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Participation of (p)ppGpp molecules in the formation of “stringent response” in bacteria, as well as in the biosynthesis of antibiotics and morphological differentiation in actinomycetes

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Abstract

Stringent response is a pleiotropic physiological response of cells caused by deficiency of aminoacetylated tRNAs and, correspondingly, by the arrest of protein synthesis. This response can experimentally be induced by amino acid deficiency in a culture medium and limitation of the aminoacylation capacity of tRNA molecules even in the presence of the respective amino acids in the cell. Many traits of this response indicate its dependence on the accumulation of ppGpp molecules. There are links between the growth rate of actinomycetes and the biosynthesis of secondary metabolites by the bacteria. In particular, it has been established that the introduction of additional relA gene copies of the ppGpp synthetase can affect the production of antibiotics in streptomycetes. The survey presents the authors’ own experimental data obtained in the studies on the effect of heterologous relA gene expression in Streptomyces nogalater, the nogalamycin producer.

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References

  1. Magnusson, L., Farewell, A., and Nystrom, T., ppGpp: a global regulator in Escherichia coli, Trends Microbiol., 2005, vol. 13, pp. 236–242.

  2. Hara, A. and Sy, J., Guanosine 5'-triphosphate, 3'diphosphate 5'-phosphohydrolase. Purification and substrate specificity, J. Biol. Chem., 1983, vol. 258, no. 3, pp. 1678–1683.

    CAS  Google Scholar 

  3. Carneiro, S., Lourenco, A., Ferreira, E., and Rocha, I., Stringent response of Escherichia coli: revisiting the bibliome using literature mining, Microb. Inform. Exp., 2011, vol. 1, no. 1, p. 14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jain, V., Kumar, M., and Chatterji, D., ppGpp: stringent response and survival, J. Microbiol., 2006, vol. 44, pp. 1–10.

    CAS  PubMed  Google Scholar 

  5. Cashel, M., Gentry, D., Hernández, V., and Vinella, D., The stringent response, tEscherichia coli and Salmonella, Cell. Mol. Biol., Neidhardt, F.C., Ed., Washington, DC, 1996, vol. 1, pp. 1458–1496.

    Google Scholar 

  6. Spira, B. and Yagil, E., The relation between ppGpp and the PHO regulon in Escherichia coli, Mol. Gen. Genet., 1998, vol. 257, no. 4, pp. 469–477.

    Article  CAS  PubMed  Google Scholar 

  7. Metzger, S., Sarubbi, E., Glaser, G., and Cashel, M., Protein sequences encoded by the relA and the spoT genes of Escherichia coli are interrelated, J. Biol. Chem., 1989, vol. 264, no. 16, pp. 9122–9125.

    CAS  PubMed  Google Scholar 

  8. Gentry, D.R. and Cashel, M., Mutational analysis of the Escherichia coli spoT gene identifies distinct but overlapping regions involved in ppGpp synthesis and degradation, Mol. Microbiol., 1996, vol. 19, no. 6, pp. 1373–1384.

    Article  CAS  PubMed  Google Scholar 

  9. Mechold, U., Cashel, M., Steiner, K., Gentry, D., and Malke, H., Functional analysis of a relA/sopT gene homolog from Streptococcus equisimilis, J. Bacteriol., 1996, vol. 178, no. 5, pp. 1401–1411.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wehmeier, L., Schafer, A., Burkovski, A., Kramer, R., Mechold, U., Malke, H., Puhler, A., and Kalinowski, J., The role of the Corynebacterium glutamicum rel gene in (p)ppGpp metabolism, Microbiology, 1998, vol. 144, pp. 1853–1862.

    Article  CAS  PubMed  Google Scholar 

  11. Braeken, K., Moris, M., Daniels, R., Vanderleyden, J., and Michels, J., New horizons for (p)ppGpp in bacterial and plant physiology, Trends Microbiol., 2006, vol. 14, no. 1, pp. 45–54.

    Article  CAS  PubMed  Google Scholar 

  12. Yang, X. and Ishiguro, E., Involvement of the N terminus of ribosomal protein L11 in regulation of the RelA protein of Escherichia coli, J. Bacteriol., 2001, vol. 183, no. 22, pp. 6532–6537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gropp, M., Strausz, Y., Gross, M., and Glaser, G., Regulation of Escherichia coli RelA requires oligomerization of the C-terminal domain, J. Bacteriol., 2001, vol. 183, no. 2, pp. 570–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Durfee, T., Hansen, A., Zhi, H., Blattner, F., and Jin, D., Transcription profiling of the stringent response in Escherichia, J. Bacteriol., 2008, vol. 190, no. 3, pp. 1084–1096.

  15. Barker, M.M., Gaal, T., Josaitis, C.A., and Gourse, R.L., Mechanism of regulation of transcription initiation by ppGpp. 1. Effects of ppGpp on transcription initiation in vivo and in vitro, J. Mol. Biol., 2001, vol. 305, no. 4, pp. 673–688.

    Article  CAS  PubMed  Google Scholar 

  16. Chang, D.E., Smalley, D.J., and Conway, T., Gene expression profiling of Escherichia coli growth transitions: an expanded stringent response model, Mol. Microbiol., 2002, vol. 45, no. 2, pp. 289–306.

    Article  CAS  PubMed  Google Scholar 

  17. Lagosky, P.A. and Chang, F.N., Influence of amino acid starvation on guanosine 5'-diphosphate 3'-diphosphate basal-level synthesis in Escherichia coli, J. Bacteriol., 1980, vol. 144, no. 2, pp. 499–508.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rao, N.N., Liu, S., and Kornberg, A., Inorganic polyphosphate in Escherichia coli: the phosphate regulon and the stringent, J. Bacteriol., 1998, vol. 180, no. 5, pp. 2186–2193.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Battesti, A. and Bouveret, E., Bacteria possessing two RelA/SpoT-like proteins have evolved a specific stringent response involving the Acyl Carrier Protein–SpoT interaction, J. Bacteriol., 2009, vol. 191, no. 2, pp. 616–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, S.R., Construction of Escherichia coli K-12 strain deficient in relA and spoT using the red site-specific recombinase system, J. Exp. Microbiol. Immunol., 2012, vol. 16, pp. 90–95.

    CAS  Google Scholar 

  21. Bech, F.W., Jorgensen, S.T., Diderichsen, B., and Karlström, O.H., Sequence of the relB transcription unit from Escherichia coli and identification of the relB gene, EMBO J., 1985, vol. 4, no. 4, pp. 1059–1066.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Diderichsen, B. and Desmarez, L., Variations in phenotype of relB mutants of Escherichia coli and the effect of pus and sup mutations, Mol. Gen. Genet., 1980, vol. 180, no. 2, pp. 429–437.

    Article  CAS  PubMed  Google Scholar 

  23. Fiil, N.P., Willumsen, B.M., Friesen, J.D., and von Meyenburg, K., Interaction of alleles of the relA, relC and spoT genes in Escherichia coli: analysis of the interconversion of GTP, ppGpp and pppGpp, Mol. Gen. Genet., 1977, vol. 150, no. 1, pp. 87–101.

    CAS  PubMed  Google Scholar 

  24. Parker, J., Watson, R.J., Friesen, J.D., and Fiil, N.P., A relaxed mutant with an altered ribosomal protein L11, Mol. Gen. Genet., 1976, vol. 144, pp. 111–114.

    Article  CAS  PubMed  Google Scholar 

  25. Gallant, J., Stringent control in E. coli, Annu. Rev. Genet., 1979, vol. 13, pp. 393–415.

    Article  CAS  PubMed  Google Scholar 

  26. Gong, L., Takayama, K., and Kjelleberg, S., Role of spoT-dependent ppGpp accumulation in the survival of light-exposed starved bacteria, Microbiology, 2002, vol. 148, pp. 559–570.

    Article  CAS  PubMed  Google Scholar 

  27. Srivatsan, A. and Wang, J.D., Control of bacterial transcription, translation and replication by (p)ppGpp, Curr. Opin. Microbiol., 2008, vol. 11, no. 2, pp. 100–105.

    Article  CAS  PubMed  Google Scholar 

  28. Chatterji, D., Ogawa, Y., Shimada, T., and Ishihama, A., The role of the omega subunit of RNA polymerase in expression of the relA gene in Escherichia coli, FEMS Microbiol. Letts., 2007, vol. 267, no. 1, pp. 51–55.

    Article  CAS  Google Scholar 

  29. Roberts, J.W., Promoter-specific control of E. coli RNA polymerase by ppGpp and a general transcription factor, Genes Dev., 2009, vol. 23, no. 2, pp. 143–146.

    Article  CAS  PubMed  Google Scholar 

  30. Sun, J., Hesketh, A., and Bibb, M., Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2), J. Bacteriol., 2001, vol. 183, no. 11, pp. 3488–3498.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Saito, N., Xu, J., Hosaka, T., Okamoto, S., Aoki, H., Bibb, M., and Ochi, K., EshA accentuates ppGpp accumulation and is conditionally required for antibiotic production in Streptomyces coelicolor A3(2), J. Bacteriol., 2006, vol. 188, no. 13, pp. 4952–4961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chakraburtty, R., White, J., Takano, E., and Bibb, M., Cloning, characterization and disruption of a (p)ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2), Mol. Microbiol., 1996, vol. 19, no. 2, pp. 357–368.

    Article  CAS  PubMed  Google Scholar 

  33. Chakraburtty, R. and Bibb, M., The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation, J. Bacteriol., 1997, vol. 179, no. 18, pp. 5854–5861.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hesketh, A., Chen, J.W., Ryding, J., Chang, S., and Bibb, M., The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2), Genome Biol., 2007, vol. 8, no. 8, p. R161.

    Google Scholar 

  35. Gatewood, M.L. and Jones, G.H., (p)ppGpp inhibits polynucleotide phosphorylase from Streptomyces but not from Escherichia coli and increases the stability of bulk mRNA in Streptomyces coelicolor, J. Bacteriol., 2010, vol. 192, no. 17, pp. 4275–4280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoyt, S. and Jones, G.H., relA is required for actinomycin production in Streptomyces antibioticus, J. Bacteriol., 1999, vol. 181, no. 12, pp. 3824–3829.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gomez-Escribano, J.P., Martin, J.F., Hesketh, A., Bibb, M.J., and Liras, P., Streptomyces clavuligerus relA-null mutants overproduce clavulanic acid and cephamycin C: negative regulation of secondary metabolism by (p)ppGpp, Microbiology, 2008, vol. 154, pp. 744–755.

    Article  CAS  PubMed  Google Scholar 

  38. Jin, W., Ryu, Y., Kang, S., Kim, S., Saito, N., Ochi, K., Lee, S., and Lee, K., Two relA/spoT homologous genes are involved in the morphological and physiological differentiation of Streptomyces clavuligerus, Microbiology, 2004, vol. 150, pp. 1485–1493.

    Article  CAS  PubMed  Google Scholar 

  39. Ochi, K., Metabolic initiation of differentiation and secondary metabolism by Streptomyces griseus: significance of the stringent response (ppGpp) and GTP content in relation to a factor, J. Bacteriol., 1987, vol. 169, no. 8, pp. 3608–3616.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Klymyshin, D., Gren, T., and Fedorenko, V., Role of snorA gene in Streptomyces nogalater Lv65 biosynthesis, Microbiology, 2011, vol. 80, no. 4, pp. 496–501.

    Article  CAS  Google Scholar 

  41. Klymyshin, D., Nimets, O., Stefanyshyn, O., and Fedorenko, V., Heterologous expression of the lndYR and wblAgh genes in Streptomyces nogalater Lv65, S. echinatus DSM40730, and S. peucetius subsp. caesius atcc27952 (producers of anthracycline antibiotics), Cytol. Genet., 2013, vol. 47, no. 4, pp. 197–201.

    Google Scholar 

  42. Klimishin, D., Rabyk, M., Gren, T., Nimets, O., and Fedorenko, V., Construction of Streptomyces nogalater Lv65 strains with enhanced nogalamicin biosynthesis using regulatory genes, Appl. Biochem. Microbiol., 2011, vol. 47, no. 6, pp. 594–598.

    Article  CAS  Google Scholar 

  43. Klimishin, D., Rabyk, M., and Fedorenko, V., Methylation of nogalose during nogalomycin biosynthesis by Streptomyces nogalater Lv65, Microbiology, 2013, vol. 82, no. 2, pp. 162–168.

    Article  CAS  PubMed  Google Scholar 

  44. Klymyshyn, D.O., Gromyko, O.M., and Fedorenko, V.O., Application of intergeneric conjugation of Escherichia coli–Streptomyces for transfer of recombinant DNA into the strain S. nogalater IMET43360, Cytol. Genet., 2007, vol. 41, pp. 263–267.

    Article  Google Scholar 

  45. Klymyshin, D., Stefanyshyn, O., and Fedorenko, V., Role of genes snoaM, snoaL, and snoaE in the biosynthesis of nogalamycin in Streptomyces nogalater Lv65, Cytol. Genet., 2015, vol. 49, no. 3, pp. 152–157.

    Google Scholar 

  46. Klymyshyn, D., Gren, T., and Fedorenko, V., Cloning and investigation of snorA gene, a putative positive regulator of nogalamycin biosynthesis in Streptomyces nogalater, Visn. Lviv. Univ. Ser. Biol., 2009, vol. 50, pp. 3–10.

    Google Scholar 

  47. Klymyshin, D., Gromyko, O., Gren, T., Nymets, I., Honchar, I., and Fedorenko, V., Chemistry and biology of nogalamycins, Visn. Lviv. Univ. Ser. Biol., 2010, vol. 54, pp. 15–26.

    Google Scholar 

  48. Gren, T., Ostash, B., Hrubskyy, Y., Lopatniuk, M., and Fedorenko, V., Influence of pleiotropic regulatory genes absB, relA, afsS on siomycin production by Stroptomyces sioyaensis Lv81, Visn. Lviv. Univ. Ser. Biol., 2011, vol. 57, pp. 30–37.

    Google Scholar 

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Authors and Affiliations

  1. Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

    D. O. Klymyshin & V. O. Fedorenko

  2. Institute of Animal Biology, Lviv, Ukraine

    D. O. Klymyshin & O. M. Stephanyshyn

  3. Ivan Franko Lviv National University, Lviv, Ukraine

    D. O. Klymyshin

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  1. D. O. Klymyshin
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  2. O. M. Stephanyshyn
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  3. V. O. Fedorenko
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Correspondence to D. O. Klymyshin.

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Original Ukrainian Text © D.O. Klymyshin, O.M. Stephanyshyn, V.O. Fedorenko, 2016, published in Tsitologiya i Genetika, 2016, Vol. 50, No. 2, pp. 65–74.

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Klymyshin, D.O., Stephanyshyn, O.M. & Fedorenko, V.O. Participation of (p)ppGpp molecules in the formation of “stringent response” in bacteria, as well as in the biosynthesis of antibiotics and morphological differentiation in actinomycetes. Cytol. Genet. 50, 134–142 (2016). https://doi.org/10.3103/S0095452716020067

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