@article{KrumbholzIshidaBaunachetal.2022, author = {Krumbholz, Julia and Ishida, Keishi and Baunach, Martin and Teikari, Jonna and Rose, Magdalena M. and Sasso, Severin and Hertweck, Christian and Dittmann, Elke}, title = {Deciphering chemical mediators regulating specialized metabolism in a symbiotic cyanobacterium}, series = {Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker. International edition}, journal = {Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker. International edition}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1433-7851}, doi = {10.1002/anie.202204545}, pages = {10}, year = {2022}, abstract = {Genomes of cyanobacteria feature a variety of cryptic biosynthetic pathways for complex natural products, but the peculiarities limiting the discovery and exploitation of the metabolic dark matter are not well understood. Here we describe the discovery of two cell density-dependent chemical mediators, nostoclide and nostovalerolactone, in the symbiotic model strain Nostoc punctiforme, and demonstrate their pronounced impact on the regulation of specialized metabolism. Through transcriptional, bioinformatic and labeling studies we assigned two adjacent biosynthetic gene clusters to the biosynthesis of the two polyketide mediators. Our findings provide insight into the orchestration of specialized metabolite production and give lessons for the genomic mining and high-titer production of cyanobacterial bioactive compounds.}, language = {en} } @article{GuoSchwitallaBenndorfetal.2020, author = {Guo, Huijuan and Schwitalla, Jan W. and Benndorf, Ren{\´e} and Baunach, Martin and Steinbeck, Christoph and G{\"o}rls, Helmar and de Beer, Z. Wilhelm and Regestein, Lars and Beemelmanns, Christine}, title = {Gene cluster activation in a bacterial symbiont leads to halogenated angucyclic maduralactomycins and spirocyclic actinospirols}, series = {Organic letters}, volume = {22}, journal = {Organic letters}, number = {7}, publisher = {American Chemical Society}, address = {Washington, DC}, issn = {1523-7060}, doi = {10.1021/acs.orglett.0c00601}, pages = {2634 -- 2638}, year = {2020}, abstract = {Growth from spores activated a biosynthetic gene cluster in Actinomadura sp. RB29, resulting in the identification of two novel groups of halogenated polyketide natural products, named maduralactomycins and actinospirols. The unique tetracyclic and spirocyclic structures were assigned based on a combination of NMR analysis, chemoinformatic calculations, X-ray crystallography, and C-13 labeling studies. On the basis of HRMS2 data, genome mining, and gene expression studies, we propose an underlying noncanonical angucycline biosynthesis and extensive post-polyketide synthase (PKS) oxidative modifications.}, 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} } @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} }