Genome-scale metabolic model in guiding metabolic engineering of microbial improvement

Xu, Chuan; Liu, Huan; Zhang, Zhao; Jin, Di; Qiu, Juanping; Chen, Ming

doi:10.1007/s00253-012-4543-9

Cited by 54 publications

(34 citation statements)

References 201 publications

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“…To address this problem, metabolic modeling can be applied for both computational simulation of metabolic flux networks and experimental flux analyses. These analyses are then employed to predict targets for metabolic engineering to enhance productivity (Xu et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Model based engineering of Pichia pastoris central metabolism enhances recombinant protein production

Nocon

Steiger

Pfeffer

et al. 2014

Metabolic Engineering

131

104

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The production of recombinant proteins is frequently enhanced at the levels of transcription, codon usage, protein folding and secretion. Overproduction of heterologous proteins, however, also directly affects the primary metabolism of the producing cells. By incorporation of the production of a heterologous protein into a genome scale metabolic model of the yeast Pichia pastoris, the effects of overproduction were simulated and gene targets for deletion or overexpression for enhanced productivity were predicted. Overexpression targets were localized in the pentose phosphate pathway and the TCA cycle, while knockout targets were found in several branch points of glycolysis. Five out of 9 tested targets led to an enhanced production of cytosolic human superoxide dismutase (hSOD). Expression of bacterial β-glucuronidase could be enhanced as well by most of the same genetic modifications. Beneficial mutations were mainly related to reduction of the NADP/H pool and the deletion of fermentative pathways. Overexpression of the hSOD gene itself had a strong impact on intracellular fluxes, most of which changed in the same direction as predicted by the model. In vivo fluxes changed in the same direction as predicted to improve hSOD production. Genome scale metabolic modeling is shown to predict overexpression and deletion mutants which enhance recombinant protein production with high accuracy.

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Section: Introductionmentioning

confidence: 99%

Model based engineering of Pichia pastoris central metabolism enhances recombinant protein production

Nocon

Steiger

Pfeffer

et al. 2014

Metabolic Engineering

131

104

View full text Add to dashboard Cite

show abstract

“…Overexpressions of ZWF1, SOL3, MDH1, and GDH3 were positive for improved recombinant protein production, which demonstrated the high accuracy of prediction by GEM for heterologous enzyme production. Based on the successful application of GEMs in the metabolic engineering of model microorganism such as like E. coli and Saccharomyces cerevisiae (McCloskey et al 2013;Xu et al 2012Xu et al , 2013a, the GEMs of industrially important strains such as Candida glabrata, Ketogulonicigenium vulgare WSH-001, and Bacillus megaterium WSH002 have also been reconstructed (Xu et al 2013b;Zou et al 2012Zou et al , 2013. In silico metabolic engineering has further enhanced their cellular properties for industrial production.…”

Section: Gem-guided Metabolic Engineeringmentioning

confidence: 99%

Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects

Liu

Shin

et al. 2014

Appl Microbiol Biotechnol

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Metabolic engineering facilitates the rational development of recombinant bacterial strains for metabolite overproduction. Building on enormous advances in system biology and synthetic biology, novel strategies have been established for multivariate optimization of metabolic networks in ensemble, spatial, and dynamic manners such as modular pathway engineering, compartmentalization metabolic engineering, and metabolic engineering guided by genome-scale metabolic models, in vitro reconstitution, and systems and synthetic biology. Herein, we summarize recent advances in novel metabolic engineering strategies. Combined with advancing kinetic models and synthetic biology tools, more efficient new strategies for improving cellular properties can be established and applied for industrially important biochemical production.

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“…42 Based on this, GSMMs can be used in guiding metabolic engineering of microorganisms for secondary metabolite improvement. 43 Hemophilus influenza was the first organism for which a GSMM was created and published in 1999. 44 Since then, GSMM have been reconstructed for several bacterial species with improved efficiency and quality.…”

Section: Genome-scale Metabolic Models (Gsmm)mentioning

confidence: 99%

Tools for metabolic engineering inStreptomyces

et al. 2014

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During the last few decades, Streptomycetes have shown to be a very important and adaptable group of bacteria for the production of various beneficial secondary metabolites. These secondary metabolites have been of great interest in academia and the pharmaceutical industries. To date, a vast variety of techniques and tools for metabolic engineering of relevant structural biosynthetic gene clusters have been developed. The main aim of this review is to summarize and discuss the published literature on tools for metabolic engineering of Streptomyces over the last decade. These strategies involve precursor engineering, structural and regulatory gene engineering, and the up or downregulation of genes, as well as genome shuffling and the use of genome scale metabolic models, which can reconstruct bacterial metabolic pathways to predict phenotypic changes and hence rationalize engineering strategies. These tools are continuously being developed to simplify the engineering strategies for this vital group of bacteria.

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Genome-scale metabolic model in guiding metabolic engineering of microbial improvement

Cited by 54 publications

References 201 publications

Model based engineering of Pichia pastoris central metabolism enhances recombinant protein production

Model based engineering of Pichia pastoris central metabolism enhances recombinant protein production

Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects

Tools for metabolic engineering inStreptomyces

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