Dissecting and exploiting intermodular communication in polyketide synthases

Modular polyketide synthases catalyze the biosynthesis of medicinally impor tant natural products through an assembly-line mechanism. Although these me gasynthases display very precise overall selectivity, we show that their co nstituent modules are remarkably tolerant toward diverse incoming acyl chai ns. By appropriate engineering of linkers, which exist within and between p olypeptides, it is possible to exploit this tolerance to facilitate the tra nsfer of biosynthetic intermediates between unnaturally linked modules. Thi s protein engineering strategy also provides insights into the evolution of modular polyketide synthases.