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Acyl-chain elongation drives ketosynthase substrate selectivity in trans-acyltransferase polyketide synthases

Jenner, Matthew; Afonso, José Pedro; Bailey, Hannah R.; Frank, Sarah; Kampa, Annette; Piel, Jörn; Oldfield, Neil J.

Authors

Matthew Jenner M.Jenner@warwick.ac.uk

José Pedro Afonso jose.afonso@nottingham.ac.uk

Hannah R. Bailey

Sarah Frank

Annette Kampa

Jörn Piel

NEIL OLDHAM neil.oldham@nottingham.ac.uk
Professor of Biomolecular Spectrometry



Abstract

Type I modular polyketide synthases (PKSs), responsible for the biosynthesis of many biologically active agents, possess a ketosynthase (KS) domain within each module to catalyze chain elongation.
Acylation of the KS active site Cys residue is followed by transfer to malonyl-acyl carrier protein, yielding an extended β-ketoacyl chain. To date, the precise contribution of KS selectivity in controlling product fidelity has been unclear. We submitted six KS domains from the trans-acyl transferase PKSs to a mass spectrometry-basedelongation assay, and identified higher substrat selectivity in the elongating step than in preceding acylation. A close correspondence between observed KS selectivity and that predicted by phylogenetic analysis was seen. Our findings provide insights into the mechanism of KS selectivity in this important group of PKSs, can serve as guidance for engineering, and show that targeted mutagenesis can be used to expand the repertoire of acceptable substrates.

Journal Article Type Article
Publication Date Feb 2, 2015
Journal Angewandte Chemie International Edition
Print ISSN 1433-7851
Electronic ISSN 1433-7851
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 54
Issue 6
APA6 Citation Jenner, M., Afonso, J. P., Bailey, H. R., Frank, S., Kampa, A., Piel, J., & Oldfield, N. J. (2015). Acyl-chain elongation drives ketosynthase substrate selectivity in trans-acyltransferase polyketide synthases. Angewandte Chemie International Edition, 54(6), https://doi.org/10.1002/anie.201410219
DOI https://doi.org/10.1002/anie.201410219
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/anie.201410219/abstract;jsessionid=5CB1491BBFD74477E18B7BE69BBAD0D9.f02t03
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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