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 - 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 - 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 - 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 -