(211e) Metabolic Engineering of Complex Plant Processes in Bacteria

Parayil, A., Massachusetts Institute of Technology

Specialized (secondary) metabolites are products of complex biochemistries found in nature and include a vast number of chemical candidates (>200,000) with a myriad of applications in drugs, food additives, consumer products and industrial chemicals.  However, sourcing of these valuable materials remains a significant barrier to more widespread utilization.  The low accumulation of these molecules in nature (ppm levels) translates to inefficient plant extraction processes which remain economically unviable and present an undue burden on our land resources.  In addition, the structural complexity of these natural products, which are typically heavily functionalized molecules with multiple chiral centers, precludes the development of economical chemical synthesis routes to these molecules. Therefore, developing tools and technologies for the rapid and efficient construction of microbial strains capable of producing specialized natural products is a high priority research area for the metabolic engineering community.

We have developed a new metabolic engineering approach, multivariate modular metabolic engineering (MMME), for systematically engineering such complex multi-step biosynthetic pathways. Recently, we also expanded the scope of our approach to merge quick construction and optimization tools with a thorough characterization of strains (using transcriptomics, proteomics and metabolomics) to expedite strain development. These enabled not only the rapid construction of microbial strains for synthesizing complex biochemicals in useful accessible quantities, but also provided several key insights on natural product biosynthesis and the origins of biosynthetic diversity of these specialized products. Here, I focus on the MMME for optimizing the multi-step pathways with complex chemistries, including multi-step P450 chemistry engineered in bacterial cells for scalable synthesis of complex molecules.