Evaluating Ketoreductase Exchanges as a Means of Rationally Altering Polyketide Stereochemistry - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue ChemBioChem Année : 2015

Evaluating Ketoreductase Exchanges as a Means of Rationally Altering Polyketide Stereochemistry

Résumé

Modular polyketide synthases (PKSs) are multidomain multienzymes responsible for the biosynthesis in bacteria of a wide range of polyketide secondary metabolites of clinical value. The stereochemistry of these molecules is an attractive target for genetic engineering in attempts to produce analogues exhibiting novel therapeutic properties. The exchange of ketoreductase (KR) domains in model PKSs has been shown in several cases to predictably alter the configuration of the -hydroxy functionalities but not of the -methyl groups. By systematic screening of a broad panel of KR domains, we have identified two donor KRs that afford modification of -methyl group stereochemistry. To the best of our knowledge, this provides the first direct in vivo evidence of KR-catalyzed epimerization. However, none of the introduced KRs afforded simultaneous alteration of methyl and hydroxy configurations in high yield. Therefore, swapping of whole modules might be necessary to achieve such changes in stereochemistry.

Dates et versions

hal-01278114 , version 1 (23-02-2016)

Identifiants

Citer

Thibault Annaval, Cedric Paris, Peter F. Leadlay, Christophe Jacob, Kira J. Weissman. Evaluating Ketoreductase Exchanges as a Means of Rationally Altering Polyketide Stereochemistry. ChemBioChem, 2015, 16 (9), pp.1357-1364. ⟨10.1002/cbic.201500113⟩. ⟨hal-01278114⟩
61 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More