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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)685-692
Number of pages8
JournalNature Chemical Biology
Volume9
Issue number11
Early online date22 Sep 2013
DOIs
DateE-pub ahead of print - 22 Sep 2013
DatePublished (current) - Nov 2013

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.

    Research areas

  • PSEUDOMONAS-FLUORESCENS NCIMB-10586, CYANOBACTERIUM LYNGBYA-MAJUSCULA, BIOSYNTHESIS GENE-CLUSTER, NMR-SPECTROSCOPY, NATURAL-PRODUCT, ANTIBIOTIC MUPIROCIN, BACILLUS-SUBTILIS, DIPOLAR COUPLINGS, COELICOLOR A3(2), CURACIN-A

    Structured keywords

  • Bristol BioDesign Institute

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