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Predicted Incorporation of Non‐native Substrates by a Polyketide Synthase Yields Bioactive Natural Product Derivatives
Author(s) -
BravoRodriguez Kenny,
IsmailAli Ahmed F.,
Klopries Stephan,
Kushnir Susanna,
Ismail Shehab,
Fansa Eyad K.,
Wittinghofer Alfred,
Schulz Frank,
SanchezGarcia Elsa
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402206
Subject(s) - polyketide , polyketide synthase , acyltransferase , natural product , acyltransferases , chemistry , monensin , atp synthase , stereochemistry , acyl carrier protein , biosynthesis , enzyme , fatty acid synthase , combinatorial chemistry , biochemistry
The polyether ionophore monensin is biosynthesized by a polyketide synthase that delivers a mixture of monensins A and B by the incorporation of ethyl‐ or methyl‐malonyl‐CoA at its fifth module. Here we present the first computational model of the fifth acyltransferase domain (AT5 mon ) of this polyketide synthase, thus affording an investigation of the basis of the relaxed specificity in AT5 mon , insights into the activation for the nucleophilic attack on the substrate, and prediction of the incorporation of synthetic malonic acid building blocks by this enzyme. Our predictions are supported by experimental studies, including the isolation of a predicted derivative of the monensin precursor premonensin. The incorporation of non‐native building blocks was found to alter the ratio of premonensins A and B. The bioactivity of the natural product derivatives was investigated and revealed binding to prenyl‐binding protein. We thus show the potential of engineered biosynthetic polyketides as a source of ligands for biological macromolecules.