A Close Look at a Ketosynthase from a Trans-Acyltransferase Modular Polyketide Synthase

• Structure of a natural polyketide bound to a polyketide synthase enzyme
• Interactions between bound polyketide and gatekeeping residues observed
• Highest resolution structure of a modular polyketide synthase ketosynthase
• Ketosynthase substrate specificity investigated with mass spectrometry

SummaryThe recently discovered trans-acyltransferase modular polyketide synthases catalyze the biosynthesis of a wide range of bioactive natural products in bacteria. Here we report the structure of the second ketosynthase from the bacillaene trans-acyltransferase polyketide synthase. This 1.95 Å resolution structure provides the highest resolution view available of a modular polyketide synthase ketosynthase and reveals a flanking subdomain that is homologous to an ordered linker in cis-acyltransferase modular polyketide synthases. The structure of the cysteine-to-serine mutant of the ketosynthase acylated by its natural substrate provides high-resolution details of how a native polyketide intermediate is bound and helps explain the basis of ketosynthase substrate specificity. The substrate range of the ketosynthase was further investigated by mass spectrometry.

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