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      Evaluating Ketoreductase Exchanges as a Means of Rationally Altering Polyketide Stereochemistry.

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          Abstract

          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.

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          Author and article information

          Journal
          Chembiochem
          Chembiochem : a European journal of chemical biology
          Wiley-Blackwell
          1439-7633
          1439-4227
          Jun 15 2015
          : 16
          : 9
          Affiliations
          [1 ] UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus biologie-santé, 9 Avenue de la Forêt de Haye, CS 50184, 54505 Vandœuvre-lès-Nancy Cedex (France).
          [2 ] Laboratoire d'Ingénierie des Biomolécules, Ecole Nationale Supérieure d'Agronomie et des Industries Alimentaires (ENSAIA), Université de Lorraine, 2, Avenue de la Fôret de Haye, B. P. 172, 54518 Vandœuvre-lès-Nancy Cedex (France).
          [3 ] Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA (UK).
          [4 ] UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus biologie-santé, 9 Avenue de la Forêt de Haye, CS 50184, 54505 Vandœuvre-lès-Nancy Cedex (France). christophe.jacob@univ-lorraine.fr.
          [5 ] UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus biologie-santé, 9 Avenue de la Forêt de Haye, CS 50184, 54505 Vandœuvre-lès-Nancy Cedex (France). kira.weissman@univ-lorraine.fr.
          Article
          10.1002/cbic.201500113
          25851784
          4a512ad9-3479-40b0-a6e7-6a942f34e212
          History

          biosynthesis,genetic engineering,ketoreductases,polyketides,stereocontrol

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