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Elucidating central metabolic redox obstacles hindering ethanol production in Clostridium thermocellum.

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Title: Elucidating central metabolic redox obstacles hindering ethanol production in Clostridium thermocellum.
Authors: Thompson, R. Adam1,2, Layton, Donovan S.2,3, Guss, Adam M.1,2,4, Olson, Daniel G.2,5, Lynd, Lee R.2,5, Trinh, Cong T.1,2,3 ctrinh@utk.edu
Source: Metabolic Engineering. Nov2015, Vol. 32, p207-219. 13p.
Subjects: Oxidation-reduction reaction, Ethanol, Clostridium thermocellum, Lignocellulose, Metabolic flux analysis
Abstract: Clostridium thermocellum is an anaerobic, Gram-positive, thermophilic bacterium that has generated great interest due to its ability to ferment lignocellulosic biomass to ethanol. However, ethanol production is low due to the complex and poorly understood branched metabolism of C. thermocellum , and in some cases overflow metabolism as well. In this work, we developed a predictive stoichiometric metabolic model for C. thermocellum which incorporates the current state of understanding, with particular attention to cofactor specificity in the atypical glycolytic enzymes and the complex energy, redox, and fermentative pathways with the goal of aiding metabolic engineering efforts. We validated the model’s capability to encompass experimentally observed phenotypes for the parent strain and derived mutants designed for significant perturbation of redox and energy pathways. Metabolic flux distributions revealed significant alterations in key metabolic branch points (e.g., phosphoenol pyruvate, pyruvate, acetyl-CoA, and cofactor nodes) in engineered strains for channeling electron and carbon fluxes for enhanced ethanol synthesis, with the best performing strain doubling ethanol yield and titer compared to the parent strain. In silico predictions of a redox-imbalanced genotype incapable of growth were confirmed in vivo , and a mutant strain was used as a platform to probe redox bottlenecks in the central metabolism that hinder efficient ethanol production. The results highlight the robustness of the redox metabolism of C. thermocellum and the necessity of streamlined electron flux from reduced ferredoxin to NAD(P)H for high ethanol production. The model was further used to design a metabolic engineering strategy to phenotypically constrain C. thermocellum to achieve high ethanol yields while requiring minimal genetic manipulations. The model can be applied to design C. thermocellum as a platform microbe for consolidated bioprocessing to produce ethanol and other reduced metabolites. [ABSTRACT FROM AUTHOR]
Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Elucidating central metabolic redox obstacles hindering ethanol production in Clostridium thermocellum.
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  Data: <searchLink fieldCode="JN" term="%22Metabolic+Engineering%22">Metabolic Engineering</searchLink>. Nov2015, Vol. 32, p207-219. 13p.
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  Data: <searchLink fieldCode="DE" term="%22Oxidation-reduction+reaction%22">Oxidation-reduction reaction</searchLink><br /><searchLink fieldCode="DE" term="%22Ethanol%22">Ethanol</searchLink><br /><searchLink fieldCode="DE" term="%22Clostridium+thermocellum%22">Clostridium thermocellum</searchLink><br /><searchLink fieldCode="DE" term="%22Lignocellulose%22">Lignocellulose</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolic+flux+analysis%22">Metabolic flux analysis</searchLink>
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  Data: Clostridium thermocellum is an anaerobic, Gram-positive, thermophilic bacterium that has generated great interest due to its ability to ferment lignocellulosic biomass to ethanol. However, ethanol production is low due to the complex and poorly understood branched metabolism of C. thermocellum , and in some cases overflow metabolism as well. In this work, we developed a predictive stoichiometric metabolic model for C. thermocellum which incorporates the current state of understanding, with particular attention to cofactor specificity in the atypical glycolytic enzymes and the complex energy, redox, and fermentative pathways with the goal of aiding metabolic engineering efforts. We validated the model’s capability to encompass experimentally observed phenotypes for the parent strain and derived mutants designed for significant perturbation of redox and energy pathways. Metabolic flux distributions revealed significant alterations in key metabolic branch points (e.g., phosphoenol pyruvate, pyruvate, acetyl-CoA, and cofactor nodes) in engineered strains for channeling electron and carbon fluxes for enhanced ethanol synthesis, with the best performing strain doubling ethanol yield and titer compared to the parent strain. In silico predictions of a redox-imbalanced genotype incapable of growth were confirmed in vivo , and a mutant strain was used as a platform to probe redox bottlenecks in the central metabolism that hinder efficient ethanol production. The results highlight the robustness of the redox metabolism of C. thermocellum and the necessity of streamlined electron flux from reduced ferredoxin to NAD(P)H for high ethanol production. The model was further used to design a metabolic engineering strategy to phenotypically constrain C. thermocellum to achieve high ethanol yields while requiring minimal genetic manipulations. The model can be applied to design C. thermocellum as a platform microbe for consolidated bioprocessing to produce ethanol and other reduced metabolites. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1016/j.ymben.2015.10.004
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        Text: English
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        PageCount: 13
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        Type: general
      – SubjectFull: Ethanol
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      – SubjectFull: Clostridium thermocellum
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      – SubjectFull: Lignocellulose
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      – SubjectFull: Metabolic flux analysis
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      – TitleFull: Elucidating central metabolic redox obstacles hindering ethanol production in Clostridium thermocellum.
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              Text: Nov2015
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