Merging the computational design of chimeric type I polyketide synthases with enzymatic pathways for chemical biosynthesis

Synthetic biology offers the promise of manufacturing chemicals more sustainably than petrochemistry. Yet, both the rate at which biomanufacturing can synthesize these molecules and the net chemical accessible space are limited by existing pathway discovery methods, which can often rely on arduous literature searches. Here, we introduce BioPKS pipeline, an automated retrobiosynthesis tool combining multifunctional type I polyketide synthases (PKSs) and monofunctional enzymes via two complementary tools: RetroTide and DORAnet. Monofunctional enzymes are valuable for carefully decorating a substrate’s carbon backbone while PKSs are unique in their ability to iteratively catalyze carbon-carbon bond formation reactions, thereby expanding carbon backbones in a predictable fashion. We evaluate the performance of BioPKS pipeline using a previously reported set of 155 biomanufacturing candidates, achieving exact synthetic designs for 93 compounds and generating chemically similar pathways for most remaining targets. Furthermore, BioPKS pipeline can propose pathways for the complex therapeutic natural products cryptofolione and basidalin.