ArticleJournal of industrial microbiology & biotechnology2013
Enhancement of FK506 production by engineering secondary pathways of Streptomyces tsukubaensis and exogenous feeding strategies.
Article in Journal of industrial microbiology & biotechnology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 75 citations in OpenAlex.
- Enhancement of tacrolimus production in Streptomyces tsukubaensis by genetic engineering and process optimization.World journal of microbiology & biotechnology · 2025Article
- Regulatory orchestration of FK506 biosynthesis iniScience · 2025Article
- Enhancement of FK520 production in Streptomyces hygroscopicus var. ascomyceticus ATCC 14891 by overexpressing the regulatory gene fkbR2.Bioprocess and biosystems engineering · 2025Article
- Improvement of FK506 production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis.Microbial cell factories · 2021Article
- Biosynthetic Potential ofAntibiotics (Basel, Switzerland) · 2021Article
- Optimization of tetramycin production in Streptomyces ahygroscopicus S91.Journal of biological engineering · 2021Article
- Enhanced ascomycin production in Streptomyces hygroscopicus var. ascomyceticus by employing polyhydroxybutyrate as an intracellular carbon reservoir and optimizing carbon addition.Microbial cell factories · 2021Article
- Comparative metabolomics analysis of amphotericin B high-yield mechanism for metabolic engineering.Microbial cell factories · 2021Article
- Bioengineering of Anti-Inflammatory Natural Products.ChemMedChem · 2021Review
- Article
- The Onset of Tacrolimus Biosynthesis inAntibiotics (Basel, Switzerland) · 2020Article
- Evaluation of carbon:nitrogen ratio in semi-defined culture medium to tacrolimus biosynthesis byBiotechnology reports (Amsterdam, Netherlands) · 2020Article
- Streptomyces sp. BV410 isolate from chamomile rhizosphere soil efficiently produces staurosporine with antifungal and antiangiogenic properties.MicrobiologyOpen · 2020Article
- Amphotericin B biosynthesis in Streptomyces nodosus: quantitative analysis of metabolism via LC-MS/MS based metabolomics for rational design.Microbial cell factories · 2020Article
- Enhanced production of individual ganoderic acids by integrating Vitreoscilla haemoglobin expression and calcium ion induction in liquid static cultures of Ganoderma lingzhi.Microbial biotechnology · 2019Article
- Unraveling Nutritional Regulation of Tacrolimus Biosynthesis inAntibiotics (Basel, Switzerland) · 2018Review
- dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome.RNA biology · 2017Article
- 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
- Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function.Natural product reports · 2017Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FK506 is a clinically important macrocyclic polyketide with immunosuppressive activity produced by Streptomyces tsukubaensis. However, the low titer at which it is produced is a bottleneck to its application and use in industrial processes. We have overexpressed five potential targets associated with FK506 production (fkbO, fkbL, fkbP, fkbM, fkbD) which were identified in our previous study, with the aim to improve FK506 production. The results of the analysis showed that the constructed strains with an additional copy of each gene increased FK506 production by approximately 10-40 % compared with the wild-type strain D852. The results of the gene expression analysis indicated that each gene was upregulated. Combinatorial overexpression of the five genes resulted in a 146 % increase in the FK506 titer to 353.2 mg/L, in comparison with the titer produced by D852. To further improve the production of FK506 by the engineered strain HT-FKBOPLMD, we supplemented the medium with various nutrients, including soybean oil, lactate, succinate, shikimate, chorismate, lysine, pipecolate, isoleucine and valine. Optimization of feeding concentrations and times resulted in HT-FKBOPLMD being able to produce approximately 70 % more FK506, thereby reaching the maximal titer of 457.5 mg/L, with lower amounts of by-products (FK520 and 37,38-dihydro-FK506). These results demonstrate that the combination of the metabolically engineered secondary pathways and the exogenous feeding strategies developed here was able to be successfully applied to improve the production of industrially and clinically important compounds.
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