TY  - JOUR
A1  - Pancrace, Claire
A1  - Ishida, Keishi
A1  - Briand, Enora
A1  - Pichi, Douglas Gatte
A1  - Weiz, Annika R.
A1  - Guljarmow, Arthur
A1  - Scalvenzi, Thibault
A1  - Sassoon, Nathalie
A1  - Hertweck, Christian
A1  - Dittmann, Elke
A1  - Gugger, Muriel
T1  - Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines
JF  - ACS chemical biology
N2  - The cyanobacterial genus Microcystis is known to produce an elaborate array of structurally unique and biologically active natural products, including hazardous cyanotoxins. Cytotoxic aeruginoguanidines represent a yet unexplored family of peptides featuring a trisubstituted benzene unit and farnesylated arginine derivatives. In this study, we aimed at assigning these compounds to a biosynthetic gene cluster by utilizing biosynthetic attributes deduced from public genomes of Microcystis and the sporadic distribution of the metabolite in axenic strains of the Pasteur Culture Collection of Cyanobacteria. By integrating genome mining with untargeted metabolomics using liquid chromatography with mass spectrometry, we linked aeruginoguanidine (AGD) to a nonribosomal peptide synthetase gene cluster and coassigned a significantly smaller product to this pathway, microguanidine (MGD), previously only reported from two Microcystis blooms. Further, a new intermediate class of compounds named microguanidine amides was uncovered, thereby further enlarging this compound family. The comparison of structurally divergent AGDs and MGDs reveals an outstanding versatility of this biosynthetic pathway and provides insights into the assembly of the two compound subfamilies. Strikingly, aeruginoguanidines and microguanidines were found to be as widespread as the hepatotoxic microcystins, but the occurrence of both toxin families appeared to be mutually exclusive.
Y1  - 2018
U6  - https://doi.org/10.1021/acschembio.8b00918
SN  - 1554-8929
SN  - 1554-8937
VL  - 14
IS  - 1
SP  - 67
EP  - 75
PB  - American Chemical Society
CY  - Washington
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  - 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  - 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  - Arnison, Paul G.
A1  - Bibb, Mervyn J.
A1  - Bierbaum, Gabriele
A1  - Bowers, Albert A.
A1  - Bugni, Tim S.
A1  - Bulaj, Grzegorz
A1  - Camarero, Julio A.
A1  - Campopiano, Dominic J.
A1  - Challis, Gregory L.
A1  - Clardy, Jon
A1  - Cotter, Paul D.
A1  - Craik, David J.
A1  - Dawson, Michael
A1  - Dittmann-Thünemann, Elke
A1  - Donadio, Stefano
A1  - Dorrestein, Pieter C.
A1  - Entian, Karl-Dieter
A1  - Fischbach, Michael A.
A1  - Garavelli, John S.
A1  - Goeransson, Ulf
A1  - Gruber, Christian W.
A1  - Haft, Daniel H.
A1  - Hemscheidt, Thomas K.
A1  - Hertweck, Christian
A1  - Hill, Colin
A1  - Horswill, Alexander R.
A1  - Jaspars, Marcel
A1  - Kelly, Wendy L.
A1  - Klinman, Judith P.
A1  - Kuipers, Oscar P.
A1  - Link, A. James
A1  - Liu, Wen
A1  - Marahiel, Mohamed A.
A1  - Mitchell, Douglas A.
A1  - Moll, Gert N.
A1  - Moore, Bradley S.
A1  - Mueller, Rolf
A1  - Nair, Satish K.
A1  - Nes, Ingolf F.
A1  - Norris, Gillian E.
A1  - Olivera, Baldomero M.
A1  - Onaka, Hiroyasu
A1  - Patchett, Mark L.
A1  - Piel, Jörn
A1  - Reaney, Martin J. T.
A1  - Rebuffat, Sylvie
A1  - Ross, R. Paul
A1  - Sahl, Hans-Georg
A1  - Schmidt, Eric W.
A1  - Selsted, Michael E.
A1  - Severinov, Konstantin
A1  - Shen, Ben
A1  - Sivonen, Kaarina
A1  - Smith, Leif
A1  - Stein, Torsten
A1  - Suessmuth, Roderich D.
A1  - Tagg, John R.
A1  - Tang, Gong-Li
A1  - Truman, Andrew W.
A1  - Vederas, John C.
A1  - Walsh, Christopher T.
A1  - Walton, Jonathan D.
A1  - Wenzel, Silke C.
A1  - Willey, Joanne M.
A1  - van der Donk, Wilfred A.
T1  - Ribosomally synthesized and post-translationally modified peptide natural products overview and recommendations for a universal nomenclature
JF  - Natural product reports : a journal of current developments in bio-organic chemistry
N2  - 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.
Y1  - 2013
U6  - https://doi.org/10.1039/c2np20085f
SN  - 0265-0568
VL  - 30
IS  - 1
SP  - 108
EP  - 160
PB  - Royal Society of Chemistry
CY  - Cambridge
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  - 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  -