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Publication - Professor Matthew Crump

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

    Citation

    Haines, AS, Dong, X, Song, Z, Farmer, R, Williams, C, Hothersall, J, Ploskon, E, Wattana-amorn, P, Stephens, ER, Yamada, E, Gurney, R, Takebayashi, Y, Masschelein, J, Cox, RJ, Lavigne, R, Willis, CL, Simpson, TJ, Crosby, J, Winn, PJ, Thomas, CM & Crump, MP, 2013, ‘A conserved motif flags acyl carrier proteins for β-branching in polyketide synthesis’. Nature Chemical Biology, vol 9., pp. 685-692

    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.

    Full details in the University publications repository