TY - JOUR
T1 - Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline
AU - Dornisch, Elisabeth
AU - Pletz, Jakob
AU - Glabonjat, Ronald A.
AU - Martin, Florian
AU - Lembacher-Fadum, Christian
AU - Neger, Margit
AU - Högenauer, Christoph
AU - Francesconi, Kevin A.
AU - Kroutil, Wolfgang
AU - Zangger, Klaus
AU - Breinbauer, Rolf
AU - Zechner, Ellen L.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1002/anie.201707737
DO - 10.1002/anie.201707737
M3 - Article
SN - 1433-7851
VL - 56
SP - 14753
EP - 14757
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 46
ER -