Uncovering & Engineering Plant Natural Product Biosynthesis in Yeast

Plant natural products are valuable compounds with diverse therapeutic activities whose biosynthesis is poorly understood due to the challenges in functionally identifying and characterizing pathway enzymes. While the recent discovery of plant gene clusters offers the potential to accelerate pathway discovery in plants, current enzyme characterization strategies limit the efficiency and accuracy of subsequent pathway elucidation. We describe an approach for the rapid elucidation of complex plant biosynthetic pathways through the step-wise reconstruction of plant gene clusters in Saccharomyces cerevisiae. We demonstrate this approach for the elucidation of one of the more highly complex gene clusters identified to date. The synthetic biology-based approach offers several advantages over traditional elucidation strategies and allows simultaneous development of scalable synthesis platforms for intermediates and novel derivatives.