Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System.

ABSTRACT: Modular type I polyketide synthases (PKSs) comprise a family of enzymes that synthesize a diverse class of natural products with medicinal applications. The biochemical features of these systems include the extension and processing of polyketide chains in a stepwise, stereospecific manner, organized by a series of modules divided into distinct catalytic domains. Previous work revealed that a primary hurdle for utilizing PKS modules to create diverse macrolactones hinges on the selectivity of the thioesterase (TE) domain. Herein, we generated novel hybrid 12-membered macrolactone/lactam ring systems employing unnatural amide-containing hexaketide intermediates in conjunction with an engineered TE S148C mutant from the pikromycin (Pik) biosynthetic pathway. Specifically, unnatural macrocycle

SUBMITTER: Adrover-Castellano ML 

PROVIDER: S-EPMC12083843 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature