Applied Microbiology and Biotechnology

, Volume 101, Issue 6, pp 2447–2465 | Cite as

Comparative proteomic and metabolomic analysis of Streptomyces tsukubaensis reveals the metabolic mechanism of FK506 overproduction by feeding soybean oil

  • Jun Wang
  • Huanhuan Liu
  • Di Huang
  • Lina Jin
  • Cheng Wang
  • Jianping WenEmail author
Genomics, transcriptomics, proteomics


FK506 (tacrolimus) is a 23-membered polyketide macrolide that possesses powerful immunosuppressant activity. In this study, feeding soybean oil into the fermentation culture of Streptomyces tsukubaensis improved FK506 production by 88.8%. To decipher the overproduction mechanism, comparative proteomic and metabolomic analysis was carried out. A total of 72 protein spots with differential expression in the two-dimensional gel electrophoresis (2-DE) were identified by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF-MS), and 66 intracellular metabolites were measured by gas chromatography-mass spectrometer (GC-MS). The analysis of proteome and metabolome indicated that feeding soybean oil as a supplementary carbon source could not only strengthen the FK506 precursor metabolism and energy metabolism but also tune the pathways related to transcriptional regulation, translation, and stress response, suggesting a better intracellular metabolic environment for the synthesis of FK506. Based on these analyses, 20 key metabolites and precursors of FK506 were supplemented into the soybean oil medium. Among them, lysine, citric acid, shikimic acid, and malonic acid performed excellently for promoting the FK506 production and biomass. Especially, the addition of malonic acid achieved the highest FK506 production, which was 1.56-fold of that in soybean oil medium and 3.05-fold of that in initial medium. This report represented the first comprehensive study on the comparative proteomics and metabolomics applied in S. tsukubaensis, and it would be a rational guidance to further strengthen the FK506 production.


Streptomyces tsukubaensis Soybean oil FK506 Comparative proteomics Metabolomics 



This work was financially supported by the National Natural Science Foundation of China (No. 21376171), the key technologies R & D program of Tianjin (No. 16YFZCSY00780), the National 973 Project of China (No. 2013CB733600), and the Key Program of National Natural Science Foundation of China (No. 21236005).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jun Wang
    • 1
    • 2
  • Huanhuan Liu
    • 1
    • 2
  • Di Huang
    • 3
    • 4
  • Lina Jin
    • 1
    • 2
  • Cheng Wang
    • 1
    • 2
  • Jianping Wen
    • 1
    • 2
    Email author
  1. 1.Key Laboratory of System Bioengineering (Tianjin University), Ministry of EducationTianjinPeople’s Republic of China
  2. 2.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and TechnologyTianjin UniversityTianjinPeople’s Republic of China
  3. 3.TEDA School of Biological Sciences and BiotechnologyNankai University, TEDATianjinPeople’s Republic of China
  4. 4.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)Nankai UniversityTianjinPeople’s Republic of China

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