Analysis of siderochelin biosynthesis reveals that a type II polyketide synthase catalyses diketide formation

Polyketide synthases (PKSs) programme the assembly of polyketides that possess a wide range of pharmacological properties. In addition to assembly logic, carboxylic-acid-derived substrates underpin the structures and associated biological activities of these biosynthetically related natural products. Known type II PKSs exclusively use a malonyl extender unit for decarboxylative condensation and elongation, restricting the structural diversity. Based on investigations into the biosynthesis of siderochelins, a group of ferrous ion chelators, here we report a distinct five-component type II PKS that catalyses diketide formation and uses a methylmalonyl extender unit for condensation with the 3-hydroxypicolinyl starter unit during the formation of the pyrroline ring. Genome mining, gene inactivation, isotopic labelling and detailed biochemical characterization rationalize the capability of this type II PKS to use non-malonyl carboxylic substrates for starting and extending polyketide synthesis. The utility of this type II PKS is further recognized by its high compatibility with carboxylic acid substrate variation and by its ability to evolve to tolerate unnatural and/or unacceptable extenders.