Studying a bottleneck of multimodular polyketide synthase processing : the polyketide structure-dependent performance of ketoreductase domains

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Schröder, Marius ; Roß, Theresa ; Hemmerling, Franziska ; Hahn, Frank:
Studying a bottleneck of multimodular polyketide synthase processing : the polyketide structure-dependent performance of ketoreductase domains.
In: ACS Chemical Biology. Bd. 17 (2022) Heft 5 . - S. 1030-1037.
ISSN 1554-8937
DOI: https://doi.org/10.1021/acschembio.2c00047

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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.