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Cited by 252Microbial Metabolic Engineering and BioproductionBacterial Genetics and BiotechnologyFungal and yeast genetics research

Exacerbation of substrate toxicity by IPTG in Escherichia coli BL21(DE3) carrying a synthetic metabolic pathway

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Dvorak, Pavel, Chrast, Lukas, Nikel, Pablo I., Fedr, Radek, Soucek, Karel, Sedlackova, Miroslava, Chaloupkova, Radka, de Lorenzo, Víctor +2 more·2015·Microbial Cell Factories
DOI 10.1186/s12934-015-0393-3PMC PMC4687329
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Abstract

BACKGROUND: Heterologous expression systems based on promoters inducible with isopropyl-β-D-1-thiogalactopyranoside (IPTG), e.g., Escherichia coli BL21(DE3) and cognate LacI(Q)/P(lacUV5)-T7 vectors, are commonly used for production of recombinant proteins and metabolic pathways. The applicability of such cell factories is limited by the complex physiological burden imposed by overexpression of the exogenous genes during a bioprocess. This burden originates from a combination of stresses that may include competition for the expression machinery, side-reactions due to the activity of the recombinant proteins, or the toxicity of their substrates, products and intermediates. However, the physiological impact of IPTG-induced conditional expression on the recombinant host under such harsh conditions is often overlooked. RESULTS: The physiological responses to IPTG of the E. coli BL21(DE3) strain and three different recombinants carrying a synthetic metabolic pathway for biodegradation of the toxic anthropogenic pollutant 1,2,3-trichloropropane (TCP) were investigated using plating, flow cytometry, and electron microscopy. Collected data revealed unexpected negative synergistic effect of inducer of the expression system and toxic substrate resulting in pronounced physiological stress. Replacing IPTG with the natural sugar effector lactose greatly reduced such stress, demonstrating that the effect was due to the original inducer's chemical properties. CONCLUSIONS: IPTG is not an innocuous inducer; instead, it exacerbates the toxicity of haloalkane substrate and causes appreciable damage to the E. coli BL21(DE3) host, which is already bearing a metabolic burden due to its content of plasmids carrying the genes of the synthetic metabolic pathway. The concentration of IPTG can be effectively tuned to mitigate this negative effect. Importantly, we show that induction with lactose, the natural inducer of P lac , dramatically lightens the burden without reducing the efficiency of the synthetic TCP degradation pathway. This suggests that lactose may be a better inducer than IPTG for the expression of heterologous pathways in E. coli BL21(DE3).

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  • In genome-integrated T7 expression systems, IPTG results in a better inductor compared to lactose in terms of cell fitness and Fab fragment productivity, as opposed to known toxic effects of IPTG in plasmid-based T7 expression systems.

    “They have demonstrated that in genome-integrated T7 expression systems, IPTG results in a better inductor compared to lactose in terms of cell fitness and Fab fragment productivity, as opposed to the known toxic effects of IPTG in plasmid-based T7 expression systems [106].”

    From Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments (2020) · cites this paper as [106]

    The Results and discussion section (page unavailable) reports that, in the studied plasmid-bearing E. coli pathway, lactose gave higher cell viability than IPTG; the Conclusions likewise describe IPTG-related burden. This supports the contrast about IPTG's harmful effects, but the paper does not report a genome-integrated T7 system or Fab fragment productivity, so it cannot support the claimed advantage of IPTG over lactose in that setting. (LLM, conf=0.88)

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Authors
Dvorak, P., Chrast, L., Nikel, P. I., Fedr, R., Soucek, K., Sedlackova, M., Chaloupkova, R., de Lorenzo, V., Prokop, Z., & Damborsky, J.
Affiliations
  • Centro Nacional de Biotecnología (ES)
  • Czech Academy of Sciences (CZ)
ORCID
Venue
Microbial Cell Factories
Publisher
Springer Science and Business Media LLC
Published
2015-12
Volume
14
Issue
1
Pages
201-201
ISSN
1475-2859 (ISSN-L)
DOI
10.1186/s12934-015-0393-3
PMC
PMC4687329
OpenAlex
W2200387749
Cited by
252
References
0
Citations by year
2026: 22 · 2025: 25 · 2024: 48 · 2023: 24 · 2022: 20 · 2021: 33 · 2020: 22 · 2019: 17 · 2018: 22 · 2017: 16 · 2016: 3
FWCI
5.94
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Microbial Cell Factories (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ASEP (publishedVersion)
Funders
  • Grant Agency of the Czech Republic (P503/12/0572)
  • European Regional Development Fund (CZ.1.05/1.1.00/02.0123)
  • Ministry of Education of the Czech Republic (LO1214, LM2011028)
  • Europen Union (REGPOT 316345)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
Escherichia coli BL21(DE3), synthetic metabolic pathways, Inducer Effects, lactose induction, physiological stress, heterologous expression
MeSH terms
Escherichia coli, Isopropyl Thiogalactoside, Metabolic Networks and Pathways, Metabolic Engineering

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