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

作者：Haines Anthony S^*; Dong Xu; Song Zhongshu; Farmer Rohit; Williams Christopher; Hothersall Joanne; Ploskon Eliza; Wattana amorn Pakorn; Stephens Elton R; Yamada Erika; Gurney Rachel; Takebayashi Yuiko; Masschelein Joleen; Cox Russell J; Lavigne Rob; Willis Christine L; Simpson Thomas J; Cro**y John; Winn Peter J; Thomas Christopher M; Crump Matthew P

来源：Nature Chemical Biology, 2013, 9(11): 685-+.

DOI：10.1038/NCHEMBIO.1342

Type I polyketide synthases often use programmed beta-branching, via enzymes of a %26apos;hydroxymethylglutaryl-CoA synthase (HCS) cassette%26apos;, 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 beta-branching is known to occur. Substituting ACPs confirmed a correlation of ACP type with beta-branching specificity. Although these ACPs often occur in tandem, NMR analysis of tandem beta-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 beta-carbon branching expands the potential for engineering new polyketides and lays a basis for determining specificity rules.

• 出版日期2013-11