ArticleMicrobial cell factories2013
Genome-scale metabolic network guided engineering of Streptomyces tsukubaensis for FK506 production improvement.
Article in Microbial cell factories, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 81 citations in OpenAlex.
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- Integrated Metabolomic and Network Analysis to Explore the Potential Mechanism of Three Chemical Elicitors in Rapamycin Overproduction.Microorganisms · 2022Article
- Optimization of the precursor supply for an enhanced FK506 production inFrontiers in bioengineering and biotechnology · 2022Article
- Metabolic engineering of3 Biotech · 2021Article
- Improvement of FK506 production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis.Microbial cell factories · 2021Article
- Article
- The Onset of Tacrolimus Biosynthesis inAntibiotics (Basel, Switzerland) · 2020Article
- Development and validation of an updated computational model of Streptomyces coelicolor primary and secondary metabolism.BMC genomics · 2018Article
- Unraveling Nutritional Regulation of Tacrolimus Biosynthesis inAntibiotics (Basel, Switzerland) · 2018Review
- Substrate Specificity of Acyltransferase Domains for Efficient Transfer of Acyl Groups.Frontiers in microbiology · 2018Article
- Combining metabolomics and network analysis to improve tacrolimus production in Streptomyces tsukubaensis using different exogenous feedings.Journal of industrial microbiology & biotechnology · 2017Article
- Metabolic network model guided engineering ethylmalonyl-CoA pathway to improve ascomycin production in Streptomyces hygroscopicus var. ascomyceticus.Microbial cell factories · 2017Article
- Development of fungal cell factories for the production of secondary metabolites: Linking genomics and metabolism.Synthetic and systems biotechnology · 2017Review
- Enhancement of rapamycin production by metabolic engineering in Streptomyces hygroscopicus based on genome-scale metabolic model.Journal of industrial microbiology & biotechnology · 2017Article
- Time-Resolved Transcriptomics and Constraint-Based Modeling Identify System-Level Metabolic Features and Overexpression Targets to Increase Spiramycin Production inFrontiers in microbiology · 2017Article
- FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19.Journal of industrial microbiology & biotechnology · 2016Article
- The secondary metabolite bioinformatics portal: Computational tools to facilitate synthetic biology of secondary metabolite production.Synthetic and systems biotechnology · 2016Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundFK506 is an important immunosuppressant, which can be produced by Streptomyces tsukubaensis. However, the production capacity of the strain is very low. Hereby, a computational guided engineering approach was proposed in order to improve the intracellular precursor and cofactor availability of FK506 in S. tsukubaensis.
resultsFirst, a genome-scale metabolic model of S. tsukubaensis was constructed based on its annotated genome and biochemical information. Subsequently, several potential genetic targets (knockout or overexpression) that guaranteed an improved yield of FK506 were identified by the recently developed methodology. To validate the model predictions, each target gene was manipulated in the parent strain D852, respectively. All the engineered strains showed a higher FK506 production, compared with D852. Furthermore, the combined effect of the genetic modifications was evaluated. Results showed that the strain HT-ΔGDH-DAZ with gdhA-deletion and dahp-, accA2-, zwf2-overexpression enhanced FK506 concentration up to 398.9 mg/L, compared with 143.5 mg/L of the parent strain D852. Finally, fed-batch fermentations of HT-ΔGDH-DAZ were carried out, which led to the FK506 production of 435.9 mg/L, 1.47-fold higher than the parent strain D852 (158.7 mg/L).
conclusionsResults confirmed that the promising targets led to an increase in FK506 titer. The present work is the first attempt to engineer the primary precursor pathways to improve FK506 production in S. tsukubaensis with genome-scale metabolic network guided metabolic engineering. The relationship between model prediction and experimental results demonstrates the rationality and validity of this approach for target identification. This strategy can also be applied to the improvement of other important secondary metabolites.
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