Enterobacteriaceae for succinic acid biomanufacturing: metabolic blueprints, systems-level engineering and future...

Succinic acid (SA) is a key C4 platform molecule with wide industrial relevance, including bio-based polymers and solvents. Current reviews largely emphasize traditional producers (e.g., Actinobacillus, Mannheimia, and Basfia) and rarely synthesize progress in Enterobacteriaceae. Here, we close this gap by providing a systems-level review of SA biomanufacturing in Enterobacteriaceae, focusing on non-model genera (Enterobacter, Klebsiella, Citrobacter) that combine fast growth, facultative anaerobiosis, broad feedstock utilization, and high engineering amenability. We outline the metabolic blueprint underpinning SA formation, highlighting the reductive TCA branch, anaplerotic CO₂ fixation (PEPC/PEPCK), the glyoxylate shunt, and redox constraints that govern carbon partitioning. We then summarize recent advances in strain development, including pathway rewiring, stronger carboxylation, adaptive laboratory evolution, and dynamic control, that increase SA titers, yields, and productivities. Finally, we discuss downstream processing and techno-economic bottlenecks, biosafety and regulatory considerations, and emerging directions including division-of-labour consortia and circular-carbon integration for scalable, carbon-efficient SA biorefineries.