We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships.
- Authors
Wenzel, Silke C.; Hoffmann, Holger; Zhang, Jidong; Debussche, Laurent; Haag ‐ Richter, Sabine; Kurz, Michael; Nardi, Frederico; Lukat, Peer; Kochems, Irene; Tietgen, Heiko; Schummer, Dietmar; Nicolas, Jean ‐ Paul; Calvet, Loreley; Czepczor, Valerie; Vrignaud, Patricia; Mühlenweg, Agnes; Pelzer, Stefan; Müller, Rolf; Brönstrup, Mark
- Abstract
The bengamides, sponge-derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked ona multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half-life in mice and antitumor efficacy in a melanoma mouse model.
- Subjects
NATURAL products; METHIONINE aminopeptidase; AMINOPEPTIDASES; ANTINEOPLASTIC agents; BIOSYNTHESIS
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 51, p15560
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201508277