1 - Kehr, Jan-Christoph A1 - Suessmuth, Roderich A1 - Dittmann, Elke T1 - Prerequisites of Isopeptide Bond Formation in Microcystin Biosynthesis JF - ChemBioChem : a European journal of chemical biology N2 - The biosynthesis of the potent cyanobacterial hepatotoxin microcystin involves isopeptide bond formation through the carboxylic acid side chains of d-glutamate and -methyl d-aspartate. Analysis of the in vitro activation profiles of the two corresponding adenylation domains, McyE-A and McyB-A(2), either in a didomain or a tridomain context with the cognate thiolation domain and the upstream condensation domain revealed that substrate activation of both domains strictly depended on the presence of the condensation domains. We further identified two key amino acids in the binding pockets of both adenylation domains that could serve as a bioinformatic signature of isopeptide bond-forming modules incorporating d-glutamate or d-aspartate. Our findings further contribute to the understanding of the multifaceted role of condensation domains in nonribosomal peptide synthetase assembly lines. KW - amino acids KW - biosynthesis KW - cyanobacteria KW - nonribosomal peptide KW - substrate specificity Y1 - 2017 U6 - https://doi.org/10.1002/cbic.201700389 SN - 1439-4227 SN - 1439-7633 VL - 18 SP - 2376 EP - 2379 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Soeriyadi, Angela H. A1 - Ongley, Sarah E. A1 - Kehr, Jan-Christoph A1 - Pickford, Russel A1 - Dittmann, Elke A1 - Neilan, Brett A. T1 - Tailoring enzyme stringency masks the multispecificity of a lyngbyatoxin (indolactam alkaloid) nonribosomal peptide synthetase JF - ChemBioChem N2 - Indolactam alkaloids are activators of protein kinase C (PKC) and are of pharmacological interest for the treatment of pathologies involving PKC dysregulation. The marine cyanobacterial nonribosomal peptide synthetase (NRPS) pathway for lyngbyatoxin biosynthesis, which we previously expressed in E. coli, was studied for its amenability towards the biosynthesis of indolactam variants. Modification of culture conditions for our E. coli heterologous expression host and analysis of pathway products suggested the native lyngbyatoxin pathway NRPS does possess a degree of relaxed specificity. Site-directed mutagenesis of two positions within the adenylation domain (A-domain) substrate-binding pocket was performed, resulting in an alteration of substrate preference between valine, isoleucine, and leucine. We observed relative congruence of in vitro substrate activation by the LtxA NRPS to in vivo product formation. While there was a preference for isoleucine over leucine, the substitution of alternative tailoring domains may unveil the true in vivo effects of the mutations introduced herein. KW - a domain KW - indolactams KW - MbtH KW - natural products KW - teleocidin Y1 - 2021 U6 - https://doi.org/10.1002/cbic.202100574 SN - 1439-4227 SN - 1439-7633 VL - 23 IS - 3 PB - Wiley-VCH CY - Weinheim ER -