Invited speaker: New polyketide engineering technologies

HUGO MENZELLA

Munich, Germany

Conferencia; Natural Products in Drug Discovery & Development Conference; 2007

Type I polyketide synthases (PKSs) that make complex natural products consist of modules that add and process 2-carbon units in polyketide backbones. Rearranging intact modules from different sources can give novel enzymes to produce unnatural products, but the rules that govern module-module communication are still not well known. The construction and assay of functional hybrid bimodular units using synthetic PKS genes was recently reported. Here we describe the rational design of trimodular PKSs by combining bimodular units. A cloning-expression system was developed to assemble and test 54 unnatural trimodular PKSs flanked by the loading module and the thioesterase from the erythromycin polyketide synthase. Remarkably, 96% of them produced the expected polyketide in an engineered E. coli strain. The obtained results represent an important milestone towards the ultimate goal of making new bioactive polyketides by rational design. Additionally, these results show a path for the production of customized tetraketides by fermentation, which can be an important source of advanced intermediates to facilitate the synthesis of complex products.