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Nat Chem Biol. 2013 Nov;9(11):685-692. doi: 10.1038/nchembio.1342. Epub 2013 Sep 22.

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

Author information

School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
School of Chemistry, Cantock's Close, Clifton, Bristol, BS8 1TS, UK.
Division of Gene Technology, KU Leuven, Kasteelpark Arenberg 21 - box 2462, 3001 Heverlee, Belgium.
Contributed equally


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.

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