Skip to main content
SpringerLink
Log in

Comparative metabolomics reveals the mechanism of avermectin production enhancement by S-adenosylmethionine

  • Applied Genomics & Systems Biotechnology - Original Paper
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

It was found that S-adenosylmethionine (SAM) could effectively improve avermectin titer with 30–60 μg/mL addition to FH medium. To clearly elucidate the mechanism of SAM on intracellular metabolites of Streptomyces avermitilis, a GC–MS-based comparative metabolomics approach was carried out. First, 230 intracellular metabolites were identified and 14 of them remarkably influenced avermectin biosynthesis were discriminative biomarkers between non-SAM groups and SAM-treated groups by principal components analysis (PCA) and partial least squares (PLS). Based on further key metabolic pathway analyses, these biomarkers, such as glucose, oxaloacetic acid, fatty acids (in soybean oil), threonine, valine, and leucine, were identified as potentially beneficial precursors and added in medium. Compared with single-precursor feeding, the combined feeding of the precursors and SAM markedly increased the avermectin titer. The co-feeding approach not only directly verified our hypothesis on the mechanism of SAM by comparative metabolomics, but also provided a novel strategy to increase avermectin production.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Beyoğlu D, Idle JR (2013) Metabolomics and its potential in drug development. Biochem Pharmacol 85(1):12–20

    Article  PubMed  Google Scholar 

  2. Bo T, Liu M, Zhong C, Zhang Q, Su QZ, Tan ZL, Han PP, Jia SR (2014) Metabolomic analysis of antimicrobial mechanisms of ε-poly-l-lysine on Saccharomyces cerevisiae. J Agric Food Chem 62(19):4454–4465

    Article  CAS  PubMed  Google Scholar 

  3. Bolten CJ, Wittmann C (2008) Appropriate sampling for intracellular amino acid analysis in five phylogenetically different yeasts. Biotechnol Lett 30(11):1993–2000

    Article  CAS  PubMed  Google Scholar 

  4. Chen TS, Inamine ES (1989) Studies on the biosynthesis of avermectins. Arch Biochem Biophys 270(2):521–525

    Article  CAS  PubMed  Google Scholar 

  5. Dietmair S, Hodson MP, Quek LE, Timmins NE, Chrysanthopoulos P, Jacob SS, Gray P, Nielsen LK (2012) Metabolite profiling of CHO cells with different growth characteristics. Biotechnol Bioeng 109(9):1404–1414

    Article  CAS  PubMed  Google Scholar 

  6. Dikbas N (2010) Determination of antibiotic susceptibility and fatty acid methyl ester profiles of Bacillus cereus strains isolated from different food sources in Turkey. Afr J Biotechnol 9(11):1641–1647

    CAS  Google Scholar 

  7. Ding MZ, Zhou X, Yuan YJ (2010) Metabolome profiling reveals adaptive evolution of Saccharomyces cerevisiae during repeated vacuum fermentations. Metabolomics 6(1):42–55

    Article  CAS  Google Scholar 

  8. Dotzlaf JE, Metzger LS, Foglesong MA (1984) Incorporation of amino acid-derived carbon into tylactone by Streptomyces fradiae GS14. Antimicrob Agents Chemother 25(2):216–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fang ZZ, Tosh DK, Tanaka N, Wang H, Krausz KW, O’Connor R, Jacobson KA, Gonzalez FJ (2015) Metabolic mapping of A3 adenosine receptor agonist MRS5980. Biochem Pharmacol 97(2):215–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gao H, Liu M, Liu J, Dai H, Zhou X, Liu X, Zhuo Y, Zhang W, Zhang L (2009) Medium optimization for the production of avermectin B1a by Streptomyces avermitilis 14-12A using response surface methodology. Bioresour Technol 100(17):4012–4016

    Article  CAS  PubMed  Google Scholar 

  11. Gao H, Liu M, Zhou X, Liu J, Zhuo Y, Gou Z, Xu B, Zhang W, Liu X, Luo A, Zheng C, Chen X, Zhang L (2010) Identification of avermectin-high-producing strains by high-throughput screening methods. Appl Microbiol Biotechnol 85(5):1219–1225

    Article  CAS  PubMed  Google Scholar 

  12. Guo G, Tian PP, Tang D, Wang XX, Yang HJ, Cao P, Gao Q (2015) Metabolomics analysis between wild-type and industrial strains of Streptomyces avermitilis based on gas chromatography-mass spectrometry strategy. Lect Notes Electr Eng 333:477–485

    Article  Google Scholar 

  13. Hesse H, Kreft O, Maimann S, Zeh M, Willmitzer L, Höfgen R (2001) Approaches towards understanding methionine biosynthesis in higher plants. Amino Acids 20(3):281–289

    Article  CAS  PubMed  Google Scholar 

  14. Huh JH, Kim DJ, Zhao XQ, Li M, Jo YY, Yoon TM, Shin SK, Yong JH, Ryu YW, Yang YY, Suh JW (2004) Widespread activation of antibiotic biosynthesis by S-adenosylmethionine in streptomycetes. FEMS Microbiol Lett 238(2):439–447

    Article  CAS  PubMed  Google Scholar 

  15. Ikeda H, Kotaki H, Tanaka H, Ōmura S (1988) Involvement of glucose catabolism in avermectin production by Streptomyces avermitilis. Antimicrob Agents Chemother 32:282–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ikeda H, Ōmura S (1997) Avermectin biosynthesis. Chem Rev 97(7):2591–2610

    Article  CAS  PubMed  Google Scholar 

  17. Khaoua S, Lebrihi A, Laakel M, Schneider F, Germain P, Lefebvre G (1992) Influence of short-chain fatty acids on the production of spiramycin by Streptomyces ambofaciens. Appl Microbiol Biotechnol 36(6):763–767

    Article  CAS  PubMed  Google Scholar 

  18. Korneli C, Bolten CJ, Godard T, Franco-Lara E, Wittmann C (2012) Debottlenecking recombinant protein production in Bacillusmegaterium under large-scale conditions-targeted precursor feeding designed from metabolomics. Biotechnol Bioeng 109(6):1538–1550

    Article  CAS  PubMed  Google Scholar 

  19. Lee JJ, Chen L, Shi J, Trzcinski A, Chen WN (2014) Metabolomic profiling of Rhodosporidium toruloides grown on glycerol for carotenoid production during different growth phases. J Agric Food Chem 62(41):10203–10209

    Article  CAS  PubMed  Google Scholar 

  20. Li L, Guo J, Wen Y, Chen Z, Song Y, Li J (2010) Overexpression of ribosome recycling factor causes increased production of avermectin in Streptomyces avermitilis strains. J Ind Microbiol Biotechnol 37(7):673–679

    Article  CAS  PubMed  Google Scholar 

  21. Liu X, Lu YF, Guan X, Zhao M, Wang J, Li F (2016) Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches. Biochem Pharmacol 109:70–82

    Article  CAS  PubMed  Google Scholar 

  22. Miller GL (1959) Use of dinitrosalicylic acid reagent for determination of reducing sugar. Anal Chem 31:426–428

    Article  CAS  Google Scholar 

  23. Mrozik HH (1983) Processes for the interconversion of avermectin compounds. US Patent 4,423,209

  24. Novák J, Hájek P, Řezanka T, Vaněk Z (1992) Nitrogen regulation of fatty acids and avermectins biosynthesis in Streptomyces avermitilis. FEMS Microbiol Lett 72(1):57–61

    Article  PubMed  Google Scholar 

  25. Ochi K, Saito Y, Umehara K, Ueda I, Kohsaka M (1984) Restoration of aerial mycelium and antibiotic production in a Streptomyces griseoflavus arginine auxotroph. J Gen Microbiol 130(8):2007–2013

    CAS  PubMed  Google Scholar 

  26. Okamoto S, Lezhava A, Hosaka T, Okamoto-Hosoya O, Ochi K (2003) Enhanced expression of S-adenosylmethionine synthetase causes overproduction of actinorhodin in Streptomyces coelicolor A3(2). J Bacteriol 185(2):601–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ōmura S, Ikeda H, Tanaka H (1991) Selective production of specific components of avermectins in Streptomyces avermitilis. J Antibiot (Tokyo) 44(5):560–563

    Article  Google Scholar 

  28. Schulman MD, Acton SL, Valentino DL, Arison BH (1990) Purification and identification of dTDP-oleandrose, the precursor of the oleandrose units of the avermectins. J Biol Chem 265(8):16965–16970

    CAS  PubMed  Google Scholar 

  29. Shin SK, Xu D, Kwon HJ, Suh JW (2006) S-adenosylmethionine activates adpA transcription and promotes streptomycin biosynthesis in Streptomyces griseus. FEMS Microbiol Lett 259(1):53–59

    Article  CAS  PubMed  Google Scholar 

  30. Sima C, Dougherty ER (2006) What should be expected from feature selection in small-sample settings. Bioinformatics 22(19):2430–2436

    Article  CAS  PubMed  Google Scholar 

  31. Szeto SS, Reinke SN, Sykes BD, Lemire BD (2010) Mutations in the Saccharomyces cerevisiae succinate dehydrogenase result in distinct metabolic phenotypes revealed through 1H NMR-based metabolic footprinting. J Proteom Res 9(12):6729–6739

    Article  CAS  Google Scholar 

  32. Tang L, Zhang YX, Hutchinson CR (1994) Amino acid catabolism and antibiotic synthesis: valine is a source of precursors for macrolide biosynthesis in Streptomyces ambofaciens and Streptomyces fradiae. J Bacteriol 176(19):6107–6119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tian X, Wang Y, Chu J, Zhuang Y, Zhang S (2016) Enhanced L-lactic acid production in Lactobacillus paracasei by exogenous proline addition based on comparative metabolite profiling analysis. Appl Microbiol Biotechnol 100(5):2301–2310

    Article  CAS  PubMed  Google Scholar 

  34. Van Voorhisa WC, Hooft van Huijsduijnend R, Wells TN (2015) Profile of William C. Campbell, Satoshi Ōmura, and Youyou Tu, Nobel laureates in physiology or medicine. Proc Natl Acad Sci USA 112(52):15773–15776

    Article  Google Scholar 

  35. Wang B, Jiu J, Liu H, Huang D, Wen J (2015) Comparative metabolic profiling reveals the key role of amino acids metabolism in the rapamycin overproduction by Streptomyces hygroscopicus. J Ind Microbiol Biotechnol 42(6):949–963

    Article  PubMed  Google Scholar 

  36. Wold S, Geladi P, Esbensen K, Öhman J (1987) Multi-way principal components-and PLS-analysis. J Chemometr 1(1):41–56

    Article  CAS  Google Scholar 

  37. Wu C, Choi YH, van Wezel GP (2016) Metabolic profiling as a tool for prioritizing antimicrobial compounds. J Ind Microbiol Biotechnol 43(2–3):299–312

    Article  CAS  PubMed  Google Scholar 

  38. Xu Z, Cen P (1999) Stimulation of avermectin B1a biosynthesis in Streptomyces avermilitis by feeding glucose and propionate. Biotechnol Lett 21(1):91–95

    Article  CAS  Google Scholar 

  39. Yin P, Li YY, Zhou J, Wang YH, Zhang SL, Ye BC, Ge WF, Xia YL (2013) Direct proteomic mapping of Streptomyces avermitilis wild and industrial strain and insights into avermectin production. J Proteom 79:1–12

    Article  CAS  Google Scholar 

  40. Yoon GS, Ko KH, Kang HW, Suh JW, Kim YS, Ryu YW (2006) Characterization of S-adenosylmethionine synthetase from Streptomyces avermitilis NRRL8165 and its effect on antibiotic production. Enzyme Microb Technol 39(3):466–473

    Article  CAS  Google Scholar 

  41. Yoon YJ, Kim ES, Hwang YS, Choi CY (2004) Avermectin: biochemical and molecular basis of its biosynthesis and regulation. Appl Microbiol Biotechnol 63(6):626–634

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Basic Research Program (973 Program) of China (2013CB734004), and the Natural Science Foundation of China (31370075, 31471725, 61603273), and the Youth Innovation Fund of Tianjin University of Science and Technology of China (2014CXLG28). We also appreciate Dr. Arnold L. Demain for his valuable advice with the manuscript, Dr. Lixin Zhang for providing the experimental strain and Mr. Gang Guo for his technical support.

Author information

Authors and Affiliations

  1. Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, People’s Republic of China

    Pingping Tian, Peng Cao, Dong Hu, Depei Wang, Jian Zhang & Qiang Gao

  2. School of Computer Sciences and Information Engineering, Tianjin University of Science and Technology, Tianjin, People’s Republic of China

    Lin Wang

  3. Logistics Service Group, Tianjin University of Science and Technology, Tianjin, People’s Republic of China

    Yan Zhu

Authors
  1. Pingping Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Depei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiang Gao.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10295_2016_1883_MOESM1_ESM.ppt

Fig. 1S PCA score plots of different SAM additions at different timepoints. PCA score plots (PC1, 72.35% of total variance; PC2, 21.47% of total variance). In the score plots, the confidence interval is defined by Hotelling’s T2 ellipse (95% confidence interval), and observations outside the ellipse are considered outliers (PPT 160 kb)

10295_2016_1883_MOESM2_ESM.pptx

Fig. 2S PLS score plots (a, c, e) and loading plots (b, d, f) of samples with different contents of SAM. Sampling time (a, b) at 24 h, (c, d) at 48 h, and (e, f) at 72 h. In the score plots, the confidence interval is defined by Hotelling’s T2 ellipse (95% confidence interval), and observations outside the ellipse are considered outliers. Green icons represent the non-SAM groups; blue icons represent the 30 μg/mL SAM-treated groups; and red icons represent the 60 μg/mL SAM-treated groups (PPTX 134 kb)

10295_2016_1883_MOESM3_ESM.pptx

Fig. 3S PLS score plots (a, c, e) and loading plots (b, d, f) of samples with different contents of SAM. Sampling time (a, b) at 24 h, (c, d) at 48 h, and (e, f) at 72 h. In the score plots, the confidence interval is defined by Hotelling’s T2 ellipse (95% confidence interval), and observations outside the ellipse are considered outliers. Green icons represent the non-SAM groups; blue icons represent the 30 μg/mL SAM-treated groups; and red icons represent the 60 μg/mL SAM-treated groups (PPTX 464 kb)

Table 1S Statistical data from PLS at different sampling timepoints (PPTX 58 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tian, P., Cao, P., Hu, D. et al. Comparative metabolomics reveals the mechanism of avermectin production enhancement by S-adenosylmethionine. J Ind Microbiol Biotechnol 44, 595–604 (2017). https://doi.org/10.1007/s10295-016-1883-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-016-1883-y

Keywords

Search

Navigation