Hybrid Type I and II\nPolyketide Synthases Yield Distinct\nAromatic Polyketides

Bacterial aromatic polyketides are compounds with multiple\naromatic\nrings synthesized by bacterial type II polyketide synthases (PKSs),\nsome of which have been developed into clinical drugs. Compounds containing\naromatic polyketides synthesized by hybrid type I and type II PKSs\nare extremely rare. Here, we report the discovery of a gene cluster\nencoding both modular type I and type II PKSs as well as KAS III through\nextensive bioinformatics analysis, leading to the characterization\nof the hybrid polyketide, spirocycline A. The structure of spirocycline\nA is rare among all aromatic polyketides, featuring a unique starter\nunit and four spirocycles and forming a dimer. Biosynthetic studies\nindicate that the starter unit of this molecule is synthesized by\ntype I PKS in collaboration with two <i>trans</i>-acting\nketoreductase (KR) and enoylreductase (ER). It is then transferred\nby KAS III to the type II PKS system, which synthesizes the tricyclic\naromatic polyketide backbone. The subsequent formation of the spirocycle\nand dimerization are carried out by four redox enzymes encoded in\nthe gene cluster. Overall, the discovery of spirocycline A provides\na new approach for identifying novel aromatic polyketides and offers\npotential enzymatic tools for the bioengineering of these hybrid polyketides.