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

ABSTRACT: Type I polyketide synthases often use programmed ?-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 ?-branching is known to occur. Substituting ACPs confirmed a correlation of ACP type with ?-branching specificity. Although these ACPs often occur in tandem, NMR analysis of tandem ?-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 ?-carbon branching expands the potential for engineering new polyketides and lays a basis for determining specificity rules.

SUBMITTER: Haines AS 

PROVIDER: S-EPMC4658705 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature