Bravo-Rodriguez, K., Ismail-Ali, A. F., Klopries, S., Kushnir, S., Ismail, S. , Fansa, E. K., Wittinghofer, A., Schulz, F. and Sanchez-Garcia, E. (2014) Predicted Incorporation of Non-native Substrates by a Polyketide Synthase Yields Bioactive Natural Product Derivatives. ChemBioChem, 15(13), pp. 1991-1997. (doi: 10.1002/cbic.201402206) (PMID:25044264)
Full text not currently available from Enlighten.
Abstract
The polyether ionophore monensin is biosynthesized by a polyketide synthase that delivers a mixture of monensins A and B by the incorporation of ethyl‐ or methyl‐malonyl‐CoA at its fifth module. Here we present the first computational model of the fifth acyltransferase domain (AT5mon) of this polyketide synthase, thus affording an investigation of the basis of the relaxed specificity in AT5mon, insights into the activation for the nucleophilic attack on the substrate, and prediction of the incorporation of synthetic malonic acid building blocks by this enzyme. Our predictions are supported by experimental studies, including the isolation of a predicted derivative of the monensin precursor premonensin. The incorporation of non‐native building blocks was found to alter the ratio of premonensins A and B. The bioactivity of the natural product derivatives was investigated and revealed binding to prenyl‐binding protein. We thus show the potential of engineered biosynthetic polyketides as a source of ligands for biological macromolecules.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by the Cluster of Excellence RESOLV (EXC 1069) funded by the Deutsche Forschungsgemeinschaft. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Ismail, Dr Shehab |
| Authors: | Bravo-Rodriguez, K., Ismail-Ali, A. F., Klopries, S., Kushnir, S., Ismail, S., Fansa, E. K., Wittinghofer, A., Schulz, F., and Sanchez-Garcia, E. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | ChemBioChem |
| Publisher: | Wiley |
| ISSN: | 1439-4227 |
| ISSN (Online): | 1439-7633 |
| Published Online: | 15 July 2014 |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric