Engineering yeast membranes with mimetic and custom architecture for improved performance in biotechnological applications

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Yeast is a workhorse of modern biotechnology, preferred by industry due to its robustness and versatility. A broad range of products from medicines to small molecules, enzymes and vaccines, components of human breast milk, heme for meat substitutes, bioplastics, biomaterials and even biofuels are nowadays produced in yeast. Despite extensive efforts to understand and engineer efficient yeast cell factories, less attention has been placed on studying yeast membrane properties and their contribution to biotechnological applications. Several processes, both physiological or engineered, are greatly related to membranes, and could be limiting the performance of yeast cell factories. Current approaches mainly address the role of biological membranes as the primary target of the toxic effects of compounds produced in heterologous hosts. In reverse, there is little understanding of, or ability to predict, how differences in membrane composition of the host microorganism versus native membranes affect functional capacity of biosynthetic enzymes of different origin and interfere with intracellular transport of metabolites and their export outside of the cell. The long-term goal of the proposed research is to engineer the next generation of production platforms for biotechnological applications taking in consideration the role of biological membranes. In the short-term, we will directly address aspects related to membrane role in functionality of heterologous enzymes and pathways by modifying the yeast membrane composition to mimic that of producer organisms or by engineering non-natural yeast membranes. Thus, we will develop Phyto-yeast by biomimicking plant membrane or tailored yeast by design, and repurpose lipid droplets into storage compartments of target compounds. Using these platforms, we will evaluate the performance of model terpenoid biosynthetic pathways and formation of metabolic complexes. This program will benefit both the research scientific community and Canadian industry. We endeavor to develop advanced yeast chasses that will enable accessing high-value molecules with interesting biological activities and offer sustainable solutions to chemical production. Consequently, these compounds can be more broadly exploited for medicinal, agricultural, and other industrial applications. The knowledge developed here will provide the field with effective approaches to study and engineer biological membranes and the related processes. It will also foster innovations in industry and will address Canadian priorities for commercial R&D and manufacturing activities. Improved production platforms capable of accelerating time to market and increasing economic gain will highly benefit the Canadian economy. Thus, the relevance of this research program for the years ahead span multiple levels, including advancing scientific discoveries, tackling current and future industrial challenges, and building strong underpinning for novel strategies and innovations.