Dynamic Control of Metabolism for Renewable Production of Valuable Chemicals and Novel Biomaterials

Abstract

Increasing concerns over the environmental impact and long-term sustainability of human economic activity has motivated a search for less resource-intensive methods for the manufacture of chemicals and generation of energy. Bio-based approaches are an alternative to traditional petroleum-based methods with the potential for significantly reducing the environmental impact of these industries. However, there are major challenges to making bio-based manufacture of chemicals cost-competitive with petroleum-based approaches. Optimization of rate, titer, and yield, and predictably transferring results from lab to industrial scales remain iterative processes that are expensive and slow. Development of microbial strains that produce generalizable “platform” metabolites can help address these challenges by allowing for high production of a metabolite that can be converted to multiple chemicals of industrial importance with subsequent minor genetic modifications to the strain. This work describes development of microbes for high production of the platform metabolite malonyl-CoA. It provides a biosynthetic route to industrially important chemicals including fatty acids, waxes, solvents, nutrients and pharmaceticals. Its potential has been recognized for some time, but being the major precursor for growth-essential fatty acid synthase made deleting competition for the substrate challenging. A recently developed strategy called MOMENTuM (Microbial Optimization via Metabolic Network Minimization) helps address these issues and revisit the platform potential of this metabolite. In it, growth-decoupling of the product pathway is achieved by inducing product biosynthesis in stationary cells with nutrient limitation. Synthetic Metabolic Valves add or remove reactions from the network, leading to a customizable reorganization of metabolic flux. Using this approach, strains for improved malonyl-CoA product generation were identified for compounds of two different chemical classes and downstream uses. This provides supports the platform concept and the generalizability of the SMV-based improvements across products and pathways.