Stereochemical determination and complex biosynthetic assembly of etnangien, a highly potent RNA polymerase inhibitor from the myxobacterium Sorangium cellulosum.
A potent novel analogue of the natural macrolide antibiotic etnangien, a structurally unique RNA polymerase inhibitor from myxobacteria, is reported. It may be readily obtained from fermentation broths of Sorangium cellulosum and shows high antibiotic activity, comparable to that of etnangien. However, it is much more readily available than the notoriously labile authentic natural product itself. Importantly, it is stable under neutral conditions, allowing for elaborate NMR measurements for assignment of the 12 hydroxyl- and methyl-bearing stereogenic centers. The full absolute and relative stereochemistries of these complex polyketides were determined by a combination of extensive high-field NMR studies, including J-based configuration analysis, molecular modeling, and synthetic derivatization in combination with an innovative method based on biosynthetic studies of this polyketide which is also presented here. A first look into the solution conformation and 3D structure of these promising macrolide antibiotics is reported. Finally, the complete biosynthetic gene cluster was analyzed in detail, revealing a highly unusual and complex trans-AT type polyketide biosynthesis, which does not follow colinearity rules, most likely performs programmed iteration as well as module skipping, and exhibits HMG-CoA box-directed methylation.
Menche
Dirk
D
University of Heidelberg, Department of Organic Chemistry, INF 270, D-69120 Heidelberg, Germany. dirk.menche@oci.uni-heidelberg.de
Arikan
Fatih
F
Perlova
Olena
O
Horstmann
Nicole
N
Ahlbrecht
Wiebke
W
Wenzel
Silke C
SC
Jansen
Rolf
R
Irschik
Herbert
H
Müller
Rolf
R
D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D008968:Molecular Conformation; D009231:Myxococcales / Q000737:chemistry* / Q000378:metabolism*; D011090:Polyenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D012015:Reference Standards; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D018942:Macrolides; D011090:Polyenes; C521655:etnangien; D012321:DNA-Directed RNA Polymerases