Presentation Information
[3ASBA-14]Design of carbon engines: Substrate-informed microbial cell factories for complex renewable feedstocks
○Christoph Wittmann1 (1. Saarland University (Germany))
Keywords:
Metabolic engineering,Microbial cell factories,Lignocellulosic biomass,Lignin valorization,Bioeconomy
The transition toward a sustainable bioeconomy requires microbial cell factories capable of efficiently converting heterogeneous renewable carbon streams. However, most established production strains remain optimized for single substrates, such as glucose, and fail to perform robustly on complex feedstocks derived from lignocellulose and industrial side streams.
Here, we present a systems-level engineering framework for the design of microbial “carbon engines” that enables coordinated utilization of diverse substrates in the industrial workhorse Corynebacterium glutamicum. Starting from balanced glucose–xylose co-utilization, we established a substrate-informed metabolic engineering strategy that aligns substrate uptake, pathway capacity, and regulatory control with central metabolism. In contrast to conventional approaches that optimize pathways in isolation, this concept explicitly considers the composition and dynamics of the available substrate spectrum as a guiding principle for system design.
As a result, coordinated flux distribution across mixed substrates is achieved, reducing diauxic behavior and improving overall process performance. This design principle was extended to a genome-encoded multi-sugar chassis enabling simultaneous utilization of up to seven sugars, resulting in near-complete carbon conversion and increased volumetric performance under industrially relevant conditions, including lignocellulosic feedstocks such as spent sulfite liquor. Isotopic and systems-level analyses further revealed tight coupling between substrate-specific pathways and central metabolism, enabling efficient redistribution of carbon across key biosynthetic routes.
In parallel, regulatory and pathway engineering enabled efficient conversion of lignin-derived aromatic substrates, including hydroxycinnamates and depolymerized lignin streams, demonstrating the integration of distinct carbon classes within a unified production framework.
Together, this work establishes a generalizable platform for designing next-generation microbial cell factories, enabling the sustainable production of chemicals, materials, and functional biomolecules from renewable carbon spanning both complex sugar mixtures and lignin-derived aromatic streams, including efficient access to key C5 and C6 platform chemicals.
Here, we present a systems-level engineering framework for the design of microbial “carbon engines” that enables coordinated utilization of diverse substrates in the industrial workhorse Corynebacterium glutamicum. Starting from balanced glucose–xylose co-utilization, we established a substrate-informed metabolic engineering strategy that aligns substrate uptake, pathway capacity, and regulatory control with central metabolism. In contrast to conventional approaches that optimize pathways in isolation, this concept explicitly considers the composition and dynamics of the available substrate spectrum as a guiding principle for system design.
As a result, coordinated flux distribution across mixed substrates is achieved, reducing diauxic behavior and improving overall process performance. This design principle was extended to a genome-encoded multi-sugar chassis enabling simultaneous utilization of up to seven sugars, resulting in near-complete carbon conversion and increased volumetric performance under industrially relevant conditions, including lignocellulosic feedstocks such as spent sulfite liquor. Isotopic and systems-level analyses further revealed tight coupling between substrate-specific pathways and central metabolism, enabling efficient redistribution of carbon across key biosynthetic routes.
In parallel, regulatory and pathway engineering enabled efficient conversion of lignin-derived aromatic substrates, including hydroxycinnamates and depolymerized lignin streams, demonstrating the integration of distinct carbon classes within a unified production framework.
Together, this work establishes a generalizable platform for designing next-generation microbial cell factories, enabling the sustainable production of chemicals, materials, and functional biomolecules from renewable carbon spanning both complex sugar mixtures and lignin-derived aromatic streams, including efficient access to key C5 and C6 platform chemicals.
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