In the biosynthesis of complex polyketides, acyltransferase domains (ATs) are key determinants of structural diversity. Their specificity and position in polyketide synthases (PKSs) usually controls the location and structure of building blocks in polyketides. Many bioactive polyketides, however, are generated by trans-AT PKSs lacking internal AT domains. They were previously believed to use mainly malonyl-specific free-standing ATs. Here, we report a mechanism of structural diversification, in which the trans-AT KirCII regiospecifically incorporates the unusual extender unit ethylmalonyl-CoA in kirromycin polyketide biosynthesis.
- Acyl Carrier Protein/*metabolism Acyl Coenzyme A/*chemistry/*metabolism Acyltransferases/*chemistry/genetics/*metabolism Anti-Bacterial Agents/biosynthesis Polyketide Synthases/chemistry/*metabolism Protein Structure, Tertiary Pyridones/metabolism Stereoisomerism Streptomyces/genetics/metabolism Substrate Specificity