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Applied Microbiology and Biotechnology

, Volume 102, Issue 17, pp 7541–7553 | Cite as

Identification and metabolomic analysis of chemical elicitors for tacrolimus accumulation in Streptomyces tsukubaensis

  • Cheng Wang
  • Di Huang
  • Shaoxiong Liang
Applied microbial and cell physiology

Abstract

Tacrolimus is a widely used immunosuppressive agent in the treatment of various clinical diseases. However, the low fermentation yield seriously limits its further application. To stimulate tacrolimus synthesis, nine chemical elicitors of five groups were evaluated for their effects on tacrolimus accumulation in S. tsukubaensis. The results showed that sodium butyrate (SB), dimethylsulfoxide (DMSO), and LaCl3 could increase tacrolimus accumulation by more than 30%. Cumulative effects of different chemical elicitors exhibited that the highest tacrolimus yield was improved by 64.7% (303.60 mg/L) in DMSO and La treatment, compared to the control. To decipher possible response mechanism, a weighted correlation network analysis (WGCNA) based on metabolomics was employed and datasets showed 13 distinct metabolic modules and 16 hub metabolites were possibly related to the stimulatory roles of DMSO, La, SB, and their combination treatments. The pathway analysis further exhibited that central carbon metabolism, amino acid metabolism, and fatty acid metabolism showed significant differences in the above chemical elicitor treatments. Thereinto, the carboxylation of propionyl-CoA from isoleucine and methionine degradation was first confirmed to be the main source of methylmalonyl-CoA by RT-PCR analysis in DMSO and La treatment. By further strengthening of the supply of methylmalonyl-CoA precursor in DMSO and La treatment, the final tacrolimus yield could reach to 372.12 mg/L, 2.02-fold higher than the control. To our knowledge, this is the first study to unveil the potential mechanism of different chemical elicitor stresses in S. tsukubaensis based on metabolomics, and the established information provide valuable guidance for further improving tacrolimus production.

Keywords

Tacrolimus Chemical elicitors Metabolomic network S. tsukubaensis 

Notes

Funding information

This work was financially supported by the Research Start-up Funds of Northwest A&F University (Z109021804).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

253_2018_9177_MOESM1_ESM.pdf (120 kb)
ESM 1 (PDF 120 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Forestry Engineering, College of ForestryNorthwest A&F UniversityYanglingPeople’s Republic of China
  2. 2.TEDA Institute of Biological Sciences and Biotechnology, Tianjin Economic-Technological Development Area (TEDA)Nankai UniversityTianjinPeople’s Republic of China
  3. 3.Key Laboratory of Molecular Microbiology and TechnologyMinistry of EducationTianjinPeople’s Republic of China
  4. 4.Tianjin Key Laboratory of Microbial Functional GenomicsTianjinPeople’s Republic of China
  5. 5.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and EngineeringNankai UniversityTianjinPeople’s Republic of China
  6. 6.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and TechnologyTianjin UniversityTianjinPeople’s Republic of China

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