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      Substrate-dependent stereospecificity of Tyl-KR1: an isolated polyketide synthase ketoreductase domain from Streptomyces fradiae.

      1 , ,

      Chemistry (Weinheim an der Bergstrasse, Germany)

      Wiley

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          Abstract

          The stereospecificity of an enzymatic reaction depends on the way in which a substrate and its enantiomer bind to the active site. These binding modes cannot be easily predicted. We have studied the stereospecificity and stereoselectivity of the ketoreductase domain Tyl-KR1 of the tylactone polyketide synthase from Streptomyces fradiae by analysing the stereochemical outcome of the reduction of five different keto ester substrates. The absolute configuration of the Tyl-KR1 reduction products was determined by using vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. The conversion of only one of the tested substrates, 2-methyl-3-oxovaleric acid N-acetylcysteamine thioester, afforded the expected anti-(2R,3R) configuration of the α-methyl-β-hydroxyl ester product, representing the stereochemistry observed for the physiological polyketide product tylactone. For all other substrates, which were modified with respect to the type of ester and/or the chain length (C4 instead of C5), the opposite configuration (anti-(2S,3S)) was obtained with significant enantio- and diastereoselectivity. Inversion of both stereocentres suggests completely different binding modes invoked by only minor modifications of the substrate structure.

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          Author and article information

          Journal
          Chemistry
          Chemistry (Weinheim an der Bergstrasse, Germany)
          Wiley
          1521-3765
          0947-6539
          Jul 01 2013
          : 19
          : 27
          Affiliations
          [1 ] Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
          Article
          10.1002/chem.201300554
          23681606

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