2l22

Publication Abstract from PubMed

Type I polyketide synthases often use programmed beta-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 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.

A conserved motif flags acyl carrier proteins for beta-branching in polyketide synthesis.,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 Nat Chem Biol. 2013 Sep 22. doi: 10.1038/nchembio.1342. PMID:24056399^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.