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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

1
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
2
School of Chemistry, Cantock's Close, Clifton, Bristol, BS8 1TS, UK.
3
Division of Gene Technology, KU Leuven, Kasteelpark Arenberg 21 - box 2462, 3001 Heverlee, Belgium.
#
Contributed equally

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.

PMID:
24056399
PMCID:
PMC4658705
DOI:
10.1038/nchembio.1342
[Indexed for MEDLINE]
Free PMC Article

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