Dual-dynamic control and metabolic rebalancing guided by toxic target discovery for efficient dencichine production

Yu Zhang; Jun Wu; Jinghua Yu; Yong Tang; Chong Xie; Xiaolin Shen; Jia Wang; Yajun Yan; Xinxiao Sun; Qipeng Yuan

doi:10.59717/j.xinn-life.2026.100242

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Dual-dynamic control and metabolic rebalancing guided by toxic target discovery for efficient dencichine production

1.
State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
2.
School of Chemical, Materials and Biomedical Engineering, College of Engineering, The University of Georgia, Athens GA 30602, USA

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Corresponding authors: sunxx@mail.buct.edu.cn (S.X.); yuanqp@mail.buct.edu.cn (Y.Q.)
Received Date: March 06, 2026

Accepted Date: August 17, 2026

Published Online: August 18, 2026

The Innovation Life https://doi.org/10.59717/j.xinn-life.2026.100242 | Cite this article

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1. Elucidating the toxicity mechanism caused by overexpressing serA encoding 3-phosphoglycerate dehydrogenase.
  
  Engineering a dual-dynamic genetic circuit to improve cell growth and dencichine (β-ODAP) production.
  
  This systematic engineering strategy enables the highest reported biosynthesis titer of β-ODAP.

ABSTRACT

ABSTRACT

Construction of microbial cell factories often requires extensive reconfiguration of metabolic networks, which frequently compromises cell growth. Here, we engineered E. coli to produce dencichine (β-ODAP), a plant-derived hemostatic agent. Knocking out serB blocks the competing L-serine pathway, causing L-serine auxotrophy and severely impairing cell growth. This growth defect was only partially restored by supplementation with L-serine or L-glycine, suggesting the presence of additional growth-limiting factors. Through adaptive laboratory evolution and reverse engineering, we further uncovered that overexpression of serA to enhance the supply of the precursor L-2,3-diaminopropionate led to accumulation of the toxic byproduct 2-hydroxyglutarate (2-HG) from α-ketoglutarate. To resolve these two growth constraints, we developed a growth-phase-dependent dual-dynamic regulation circuit. This circuit gradually activates serA expression and progressively represses serB expression as cells enter the stationary phase, thereby reducing 2-HG accumulation and alleviating L-serine auxotrophy. Combined with pathway balancing and cofactor optimization, the final engineered strain produced 13.46 g L^-1 of β-ODAP with a yield of 0.32 g g^-1 in 3-L bioreactors. This study reveals a toxicity mechanism in serine-pathway engineering and provides a dynamic regulation strategy applicable to the biosynthesis of serine-pathway-derived metabolites.
- Metabolic engineering /
- Dencichine /
- Metabolic toxicity /
- Dynamic regulation /
- Adaptive laboratory evolution

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Zhang Y., Wu J., Yu J., et al. (2026). Dual-dynamic control and metabolic rebalancing guided by toxic target discovery for efficient dencichine production. The Innovation Life 4:100242. https://doi.org/10.59717/j.xinn-life.2026.100242

Zhang Y., Wu J., Yu J., et al. (2026). Dual-dynamic control and metabolic rebalancing guided by toxic target discovery for efficient dencichine production. The Innovation Life 4:100242. https://doi.org/10.59717/j.xinn-life.2026.100242

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Dual-dynamic control and metabolic rebalancing guided by toxic target discovery for efficient dencichine production

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