Evaluating Ketoreductase Exchanges as a Means of Rationally Altering Polyketide Stereochemistry.
Fiche publication
Date publication
juin 2015
Journal
Chembiochem : a European journal of chemical biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr JACOB Christophe, Pr WEISSMAN Kira
Tous les auteurs :
Annaval T, Paris C, Leadlay PF, Jacob C, Weissman KJ
Lien Pubmed
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 β-hydroxy functionalities but not of the α-methyl groups. By systematic screening of a broad panel of KR domains, we have identified two donor KRs that afford modification of α-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.
Mots clés
biosynthesis, genetic engineering, ketoreductases, polyketides, stereocontrol
Référence
Chembiochem. 2015 Jun 15;16(9):1357-64