Cloning of Genes in Streptomycetes for Secondary Metabolism

  • Teruhiko Beppu
  • Sueharu Horinouchi
Part of the NATO ASI Series book series (NSSA, volume 128)


Streptomycetes are Gram-positive bacteria with an extremely high guanine plus cystosine content (70 to 73%). Their capability to produce the great majority of secondary metabolites including most of the antibiotics makes them industrially important. A complex process of morphological differentiation displayed by Streptomyces also has biologically interesting aspects. A close relationship of secondary metabolism with cell differentiation is well recognized in streptomycetes. It seems reasonable to assume that multiple genes involved in both the complex processes are controlled by a common regulatory gene or substance.

A representative of such regulatory substances is A-factor (2-isocaρryloyl-3R-hydroxymethyl-γ-butyrolactone; Mori, 1983) which was originally found by Khokhlov et al. (1967) in the culture broth of Streptomyces griseus (Figure 1). A-factor is a self-regulatory substance or bioregulator essential for streptomycin production, streptomycin resistance, and spore formation in this organism (Khokhlov et al., 1973; Khoklov, 1980; Hara and Beppu, 1982a, 1982b). A-factor-deficient mutants of S. griseus simultaneously lose streptomycin production and resistance, and spore forming ability. In such mutants, addition of A-factor at a concentration of 10-9 M restores all the defects. These features of A-factor are similar to hormones in eukaryotes.

Recent development of host-vector systems for streptomycetes has enabled us to clone various genes involved in secondary metabolism. In order to clarify the genetic background of the A-factor regulatory system, we have cloned and characterized an A-factor determinant as well as a streptomycin synthesizing gene as a possible target of the A-factor function
Fig. 1

Chemical structure of A-factor

from streptomycin-producing Streptomyces bikiniensis. In the course of the experiments, we also found that a regulatory gene, afsB, positively controlling biosynthesis of A-factor in Streptomyces coelicolor A3(2) simultaneously regulated biosynthesis of pigmented antibiotics actinorhodin and undecylprodigiosin in this organism as well as in Streptomyces lividans. We will describe below cloning and characterization of these genes involved in secondary metabolism.


Secondary Metabolism Pigment Production Streptomyces Strain Streptomyces Griseus Streptomycin Resistance 
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  1. Aguilar, A. and Hopwood, D.A., 1982, J. Gen. Microbiol., 128:1893–1901.PubMedGoogle Scholar
  2. Bibb, M.J., Chater, K.F. and Hopwood, D.A., 1983, in: “Experimental manipulation of gene expression”, M. Inouye, ed., Academic Press,New York, pp 53–82.Google Scholar
  3. Bibb, M.J. and Cohen, S.N., 1982, Mol. Gen. Genet., 187:265–277.PubMedCrossRefGoogle Scholar
  4. Gold, L., Pribnow, D., Schneider, T., Shinedling, S., Singer, B.S. and Stormo, G., 1981, Annu. Rev. Microbiol., 35:365–403.PubMedCrossRefGoogle Scholar
  5. Hara, O. and Beppu, T., 1982a, J. Antibiot., 35:349–358.PubMedGoogle Scholar
  6. Hara, O. and Beppu, T., 1982b, J. Antibiot., 35:1208–1215.PubMedGoogle Scholar
  7. Hara, O., Horinouchi, S., Uozumi, T. and Beppu, T., 1983, J. Gen. Microbiol., 129:2939–2944.PubMedGoogle Scholar
  8. Hopwood, D.A. and Wright, U.M., 1983, J. Gen. Microbiol, 129:3573–3579.Google Scholar
  9. Horinouchi, S. and Beppu, T., 1984, Agric. Biol. Chem., 48:2131–2133.CrossRefGoogle Scholar
  10. Horinouchi, S. and Beppu, T., 1985, J. Bacteriol., in press.Google Scholar
  11. Horinouchi, S., Hara, O. and Beppu, T., 1983, J. Bacteriol., 155:1238–1248.PubMedGoogle Scholar
  12. Horinouchi, S., Kumada, U. and Beppu, T., 1984, J. Bacteriol., 158:481–487.PubMedGoogle Scholar
  13. Horinouchi, S., Nishiyama, M., Suzuki, H., Kumada, Y. and Beppu, T., 1985, J. Antibiot., in press.Google Scholar
  14. Horinouchi, S., Suzuki, H. and Beppu, T., 1985, submitted for publication.Google Scholar
  15. Khokhlov, A.S., 1980, in: “Frontiers of Bioorganic Chemistry and Molecular Biology”, S.N. Ananchenko, ed., Pergamon Press, Oxford and New York, pp 201–210.Google Scholar
  16. Khokhlov, A.S., Anisova, L.N., Tovarova, I.I., Kleiner, F.M., Kovalenko, I.V., Krasilnikova, O.I., Konitskaya, E.Ya. and Pliner, S.A., 1973, Z. Allg. Mikrobiol., 13:647–655.PubMedCrossRefGoogle Scholar
  17. Khokhlov, A.S., Tovarova, I.I., Borisova, L.N., Pliner, S.A., Shevchenko, L.A., Kornitskaya, E.Ya., Ivkina, N.S. and Rapport, I.A., 1967, Doklady AN SSSR, 177:232–235.Google Scholar
  18. Kirby, R. and Hopwood, D.A., 1977, J. Gen. Microbiol., 98:239–252.PubMedGoogle Scholar
  19. Lakey, J.H., Lea, E.J.A., Rudd, B.A.M., Wright, H.M. and Hopwood, D.A., 1983, J. Gen. Microbiol., 129:3565–3573.PubMedGoogle Scholar
  20. Mori, K., 1983, Tetrahedron, 39:3107–3109.CrossRefGoogle Scholar
  21. Rosenberg, M., Nd Court, D., 1979, Annu. Rev. Genet., 13:319–353.PubMedCrossRefGoogle Scholar
  22. Rudd, B.A.M. and Hopwood, D.A., 1979, J. Gen. Microbiol., 114:35–43.PubMedGoogle Scholar
  23. Rudd, B.A.M. and Hopwood, D.A., 1980, J. Gen. Microbiol., 119:333–340.PubMedGoogle Scholar
  24. Shine, J. and Dalgarno, L., 1974, Proc. Natl. Acad. Sci. USA, 71:1342–1346.PubMedCrossRefGoogle Scholar
  25. Thompson, C.J. and Gray, G.S., 1983, Proc. Natl. Acad. Sci. USA, 80:5190– 5194.PubMedCrossRefGoogle Scholar
  26. Westpheling, J., Ranes, M. and Losick, R., 1985, Nature, 313:22–25.PubMedCrossRefGoogle Scholar
  27. Wright, L.F. and Hopwood, D.A., 1976, J. Gen. Microbiol., 95:96–106.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Teruhiko Beppu
    • 1
  • Sueharu Horinouchi
    • 1
  1. 1.Department of Agricultural ChemistryThe University of TokyoBunkyo-ku, Tokyo 113Japan

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