Biosynthesis of Epothilone Intermediates with Alternate Starter Units: Engineering Polyketide–Nonribosomal Interfaces

The early steps of epothilone biosynthesis were reprogrammed in vitro by incorporating enzyme subunits (e.g. EntB, EntE) from other biosynthetic pathways into the epothilone (Epo) assembly line (see scheme). Recognition sequences identified at the C termini of the epothilone biosynthetic proteins enabled heterologous enzyme transfer when fused to noncognate proteins, as a step toward the reengineering of biosythetic pathways to produce natural product analogues in vivo.