3 years ago

Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline

Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline
Christoph Högenauer, Ellen L. Zechner, Kevin Francesconi, Margit Neger, Wolfgang Kroutil, Elisabeth Dornisch, Rolf Breinbauer, Jakob Pletz, Christian Lembacher-Fadum, Ronald A. Glabonjat, Florian Martin, Klaus Zangger
The nonribosomal enterotoxin tilivalline was the first naturally occurring pyrrolobenzodiazepine to be linked to disease in the human intestine. Since the producing organism Klebsiella oxytoca is part of the intestinal microbiota and the pyrrolobenzodiazepine causes the pathogenesis of colitis it is important to understand the biosynthesis and regulation of tilivalline activity. Here we report the biosynthesis of tilivalline and show that this nonribosomal peptide assembly pathway initially generates tilimycin, a simple pyrrolobenzodiazepine with cytotoxic properties. Tilivalline results from the non-enzymatic spontaneous reaction of tilimycin with biogenetically generated indole. Through a chemical total synthesis of tilimycin we could corroborate the predictions made about the biosynthesis. Production of two cytotoxic pyrrolobenzodiazepines with distinct functionalities by human gut resident Klebsiella oxytoca has important implications for intestinal disease. The Klebsiella oxytoca enterotoxin tilivalline was the first naturally occurring pyrrolobenzodiazepine to be linked to disease in the human intestine. In the biosynthesis of tilivalline the nonribosomal peptide assembly pathway initially generates the cytotoxic pyrrolobenzodiazepine tilimycin. Tilivalline results from the non-enzymatic reaction of tilimycin with biogenetically generated indole.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201707737

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