A conserved motif flags acyl carrier proteins for β-branching in polyketide synthesis

Anthony S Haines, Xu Dong, Zhongshu Song, Rohit Farmer, Christopher Williams, Joanne Hothersall, Eliza Płoskoń, Pakorn Wattana-amorn, Elton R Stephens, Erika Yamada, Rachel Gurney, Yuiko Takebayashi, Joleen Masschelein, Russell J Cox, Rob Lavigne, Christine L Willis, Thomas J Simpson, John Crosby, Peter J Winn, Christopher M ThomasMatthew P Crump

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39 Citations (Scopus)

Abstract

Type I polyketide synthases often use programmed β-branching, via enzymes of a 'hydroxymethylglutaryl-CoA synthase (HCS) cassette', to incorporate various side chains at the second carbon from the terminal carboxylic acid of growing polyketide backbones. We identified a strong sequence motif in acyl carrier proteins (ACPs) where β-branching is known to occur. Substituting ACPs confirmed a correlation of ACP type with β-branching specificity. Although these ACPs often occur in tandem, NMR analysis of tandem β-branching ACPs indicated no ACP-ACP synergistic effects and revealed that the conserved sequence motif forms an internal core rather than an exposed patch. Modeling and mutagenesis identified ACP helix III as a probable anchor point of the ACP–HCS complex whose position is determined by the core. Mutating the core affects ACP functionality, whereas ACP-HCS interface substitutions modulate system specificity. Our method for predicting β-carbon branching expands the potential for engineering new polyketides and lays a basis for determining specificity rules.
Original languageEnglish
Pages (from-to)685-692
Number of pages8
JournalNature Chemical Biology
Volume9
Issue number11
Early online date22 Sep 2013
DOIs
Publication statusPublished - Nov 2013

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  • Structure, function and dynamics in acyl carrier proteins

    Farmer, R., Thomas, C. & Winn, P., 10 Jul 2019, In: PLoS ONE. 14, 7, 17 p., e0219435.

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