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A preliminary study on the impact of exogenous A-Factor analogue 1,4-butyrolactone on stimulating bitespiramycin biosynthesis

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Abstract

Bitespiramycin is composed of nine main acylated spiramycin components with isovaleryspiramycin as the major component. However, even with excellent therapeutic effects, its application and industrialization are restricted due to its low titer. In this study, the exogenous addition of A-Factor analogue 1,4-butyrolactone (1,4-BL) stimulated an improvement in bitespiramycin biological titer by 29% with a tiny influence on concentration of major component. Moreover, the mechanism of 1,4-BL stimulating effect was preliminarily explored by the analyses of three key enzyme activities, intracellular metabolite profiling and metabolic flux distribution. All results coordinately revealed that the extensive accumulation of methylmalonyl-CoA and acetyl-CoA was the direct reason for the enhanced bitespiramycin biosynthesis. This study would provide theoretical and technical basis for the application of 1,4-BL addition strategy to industrial bitespiramycin production.

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References

  1. Biarnes-Carrera M, Breitling R, Takano E (2015) Butyrolactone signalling circuits for synthetic biology. Curr Opin Chem Biol 28:91–98

    Article  CAS  Google Scholar 

  2. Niu G, Chater KF, Tian Y, Zhang J, Tan H (2016) Specialised metabolites regulating antibiotic biosynthesis in Streptomyces spp. FEMS Microbiol Rev 40(4):554–573

    Article  CAS  Google Scholar 

  3. Mariam J, Anand R (2018) Fluorescence Quenching Studies of γ-Butyrolactone-Binding Protein (CprB) from Streptomyces coelicolor A3 (2) Quorum Sensing. Humana Press 2018:131–143

    Google Scholar 

  4. Takano E (2006) γ-Butyrolactones: Streptomyces signalling molecules regulating antibiotic production and differentiation. Curr Opin Microbiol 9(3):287–294

    Article  CAS  Google Scholar 

  5. Yang YK, Shimizu H, Shioya S, Suga KI, Nihira T, Yamada Y (1995) Optimum autoregulator addition strategy for maximum virginiamycin production in batch culture of Streptomyces virginiae. Biotechnol Bioeng 46(5):437–442

    Article  CAS  Google Scholar 

  6. Yang YK, Morikawa M, Shimizu H, Shioya S, Suga KI, Nihira T, Yamada Y (1996) Maximum virginiamycin production by optimization of cultivation conditions in batch culture with autoregulator addition. Biotechnol Bioeng 49(4):437–444

    Article  CAS  Google Scholar 

  7. Yang YH, Kim TW, Park SH, Lee K, Park HY, Song E, Joo HS, Kim YG, Hahn JS, Kim BG (2009) Cell-free Escherichia coli-based system to screen for quorum-sensing molecules interacting with quorum receptor proteins of Streptomyces coelicolor. Appl Environ Microb 75(19):6367–6372

    Article  CAS  Google Scholar 

  8. Miyake K, Horinouchi S, Yoshida M, Chiba N, Mori K, Nogawa N, Morikawa N, Beppu T (1989) Detection and properties of A-factor-binding protein from Streptomyces griseus. J Bacteriol 171(8):4298–4302

    Article  CAS  Google Scholar 

  9. Liu, X, Sun, X, He, W, Tian, X, Zhuang, Y, Chu, J (2019) Dynamic changes of metabolomics and expression of candicidin biosynthesis gene cluster caused by the presence of a pleiotropic regulator AdpA in Streptomyces ZYJ-6. Bioprocess Biosyst Eng 1–13

  10. Tan GY, Bai L, Zhong JJ (2013) Exogenous 1,4-butyrolactone stimulates A-factor-like cascade and validamycin biosynthesis in Streptomyces hygroscopicus 5008. Biotechnol Bioeng 110(11):2984–2993

    Article  CAS  Google Scholar 

  11. Wang YH, Wu CH, Chu J (2010) Regulation of branched-chain amino acid catabolism: glucose limitation enhances the component of isovalerylspiramycin for the bitespiramycin production. Bioprocess Biosyst Eng 33(2):257–265

    Article  CAS  Google Scholar 

  12. Hong M, Huang M, Chu J (2016) Impacts of proline on the central metabolism of an industrial erythromycin-producing strain Saccharopolyspora erythraea via 13C labeling experiments. J Biotechnol 231:1–8

    Article  CAS  Google Scholar 

  13. Chen Y, Huang M, Wang Z (2013) Controlling the feed rate of glucose and propanol for the enhancement of erythromycin production and exploration of propanol metabolism fate by quantitative metabolic flux analysis. Bioprocess Biosyst Eng 36:1445

    Article  CAS  Google Scholar 

  14. Choi KR, Kim WJ, Lee SY (2018) Metabolomics for industrial fermentation. Bioprocess Biosyst Eng 41(7):1073–1077

    Article  CAS  Google Scholar 

  15. Vu-Trong K, Bhuwapathanapun S, Grav PP (1980) Metabolic regulation in tylosin-producing Streptomyces fradiae: regulatory role of adenylate nucleotide pool and enzyme involved in biosynthesis of tylonolide precursors. Antimicrob Agents Chemother 17(4):519

    Article  CAS  Google Scholar 

  16. Coze F, Gilard F, Tcherkez G (2013) Carbon-flux distribution within Streptomyces coelicolor metabsolism: a comparison between the actinorhodin-producing strain M145 and its non-producing derivative M1146. PLoS ONE 8(12):e84151

    Article  Google Scholar 

  17. Borodina I, Siebring J, Zhang J (2008) Antibiotic overproduction in Streptomyces coelicolor A3 2 mediated by phosphofructokinase deletion. J Biol Chem 283(37):25186

    Article  CAS  Google Scholar 

  18. Biarnes Carrera M, Lee CK, Nihira T (2018) Orthogonal regulatory circuits for Escherichia coli based on the γ-butyrolactone system of Streptomyces coelicolor. ACS Synthetic Biol 7(4):1043–1055

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Basic Research Program of China (973 Program) (No. 2012CB721006), National Natural Science Foundation of China (No. 21276081), the National Scientific and Technological Major Special Project (Significant Creation of New drugs), No. 2011ZX09203-001-03, Research Fund for the Doctoral Program of Higher Education of China (No. 20110074110015).

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Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, P. O. Box 329#, Shanghai, 200237, People’s Republic of China

    Xiaowei Gao, Yonghong Wang & Ju Chu

Authors
  1. Xiaowei Gao
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  2. Yonghong Wang
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  3. Ju Chu
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Corresponding authors

Correspondence to Yonghong Wang or Ju Chu.

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Appendices

Appendix A

  1. 1.

    G6P + 2NADP → Ru5P + CO2 + 2NADPH

  2. 2.

    Ru5P → 0.667F6P + 0.333G3P

  3. 3.

    G6P → F6P

  4. 4.

    F6P + ATP → F1,6P

  5. 5.

    F1,6P → DHAP + G3AP

  6. 6.

    DHAP → G3P

  7. 7.

    G3P + NAD + ADP → 3PG + NADH + ATP

  8. 8.

    3PG → PEP

  9. 9.

    PEP → Pyr + ATP

  10. 10.

    Pyr + NAD → AcCoA + CO2 + NADH

  11. 11.

    AcCoA + OXA → Citrate

  12. 12.

    Citrate + NAD → AKG + CO2 + NADH

  13. 13.

    AKG + FAD + GDP + 2NAD → OXA + CO2 + GTP + FADH + 2NADH

  14. 14.

    Pyr + CO2 → OXA

  15. 15.

    FADH + ADP + 0.5O2 → FAD + 0.5H2O + ATP

  16. 16.

    NADH + ADP + 0.5O2 → NAD + 0.5H2O + 2ATP

  17. 17.

    SUCCoA → METCoA

  18. 18.

    AcCoA + HCO3−1 + ATP → MalCoA

  19. 19.

    4Malonyl-CoA + Methylmalonyl-CoA + Ethylmalonyl-CoA + Methoxymalonyl-ACP → Platenolide

  20. 20.

    Glc + ATP → G6P + ADP

  21. 21.

    0.067G6P + 0.064Ru5P + 0.009G3P + 0.065PG + 0.05PEP + 0.176Pyr + 0.095OXA + 0.102AKG + 0.249AcCoA + NADPH + NAD + ATP → C3.93H7.35O2.83N0.58 (Biomass) + NADP + NADH + CO2

Appendix B

1

3PG

3-Phosphoglycerate

2

AcCoA

Acetyl coenzyme A

3

DHAP

Dihydroxyacetone phosphate

4

F6P

Fructose-6-phosphate

5

FADH

Flavin adenine dinucleotide, reduced

6

G6P

Glucose-6-phosphate

7

G3P

Glyceraldehyde-3-phosphate

8

Glc

Glucose

9

AKG

α-Ketoglutarate

10

NADH

Nicotinamide adenine dinucleotide,reduced

11

OAA

Oxaloacetate

12

PEP

Phosphoenolpyruvate

13

PYR

Pyruvate

14

Ru5P

Ribulose-5-phosphate

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Gao, X., Wang, Y. & Chu, J. A preliminary study on the impact of exogenous A-Factor analogue 1,4-butyrolactone on stimulating bitespiramycin biosynthesis. Bioprocess Biosyst Eng 42, 1903–1913 (2019). https://doi.org/10.1007/s00449-019-02184-9

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