Enhancing Spatiotemporal Productivity of l-Tyrosine via Metabolic Flux Balancing and Population Engineering

As an essential precursor for numerous high-value chemicals, l-tyrosine is in high demand across the food, medical, and chemical sectors. While microbial cell factories offer a green and sustainable route for its production, their efficiency is often constrained by the inherent complexity of metabolic pathways and the carbon flux competition between cell growth and product synthesis. Building upon a previously established l-tryptophan-producing chassis, we fine-tuned the metabolic flux upstream and downstream of the shikimate node and implemented a cofactor recycling-driven strategy, thereby increasing the l-tyrosine titer from 2.5 to 8.6 g/L in shake-flask fermentation (a 3.4-fold improvement). To address the growth-production trade-off, a quorum-sensing-based dynamic control strategy was employed to regulate the expression of the TCA cycle gene sucA. Further integration of screening and reinforcement of glutamate dehydrogenase enabled the effective spatiotemporal decoupling of cell growth from l-tyrosine biosynthesis. Consequently, the engineered strain achieved an l-tyrosine titer of 81.3 g/L in a 5 L bioreactor, with a record-breaking cell-specific productivity of 0.048 g/g of DCW/h, representing a significant enhancement in the spatiotemporal productivity of microbial l-tyrosine biosynthesis. This study provides a robust strategy for the efficient and sustainable biomanufacturing of aromatic amino acids and their derivatives.