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Updated: Sep 27, 2025

From a Natural Product to Its Biosynthetic Gene Cluster: A Demonstration Using Polyketomycin from Streptomyces diastatochromogenes Tü6028
Published on: January 13, 2017
Studying a Bottleneck of Multimodular Polyketide Synthase Processing: the Polyketide Structure-Dependent Performance
Marius Schröder1,2, Theresa Roß1, Franziska Hemmerling1,2
1Professur für Organische Chemie (Lebensmittelchemie), Fakultät für Biologie, Chemie und Geowissenschaften, Department of Chemistry, Universität Bayreuth, 95447 Bayreuth, Germany.
Abstract:
Ketoreductases (KRs) are canonical domains of type I polyketide synthases (PKSs). They stereoselectively reduce ACP-bound β-ketothioester intermediates and are responsible for a large part of the stereocenters in reduced polyketides. Albeit essential for the understanding and engineering of PKS, the specific effects of altering the polyketide part of KR precursors on their performance has rarely been studied. We present investigations on the substrate-dependent performance of six isolated KR domains using a library of structurally diverse surrogates for PKS thioester intermediates. A pronounced correlation between the polyketide structure and the KR performance was observed with activity and stereoselectivity diminishing with growing deviation from the natural KR precursor structure. The extent of this decrease and the profile of arising side products was characteristic for the individual KRs. Our results reinforce the importance of structure-KR performance relationships and suggest extended studies with isolated domains and whole PKS modules.
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