Redirecting the Cyclization Steps of Fungal Polyketide Synthase

摘要

Regiospecific cyclizations of the nascent poly-β-ketone backbones dictate the structures of polyketide natural products. Systematic reprogramming of the cyclization steps is therefore an important goal toward combinatorial biosynthesis of polyketides. Bacterial and fungal aromatic polyketide synthases (PKSs) employ different strategies to control the regiospecificities of cyclization reactions. Whereas the bacterial PKSs use dissociated enzymes to tailor the reactive poly-β-keto backbone synthesized by the minimal PKS, the fungal iterative megasynthases use terminal thioesterase/ claisen cyclase (TE/CLC) domains to direct the fate of the polyketide chains. In this work, we present two strategies toward redirecting the cyclization steps of fungal PKSs. Most notably, we demonstrate that fungal and bacterial PKS components can be catalytically integrated in trans.