Cyanobacterial polyketide synthase docking domains: A tool for engineering natural product biosynthesis

TitleCyanobacterial polyketide synthase docking domains: A tool for engineering natural product biosynthesis
Publication TypeJournal Article
Year of Publication2013
AuthorsWhicher J.R, Smaga S.S, Hansen D.A, Brown W.C, Gerwick WH, Sherman D.H, Smith J.L
JournalChemistry & Biology
Date Published2013/11
Type of ArticleArticle
ISBN Number1074-5521
Accession NumberWOS:000328434700007
Keywordscombinatorial biosynthesis; communication; crystal-structure; gene-cluster; high-throughput; intermodular; linker; modules; pikromycin; protein-protein interactions; structural basis

Modular type I polyketide synthases (PKSs) are versatile biosynthetic systems that initiate, successively elongate, and modify acyl chains. Intermediate transfer between modules is mediated via docking domains, which are attractive targets for PKS pathway engineering to produce natural product analogs. We identified a class 2 docking domain in cyanobacterial PKSs and determined crystal structures for two docking domain pairs, revealing a distinct class 2 docking strategy for promoting intermediate transfer. The selectivity of class 2 docking interactions, demonstrated in binding and biochemical assays, could be altered by mutagenesis. We determined the ideal fusion location for exchanging class 1 and class 2 docking domains and demonstrated effective polyketide chain transfer in heterologous modules. Thus, class 2 docking domains are tools for rational bioengineering of a broad range of PKSs containing either class 1 or 2 docking domains.

Short TitleChem. Biol.
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