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The physiology and biosynthesis of secondary metabolites

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Abstract

Recently, several excellent reviews appeared /9, 12, 15, 29/ summarizing new findings of the last years and describing the topic in the new interconnections. The signalling systems through which changes in environmental conditions affecting the growth of microorganism are sensed, transmitted and converted into mechanisms controlling the production of antibiotic can now be investigated with the techniques of molecular genetics. Evidence has been accumulated that demonstrated the key roles played by diffusible molecules in regulating cellular differentiation even among prokaryotic microorganisms. This is exemplified by A-factor and its analogues, which act as auto-regulators for morphological differentiation and secondary metabolism in Streptomyces.

In our article we have concentrated on the physiological changes, which can occur during the growth in natural environment or during cultivation under laboratory conditions. Recent evidence for the presence of molecular signalling systems in Streptomyces is reviewed, along with the inherent implications. The constitution of the metabolic type during the first hours of cultivation has been previously reviewed /36/.

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References

  1. Arisawa, A., Kawamura, N., Tsunekawa, H., Okamura, K., Tone, H., Okamoto, R. (1993) Cloning and nucleotide sequences of two genes involved in the 4″-O-acylation of macrolide anti-biotics from Streptomyces thermotolerans. Biosci. Biotechnol. Biochem. 57, 2020–2025.

    Article  CAS  PubMed  Google Scholar 

  2. Arisawa, A., Tsunekawa, H., Okamura, K., Okamoto, R. (1995) Nucleotide sequence analysis of the carbomycin biosynthetic genes including the 3-O-acyltransferase gene from Streptomyces thermotolerans. Biosci. Biotechnol. Biochem. 59, 582–588.

    Article  CAS  PubMed  Google Scholar 

  3. Arisawa, A., Kawamura, N., Narita, T., Kojima, I., Okamura, K., Tsunekawa, H., Yoshioka, T., Okamoto, R. (1996) Direct fermentative production of acyltylosins by genetically-engineered strains of Streptomyces fradiae. J. Antibiot. 49, 349–354.

    Article  CAS  Google Scholar 

  4. Beppu, T. (1992) Secondary metabolites as chemical signals for cellular differentiation. Gene 95, 49–56.

    Google Scholar 

  5. Bíró, S., Békési, I., Vitális, S., Szabó, G. (1980) A substance affecting differentiation in Streptomyces griseus. Purification and properties. Eur. J. Biochem. 103, 359–363.

    Article  PubMed  Google Scholar 

  6. Brown, K. L., Wood, S., Buttner, M. J. (1992) Isolation and characterization of the major vegetative RNA polymerase of Streptomyces coelicolor A3(2); renaturation of a sigma subunit using GroEL. Molec. Microbiol. 6, 1133–1139.

    Article  CAS  Google Scholar 

  7. Buttner, M. J., Smith, A. M., Bibb, M. J. (1988) At least three different RNA polymerase holoenzymes direct transcription of the agarase gene (dag A) of Streptomyces coelicolor A3(2). Cell 52, 599–607.

    Article  CAS  PubMed  Google Scholar 

  8. Buttner, M. J., Lewis, C. G. (1992) Construction and characterization of Streptomyces coelicolor A3(2) mutants that are multiply deficient in the nonessential hrd-encoded RNA polymerase sigma factors. J. Bacteriol. 174, 5165–5167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Champness, W. C., Chater, K. F. (1994) Regulation and integration of antibiotic production and morphological differentiation in Streptomyces spp. In: Pigot, P. J., Morgan, C. P., Youngman, P. (eds) Regulation of Bacterial Differentiation. Washington D.C., American Society for Microbiology, pp. 61–93.

    Google Scholar 

  10. Chater, K. F., Bruton, C. J., Piaskitt, K. A., Buttner, M. J., Mendez, C., Helmann, J. (1989) The developmental fate of S. coelicolor hyphae depends upon a gene product homologous with mobility δ factor of B. subtilis. Cell 59, 133–143.

    Article  CAS  PubMed  Google Scholar 

  11. Chater, K. F. (1990) The improving prospects for the yield increase by genetic engineering in antibiotic producing streptomycetes. Bio/Technology 8, 115–121.

    CAS  Google Scholar 

  12. Chater, K. F., Bibb, M. J. (1996) Regulation of bacterial antibiotic production. In: Kleinkauf, H., von Dohren, H. (eds) Biotechnology. Volume 7: Products of Secondary Metabolusm. Weinheim: VCH (in press).

  13. Craig, E. A., Gross, C. A. (1991) Is hsp 70 the cellular thermometer? TIBS 16, 135–140.

    CAS  PubMed  Google Scholar 

  14. Donadio, S., Katz, L. (1992) Organization of the enzymic domains in the multifunctional polyketide synthase involved in erythromycin formation in Saccharopolyspora erythraea. Gene 111, 51–60.

    Article  CAS  PubMed  Google Scholar 

  15. Doul, J. L., Vining, L. C. (1995) Global physiological controls. In: Vining, L. C., Stuttard, C. (eds) Genetics and Biochemistry of Antibiotic Production. Newton, Butterworth—Heinemann, pp. 9–63.

    Chapter  Google Scholar 

  16. Dutton, C. J., Gibson, S. P., Goudie, A. C., Holdom, K. S., Pacey, M. S., Ruddock, J. C., Bu’Lock, J. D., Richards, M. K. (1991) Novel avermectins produced by mutational biosynthesis. J. Antibiot. 44, 357–365.

    Article  CAS  Google Scholar 

  17. Epp, J. K., Huber, M. L. B., Turner, J. R., Goodson, T., Schoner, B. E. (1989) Production of a hybrid macrolide antibiotic in Streptomyces ambofaciens and Streptomyces lividans by introduction of a cloned carbomycin biosynthetic gene from Streptomyces thermotolerans. Gene 85, 293–301.

    Article  CAS  PubMed  Google Scholar 

  18. Fisher, M. H., Mrozik, H. (1989) Chapter 1. Chemistry. In: Campbell, W. C. (ed.) Ivermectin and Abamectin. New York, Springer-Verlag, pp. 55–72.

    Google Scholar 

  19. Fisher, S. H., Sonenshein, A. L. (1991) Control of carbon and nitrogen metabolism in Bacillus subtilis. Annu. Rev. Microbiol. 45, 107–113.

    Article  CAS  PubMed  Google Scholar 

  20. Goegelman, R. T., Inamine, E. S., White, R. F. (1987) Avermectin bioconversion products. US Patent 4,666,937.

    Google Scholar 

  21. Gräfe, U., Schade, W., Eritt, I., Fleck, W. F. (1982) A new inducer of athracycline biosynthesis from Streptomyces griseus — the role of A-factor. J. Antibiot. 35, 1722–1723.

    Article  Google Scholar 

  22. Gräfe, U., Eritt, I., Hanel, F., Friedrich, W., Roth, M. et al. (1986) Factors governing polyketide and glycopeptide production by streptomycetes. In: Kleinkauf, H., Dohren, H., Dornauer, H., Nesemann, G. (eds) Regulation of Secondary Metabolite Formation. Weinheim, FRG, VCH Verlagsgesellschaft mbH, pp. 225–248.

    Google Scholar 

  23. Guglielmi, G., Mazodier, P., Thompson, C. J., Davies, J. (1991) A survey like genes and three GroEL-like proteins in Streptomyces albus. J. Bacteriol. 173, 7374–7381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hara, O., Beppu, T. (1982) Mutants blocked in streptomycin production in Streptomyces griseus — the role of A-factor. J. Antibiotic. 35, 349–358.

    Article  CAS  Google Scholar 

  25. Hara, O., Beppu, T. (1982) Induction of streptomycin inactivating enzyme by A-factor in Streptomyces griseus. J. Antibiotic. 35, 1208–1215.

    Article  CAS  Google Scholar 

  26. Hara, O., Horinouchi, S., Uozumi, T., Beppu, T. (1983) Genetic analysis of A-factor synthesis in Streptomyces coelicolor A3(2) and Streptomyces griseus. J. Gen. Microbiol. 129, 2939–2944.

    CAS  PubMed  Google Scholar 

  27. Hong, S.-K., Kito, M., Beppu, T., Horinouchi, S. (1991) Phosphorylation of the AfsR product, a global regulatory protein for secondary-metabolite formation in Streptomyces coelicolor A3(2). J. Bacteriol. 173, 2311–2318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hopwood, D. A., Malpartida, F., Kieser, H. M., Ikeda, H., Duncan, J., Fujii, J., Rudd, B. A., Floss, H. G., Omura, S. (1985) Production of “hybrid” antibiotics by genetic engineering. Nature 312, 642–644.

    Article  Google Scholar 

  29. Hopwood, D. A., Chater, K. F., Bibb, M. J. (1995) Genetics of antibiotic production in Streptomyces coelicolor A3(2), a model streptomycete. In: Vining, L. C., Stuttard, C. (eds) Genetics and Biochemistry of Antibiotic Production. Newton, Butterworth—Heinemann, pp. 65–102.

    Chapter  Google Scholar 

  30. Horinouchi, S., Kumada, Y., Beppu, T. (1984) Unstable genetic determinant of A-factor biosynthesis in streptomycin-producing organisms: cloning and characterization. J. Bacteriol. 158, 481–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Horinouchi, S., Nishiyama, M., Suzuki, K., Kumada, Y., Beppu, T. (1985) The cloned Streptomyces bikinensis A-factor determinant. 3. Antibiot. 38, 636–637.

    Article  CAS  Google Scholar 

  32. Horinouchi, S., Kito, M., Nishiyama, M., Furuya, K., Hong, N. (1990) Primary structure of AfsR, a global regulatory protein for secondary metabolism formation in Streptomyces coelicolor A3(2). Gene 95, 49–56.

    Article  CAS  PubMed  Google Scholar 

  33. Horinouchi, S., Umeyama, T., Onaka, H., Ueda, K., Beppu, T. (1995) Streptomyces species as boundary microorganisms: Eukaryotic regulatory system for secondary metabolism and morphological differentiation. Actinomycetol. 9, 244–253.

    Article  Google Scholar 

  34. Ikeda, H., Omura, S. (1995) Genetic aspects of the selective producer Streptomyces avermitilis. Actinomycetol. 7, 133–144.

    Article  Google Scholar 

  35. Ishihama, A. (1995) Genetic strategies of bacteria for stationary-phase survival. Actinomycetol. 9, 236–243.

    Article  Google Scholar 

  36. Janecek, J., Tichi, P., Spizek, J., Vanek, Z. (1997) Constitution of metabolic type in the first hours of streptomycetes cultivation. Folia Microbiol. 42, 75–96.

    Article  CAS  Google Scholar 

  37. Kawaguchi, T., Azuma, M., Horinouchi, S., Beppu, T. (1984) B-factor, an essential regulatory substance inducing the production of rifamycin in a Nocardia sp. J. Antibiot. 37, 1587–1595.

    Article  CAS  Google Scholar 

  38. Khokhlov, A. S., Tovarova, I. I., Borisova, L. A. (1967) A-factor responsible for the biosynthesis of streptomycin by a mutant strain of Actinomyces streptomycini. Dokl. Acad. Nauk SSSR 177, 232–235.

    CAS  Google Scholar 

  39. Khokhlov, A. S., Anisova, L. N., Tovarova, I. I. et al. (1973) Effect of A-factor on the growth of asporogeneous mutants of Streptomyces griseus, not producing this factor. Z. Allg. Mikrobiol. 13, 647–655.

    Article  CAS  PubMed  Google Scholar 

  40. Kormanec, J., Farkasovsky, M. (1993) Differential expression of principal sigma factor homologues of Streptomyces aureofaciens correlates with developmental stage. Nucleic Acids Res. 21, 3647–3652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lonetto, M., Gribskov, M., Gross, C. A. (1992) The δ70 family: sequence conservation and evolutionary relationships. J. Bacterid. 174, 3843–3849.

    Article  CAS  Google Scholar 

  42. McDaniel, R., Khosla, S. E., Hopwood, D. A., Khosla, C (1995) Rational design of aromatic polyketide natural products by recombinant assembly of enzymatic subunits. Nature 375, 549–554.

    Article  CAS  PubMed  Google Scholar 

  43. Miyake, K., Horinouchi, S., Yoshida, M., Chiba, N., Mori, K. et al. (1989) Detection and properties of A-factor-binding protein from Streptomyces griseus. 3. Bacteriol. 171, 7298–7302.

    Article  Google Scholar 

  44. Miyake, K., Kuzuyama, T., Horinouchi, S., Beppu, T. (1990) The A-factor-binding protein of Streptomyces griseus negatively controls streptomycin production and sporulation. J. Bacteriol. 172, 3003–3008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Novak, J., Kopecky, J., Vanek, Y. (1992) Sporulation-inducing factor in Streptomyces avermitilis. Folia Microbiol. 37, 463–465.

    Article  CAS  Google Scholar 

  46. Ohkishi, H., Iyasaka, K., Horisaka, T., Chou, H., Watanabe, Y. (1988) Strain improvement of a nosiheptide producer, Streptomyces actuosus 40037. In: Fujiwara, A. (ed.) Proc. 3rd Franco-3apanese Symp. The Impact of Genetics on Industrial Microorganisms. Tokyo, Sansei, pp. 47–49.

    Google Scholar 

  47. Omura, S., Ikeda, H., Malpartida, F., Kieser, H. M., Hopwood, D. A. (1986) Production of new hybrid antibiotics, mederrhodins A and B, by a genetically engineered strain. Antimicrob. Agents Chemother. 29, 13–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pospisil, S., Sedmera, P., Havranek, M., Krumphanzl, V., Vanek, Z. (1983) Biosynthesis of monensin A and B. J. Antibiot. 36, 617–619.

    Article  CAS  Google Scholar 

  49. Potuckova, L., Kelemen, G. H., Findlay, K. C., Lonetto, M. A., Buttner, M. J., Kormanec, J. (1995) A new RNA polymerase sigma factor, δF, is required for the late stages of morphological differentiation in Streptomyces spp. Molec. Microbiol. 17, 37–48.

    Article  CAS  Google Scholar 

  50. Puglia, A. M., Vohradsky, J., Thompson, C. J. (1995) Developmental control of the heat-shock stress regulation in Streptomyces coelicolor. Mol. Microbiol. 17, 737–746.

    Article  CAS  PubMed  Google Scholar 

  51. Queener, S. W., Hodges, R. L., Fisher, D. L., Dotzlaf, J. E., Yeh, W. K., McGilvray, D., Greaney, M., Rosteck, P. (1994) Improved expression of a hybrid Streptomyces clavuligerus cefE gene in Penicillium chrysogenum. Ann. N. Y. Acad. Sci. 721, 178–193.

    Article  CAS  PubMed  Google Scholar 

  52. Sato, K., Nihira, Y., Sakuda, S., Yanagimoto, M., Yamada, Y. (1989) Isolation and structure of a new butyrolactone autoregulator from Streptomyces sp. FRI-%. J. Ferment. Bioeng. 68, 170–173.

    Article  CAS  Google Scholar 

  53. Schellhorn, H. E., Stones, V. L. (1992) Regulation of kat F and kat F in Escherichia coli K-12 by weak acids. J. Bacteriol. 174, 4769–4776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Servant, P., Mazodier, P. (1995) Characterization of Streptomyces albus 18-kiladalton heat-shock-responsive protein. J. Bacteriol. 177, 2998–3003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Szabó, G., Békési, J., Vitális, S. (1967) Mode of action of factor C, a substance of regulatory function in cyto-differentiation. Biochim. Biophys. Acta 145, 159–165.

    Article  PubMed  Google Scholar 

  56. Szabó, G., Szeszák, F., Vitális, S., Tóth, F. (1988) New data on the formation and mode of action of factor C. In: Okami, Y., Beppu, T., Ogawara, H. (eds) Biology of Actinomycetes’ 88. Tokyo, Jpn. Sci. Soc. Press, pp. 324–329.

    Google Scholar 

  57. Tanaka, K., Shiina, T., Takahashi, H. (1988) Multiple principal sigma factor homologs in eubacteria. Identification of the “rpo D box”. Science 242, 1040–1042.

    Article  CAS  PubMed  Google Scholar 

  58. Westpheling, J., Ranes, M., Losick, R. (1985) RNA polymerase heterogenity in Streptomyces coelicolor. Nature 313, 22–27.

    Article  CAS  PubMed  Google Scholar 

  59. Yamada, Y., Sugamura, K., Kondo, K., Yanagimoto, M., Okada, H. (1987) The structure of inducing factors for virgiamycin production in Streptomyces virginiae. J. Antibiotic. 40, 496–504.

    Article  CAS  Google Scholar 

  60. Yamagimoto, M., Yamada, Y., Terui, G. (1979) Extraction and purification of inducing material produced in staphylomycin fermentation. Hakko Kogaku Kaishi 57, 6–14.

    Google Scholar 

  61. Yura, T., Nagai, H., Mori, H. (1993) Regulation of the heat-shock response in bacteria. Annu. Rev. Microbiol. 47, 321–350.

    Article  CAS  PubMed  Google Scholar 

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  1. Institute of Microbiology, Czech Academy of Sciences, Videnská 1083, 14120, Prague, Czech Republic

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Dedicated to the memory of Professor Gábor Szabó.

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Vanek, Z., Janecek, J. The physiology and biosynthesis of secondary metabolites. BIOLOGIA FUTURA 48, 339–358 (1997). https://doi.org/10.1007/BF03543205

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