Systems biology and biotechnology of Streptomyces species for the production of secondary metabolites

Hwang, Kyu-Sang; Kim, Hyun Uk; Charusanti, Pep; Palsson, Bernhard Ø.; Lee, Sang Yup

doi:10.1016/j.biotechadv.2013.10.008

Cited by 184 publications

(146 citation statements)

References 132 publications

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“…Furthermore, the integration of genetic/metabolic engineering with systems biological tools provides invaluable contributions to increase secondary metabolite production (Hwang et al, 2014). Thus, genomewide expression profiling or comparative proteomics analysis can be adopted for a better understanding of CA overproduction in our industrial strain to provide alternative ways of designing novel high-producer strains.…”

Section: Discussionmentioning

confidence: 99%

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Kurt‐Kızıldoğan¹,

Jaccard²,

Mutlu³

et al. 2017

Turk J Biol

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An industrial clavulanic acid (CA) overproducer Streptomyces clavuligerus strain, namely DEPA, was engineered to further enhance its CA production. Single or multiple copies of ccaR, claR (pathway-specific activators), and cas2 (CA synthase) genes under the control of different promoters were introduced into this strain. CA titers of the resulting recombinants were analyzed by HPLC in a dynamic fashion and compared to the vector-only controls and a wild-type strain of S. clavuligerus while their growth was monitored throughout fermentation. The addition of an extra copy of ccaR, under control of its own promoter or constitutive ermE* promoter (P ermE* ), led to 7.6-and 2.3-fold increased volumetric levels of CA in respective recombinants, namely the AK9 and ID3 strains. Its highly stable multicopy expression by the glpF promoter (P glpF ) provided up to 25.9-fold enhanced volumetric CA titers in the respective recombinant, IDG3. claR expression controlled with its own promoter or ermE* and glpF-mediated amplification in an industrial strain brought about only about 1.2-fold increase in the volumetric CA titers. An extra copy of cas2 integration with P ermE* into the S. clavuligerus DEPA genome led to 3.8-fold higher volumetric CA production by GV61. Conclusively, multicopy expression of ccaR under P glpF can result in significantly improved industrial high-titer CA producers.

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Section: Discussionmentioning

confidence: 99%

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Kurt‐Kızıldoğan¹,

Jaccard²,

Mutlu³

et al. 2017

Turk J Biol

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“…The fluctuations of these compounds are likely to be buffered in the cell, and a compound with many arcs is considered to hardly vary. In this study, we eliminated 17 compounds with arc numbers greater than 10,000: H 2 is too complicated to find new pathways, the elimination of too many compounds will cause important interactions to be missed. We assumed that the optimum number of eliminated compounds depends on the focused functions of the enzymes.…”

Section: Graph Simplificationmentioning

confidence: 99%

“…If the specific CPM to these organisms is reconstructed, then the ortholog ID in the KEGG database should be assigned to the annotated genes of these organisms by KAAS [23]. The number of nodes in each graph; 2 Percentage of the nodes among the total nodes of the entire CPM; 3 The number of arcs in each graph; 4 The average number of arcs per node; 5 The kinds of compounds in each graph. …”

Section: Construction Of the S Cerevisiae Specific Cpmmentioning

confidence: 99%

Development of an Algorithm for Reconstructing a Comprehensive Pathway Model: Application to <i>Saccharomyces cerevisiae</i>

Takeda¹,

Machida²,

Aburatani³

2015

JBiSE

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The generation of bioactive products by microbial bioprocesses is important for drug discovery, functional food development, and other beneficial purposes. Many pathways contribute to the production of these bioactive compounds, but important knowledge for improving productivity still remains in hidden pathways. Recently, an abundance of knowledge about metabolic pathways has been accumulated in metabolic pathway databases, such as BioCyc and KEGG. Many by-products are chemically transformed and actually used in other enzymatic reactions. In this work, we developed an algorithm for the reconstruction of a comprehensive genetic pathway model from a known metabolic pathway database. This model considers the interactions of the by-products, in addition to the main products. Furthermore, we developed a method for the construction of a comprehensive pathway model in a specific organism. In this study, we reconstructed a Saccharomyces cerevisiae model. From this model, the pathways among enzymes that contributed to galactose metabolism were explored. Using S. cerevisiae DNA microarray data, the activated pathways were found among the explored pathways.

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“…Also, omics techniques such as transcriptomics and proteomics have contributed to understanding the complex regulatory networks employed by streptomycetes to balance primary and secondary metabolism. [15,16] Availability of such genome and expression data has further enabled construction of genome-scale metabolic models (GSMMs) of streptomycetes to describe metabolic pathways and predict optimal routes for the production of secondary metabolites. [17] With high-quality whole genome sequences and an array of suitable genome/compound mining and molecular cloning tools readily at hand, the secondary metabolite research is now moving toward systems metabolic engineering of streptomycetes in order to fully harness their potential to produce medically valuable secondary metabolites.…”

Section: Introductionmentioning

confidence: 99%

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

Robertsen

Weber

Kim

et al. 2017

Biotechnology Journal

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Streptomycetes are known for their inherent ability to produce pharmaceutically relevant secondary metabolites. Discovery of medically useful, yet novel compounds has become a great challenge due to frequent rediscovery of known compounds and a consequent decline in the number of relevant clinical trials in the last decades. A paradigm shift took place when the first whole genome sequences of streptomycetes became available, from which silent or "cryptic" biosynthetic gene clusters (BGCs) were discovered. Cryptic BGCs reveal a so far untapped potential of the microorganisms for the production of novel compounds, which has spurred new efforts in understanding the complex regulation between primary and secondary metabolism. This new trend has been accompanied with development of new computational resources (genome and compound mining tools), generation of various high-quality omics data, establishment of molecular tools, and other strain engineering strategies. They all come together to enable systems metabolic engineering of streptomycetes, allowing more systematic and efficient strain development. In this review, the authors present recent progresses within systems metabolic engineering of streptomycetes for uncovering their hidden potential to produce novel compounds and for the improved production of secondary metabolites.

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Systems biology and biotechnology of Streptomyces species for the production of secondary metabolites

Cited by 184 publications

References 132 publications

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Development of an Algorithm for Reconstructing a Comprehensive Pathway Model: Application to <i>Saccharomyces cerevisiae</i>

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

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Systems biology and biotechnology of Streptomyces species for the production of secondary metabolites

Cited by 184 publications

References 132 publications

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Genetic engineering of an industrial strain of Streptomyces clavuligerusfor further enhancement of clavulanic acid production

Development of an Algorithm for Reconstructing a Comprehensive Pathway Model: Application to &lt;i&gt;Saccharomyces cerevisiae&lt;/i&gt;

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

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Development of an Algorithm for Reconstructing a Comprehensive Pathway Model: Application to <i>Saccharomyces cerevisiae</i>