ArticleMetabolic engineering2020
Coupling metabolic addiction with negative autoregulation to improve strain stability and pathway yield.
Article in Metabolic engineering, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 117 citations in OpenAlex.
- An Antibiotic-Free Cryptic Plasmid Platform for Modular Pathway Coupling in Probiotic Escherichia Coli Nissle 1917.Biotechnology and bioengineering · 2026Article
- Design of the biosensor-dependent coupling system stabilizes the high-synthesis phenotype of cell factory.Nature communications · 2026Article
- Engineering robustSynthetic and systems biotechnology · 2025Article
- High-Throughput Screening of Industrial Brewing Yeast with Lower Synthetic Level of Acetaldehyde During Beer Production.Foods (Basel, Switzerland) · 2025Article
- Unlocking the Synthetic Potential of Yarrowia lipolytica: Innovating Gene Expression Tools.Microbial biotechnology · 2025Review
- Metabolic Engineering ofACS engineering Au · 2025Article
- Harnessing microbial heterogeneity for improved biosynthesis fueled by synthetic biology.Synthetic and systems biotechnology · 2025Review
- Advances and perspectives in genetic expression and operation for the oleaginous yeastSynthetic and systems biotechnology · 2024Review
- A growth-coupling strategy for improving the stability of terpenoid bioproduction in Escherichia coli.Microbial cell factories · 2024Article
- Achieving robust synthetic tolerance in industrialSynthetic and systems biotechnology · 2024Article
- Concentration Recognition-Based Auto-Dynamic Regulation System (CRUISE) Enabling Efficient Production of Higher Alcohols.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Cross-feeding promotes heterogeneity within yeast cell populations.Nature communications · 2024Article
- The expanded CRISPR toolbox for constructing microbial cell factories.Trends in biotechnology · 2024Review
- Progress in the Metabolic Engineering ofBiodesign research · 2024Review
- Application of valencene and prospects for its production in engineered microorganisms.Frontiers in microbiology · 2024Review
- Genomic and metabolic instability during long-term fermentation of an industrialFrontiers in bioengineering and biotechnology · 2024Article
- Dynamic Metabolic Control: From the Perspective of Regulation Logic.Synthetic biology and engineering · 2023Article
- Divergent directed evolution of a TetR-type repressor towards aromatic molecules.Nucleic acids research · 2023Article
- Diverse mechanisms of bioproduction heterogeneity in fermentation and their control strategies.Journal of industrial microbiology & biotechnology · 2023Review
- Stability, robustness, and containment: preparing synthetic biology for real-world deployment.Current opinion in biotechnology · 2023Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metabolic addiction, an organism that is metabolically addicted with a compound to maintain its growth fitness, is an underexplored area in metabolic engineering. Microbes with heavily engineered pathways or genetic circuits tend to experience metabolic burden leading to degenerated or abortive production phenotype during long-term cultivation or scale-up. A promising solution to combat metabolic instability is to tie up the end-product with an intermediary metabolite that is essential to the growth of the producing host. Here we present a simple strategy to improve both metabolic stability and pathway yield by coupling chemical addiction with negative autoregulatory genetic circuits. Naringenin and lipids compete for the same precursor malonyl-CoA with inversed pathway yield in oleaginous yeast. Negative autoregulation of the lipogenic pathways, enabled by CRISPRi and fatty acid-inducible promoters, repartitions malonyl-CoA to favor flavonoid synthesis and increased naringenin production by 74.8%. With flavonoid-sensing transcriptional activator FdeR and yeast hybrid promoters to control leucine synthesis and cell grwoth fitness, this amino acid feedforward metabolic circuit confers a flavonoid addiction phenotype that selectively enrich the naringenin-producing pupulation in the leucine auxotrophic yeast. The engineered yeast persisted 90.9% of naringenin titer up to 324 generations. Cells without flavonoid addiction regained growth fitness but lost 94.5% of the naringenin titer after cell passage beyond 300 generations. Metabolic addiction and negative autoregulation may be generalized as basic tools to eliminate metabolic heterogeneity, improve strain stability and pathway yield in long-term and large-scale bioproduction.
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