@article{MeyerMainzKehretal.2017,
  author    = {Meyer, Sabine and Mainz, Andi and Kehr, Jan-Christoph and Suessmuth, Roderich and Dittmann, Elke},
  title     = {Prerequisites of Isopeptide Bond Formation in Microcystin Biosynthesis},
  series = {ChemBioChem : a European journal of chemical biology},
  volume    = {18},
  journal   = {ChemBioChem : a European journal of chemical biology},
  publisher = {Wiley-VCH},
  address   = {Weinheim},
  issn      = {1439-4227},
  doi       = {10.1002/cbic.201700389},
  pages     = {2376 -- 2379},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{AhmedReynaGonzalezSchmidetal.2017,
  author    = {Ahmed, Muhammad N. and Reyna-Gonzalez, Emmanuel and Schmid, Bianca and Wiebach, Vincent and Suessmuth, Roderich D. and Dittmann, Elke and Fewer, David P.},
  title     = {Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors},
  series = {ACS chemical biology},
  volume    = {12},
  journal   = {ACS chemical biology},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {1554-8929},
  doi       = {10.1021/acschembio.7b00124},
  pages     = {1538 -- 1546},
  year      = {2017},
  abstract  = {Natural products and their semisynthetic derivatives are an important source of drugs for the pharmaceutical industry. Bacteria are prolific producers of natural products and encode a vast diversity of natural product biosynthetic gene clusters. However, much of this diversity is inaccessible to natural product discovery. Here, we use a combination of phylogenomic analysis of the microviridin biosynthetic pathway and chemo-enzymatic synthesis of bioinformatically predicted microviridins to yield new protease inhibitors. Phylogenomic analysis demonstrated that microviridin biosynthetic gene clusters occur across the bacterial domain and encode three distinct subtypes of precursor peptides. Our analysis shed light on the evolution of microviridin biosynthesis and enabled prioritization of their chemo-enzymatic production. Targeted one-pot synthesis of four microviridins encoded by the cyanobacterium Cyanothece sp. PCC 7822 identified a set of novel and potent serine protease inhibitors, the most active of which had an IC50 value of 21.5 nM. This study advances the genome mining techniques available for natural product discovery and obviates the need to culture bacteria.},
  language  = {en}
}