Biosynth Pipeline: An integrated platform for merging the computational design of chimeric type I polyketide synthases with enzymatic pathways for chemical biosynthesis

Abstract

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 rely on arduous literature searches. Here, we present an automated retrobiosynthesis tool, Biosynth Pipeline, that simultaneously tackles both problems by integrating multifunctional type I polyketide synthases (PKSs) with monofunctional enzymes to propose the synthesis of desired target chemicals via two new tools: DORAnet and RetroTide. While monofunctional enzymes are valuable for carefully decorating a substrate's carbon backbone, they typically cannot expand the backbone itself. PKSs can, instead, predictably do this through their unique ability to catalyze carbon-carbon bond formation reactions iteratively. We evaluated the performance of Biosynth Pipeline against a previously published set of 155 molecules of interest for biomanufacturing, and report that Biosynth Pipeline could produce exact designs for 93 of them, as well as pipelines to a chemically similar product for most of the remaining molecules. Furthermore, Biosynth Pipeline successfully proposes biosynthetic routes for complex therapeutic natural products (cryptofolione and basidalin) for which no known biosynthetic pathway currently exists.