Recent advances in genetic engineering have enabled production of a small suite of advanced compounds at a commercial scale. However, the speed of the traditional design-build-test-learn cycle within genetic engineering can also be a barrier to producing a wider range of compounds. Thermodynamic constraints such as pH, metabolite concentration, and temperature can impact the success of genetic engineering in a given host for high volume chemical production. Integrating isotopic labelling and thermodynamic constraints into microbial metabolic models enables researchers to quantify the metabolic fluxes of various reactions in a wide range of organisms, allowing for a better understanding of metabolic networks, and aid in rational strain design at high-throughput. Via metabolomics, we demonstrate that genetic engineering of the thermophilic, anaerobic bacteria Clostridium thermocellum for increased ethanol titers is also met with an increase in the thermodynamic driving force in key reactions. We also identify metabolic bottlenecks in response to acute ethanol accumulation in both wild-type and genetically engineered strains of C. thermocellum for further strain optimization.

Investigating the barriers to high ethanol titers in Clostriudium thermocellum

2019 Spring National Meeting

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