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Genetics of Penicillin Biosynthesis in Aspergillus Nidulans

  • G. Turner
Part of the Federation of European Microbiological Societies Symposium Series book series (FEMS, volume 69)

Abstract

Ever since the development of penicillin as an antibiotic in the 1940s, there has been an interest in understanding the chemistry, biochemistry and genetics of the biosynthesis of penicillin and other β-lactam antibiotics. Of course, the main interest was with Penicillium chrysogenum and Acremonium chrysogenum (formerly named Cephalosporiwn acremoniwn), which have always been the commercial sources of these antibiotics, but in the late 1940s, screening of a wide range of fungi for new antibiotics led to the detection of penicillin production by Aspergillus nidulans (Dulaney, 1947). Although this has never been of any commercial significance, the development of A. nidulans as a model organism for genetic studies (Pontecorvo et al., 1953) led to its occasional use in projects to investigate the genetics of penicillin production (Ball, 1983).

Keywords

Aspergillus Nidulans Penicillium Chrysogenum Carbon Catabolite Repression Synthetase Gene Penicillin Production 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bailey, C. and Arst, H.N Jr. (1975) Carbon catabolite repression in Aspergillus nidulans. Eur. J.Biochem. 51, 573–577.PubMedCrossRefGoogle Scholar
  2. Ball, C. (1983) Genetics of β-lactam-producing fungi, in “Antibiotics Containing the Beta-Lactam Structure I” Demain, A.L. and Solomon, N.A., Eds.), pp. 147–162. Springer-Verlag, BerlinGoogle Scholar
  3. Bailance, D.J., Buxton, F.P. and Turner, G. (1983) Transformation of Aspergillus nidulans by the orotidine-5’-phosphate decarboxylase gene of Neurospora crassa. Biochem.Biophys.Res.Commun. 112, 284–289.CrossRefGoogle Scholar
  4. Barredo, J.L., Van Solingen, P., Diez, B., Alvarez, E., Cantoral, J.M., Kattevilder, A., Smaal, E.B., Groenen, M.A.M., Veenstra, A.E. and Martin, J.F. (1989) Cloning and characterization of the acyl-coenzyme A:6-aminopenicillanic acid-acyltransferase gene of Penicillium chrysogenum. Gene 83, 291–300.PubMedCrossRefGoogle Scholar
  5. Benz, F., Knusel, F., Nuesch, J., Treichler, H., Voser, W., Nyfeler, R. and Keller-Schlierlein, W. (1974) Stoffwechselprodukte von Mikroorganismen. Echinocandin B, ein neuartiges polypeptid-antibioticum aus Aspergillus nidulans var. echinulatus: Isolierung und Bausteine. Helv. Chim. Acta . 57, 2459–2477.CrossRefGoogle Scholar
  6. Brakhage, A.A., Browne, P. and Turner, G. (1992a) Regulation of Aspergillus nidulans pencillin biosynthesis and penicillin biosynthesis genes acvA and ipnA by glucose. J. Bacteriol. 174, 3789–3799.PubMedGoogle Scholar
  7. Brakhage, A.A. and Turner, G. (1992b) L-Lysine repression of penicillin biosynthesis and the expression of penicillin biosynthesis genes acvA and ipnA in Aspergillus nidulans. FEMS Microbiol. Lett. 98, 123–128.Google Scholar
  8. Brakhage, A.A. (1993) Identification of trans-acting mutations affecting the regulation of the expression of Aspergillus nidulans penicillin biosynthetic genes. Seventeenth Fungal Genetics Conference, Asilomar. Poster abstract.Google Scholar
  9. Burnham, M.K.R., Earl, A.J., Bull, J.H., Smith, D.J. and Turner, G. (1989) DNA encoding ACV synthetase. European Patent Application 88311655.0.Google Scholar
  10. Carr, L.G., Skatrud, P.L., Scheetz, M.E., Queener, S.W. and Ingolia, T.D. (1986) Cloning and expression of the isopenicillin N synthetase gene from Penicillium chrysogenum. Gene 48, 257–266.PubMedCrossRefGoogle Scholar
  11. Clutterbuck, A.J. (1973) Gene symbols in Aspergillus nidulans. Genet. Res. 21, 291–296.PubMedCrossRefGoogle Scholar
  12. Cohen, G., Shiffman, D., Mevarech, M. and Aharonowitz, Y. (1990) Microbial isopenicillin N synthase genes: Structure, function, diversity and evolution. TIBTECH 8, 105–111.CrossRefGoogle Scholar
  13. Cole, D.S., Holt, G. and Macdonald, K.D. (1976) Relationship of the genetic determination of impaired penicillin production in naturally occurring strains to that in induced mutants of Aspergillus nidulans. J. gen. Microbiol. 96, 423–426.PubMedCrossRefGoogle Scholar
  14. Connerton, I.F., Fincham, J.R.S., Sandeman, R.A. and Hynes, M.J. (1990) Comparison and cross-species expression of the acetyl-CoA synthetase genes of the ascomycete fungi, Aspergillus nidulans and Neurospora crassa. Mol. Microbiol. 4, 451–460.PubMedCrossRefGoogle Scholar
  15. Demain, A.L. and Masurekar, P. (1974) Lysine inhibition of in vivo homocitrate synthesis in Penicillium chrysogenum. J. gen. Microbiol. 82, 143–148.PubMedCrossRefGoogle Scholar
  16. Diez, B., Gutierrez, S., Barredo, J.L., Van Solingen, P., Van der Voort, L.H.M. and Martin, J.F. (1990) The cluster of penicillin biosynthetic genes:identification and characterization of the pcbAB gene encoding α-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J.Biol.Chem. 265, 16358–16365.PubMedGoogle Scholar
  17. Ditchburn, P., Holt, G. and Macdonald, K.D. (1976) The genetic location of mutations increasing pencillin yield in Aspergillus nidulans, in Second International Symposium on the Genetics of Industrial Microorganisms (Macdonald, K.D., Ed.), pp. 213. Academic Press, London.Google Scholar
  18. Dowzer, C.E.A. and Kelly, J.M. (1989) Cloning of the creA gene from Aspergillus nidulans: a gene involved in carbon catabolite repression. Curr.Genet. 15, 457–459.PubMedCrossRefGoogle Scholar
  19. Dulaney, E.L. (1947) Some aspects of penicillin production by Aspergillus nidulans. Mycologia 39, 570–582.PubMedCrossRefGoogle Scholar
  20. Edwards, G.F.S.T.L., Holt, G. and Macdonald, K.D. (1974) Mutants of Aspergillus nidulans impaired in penicillin biosynthesis. J. gen. Microbiol. 84, 420–422.PubMedCrossRefGoogle Scholar
  21. Espeso, E.A. and Penalva, M.A. (1992) Carbon catabolite repression can account for the temporal pattern of expression of a penicillin biosynthetic gene in Aspergillus nidulans. Mol. Microbiol. 6, 1457–1465.PubMedCrossRefGoogle Scholar
  22. Foster, J.W. and Karow, E.O. (1945) Microbial aspects of penicillin VIII. Penicillin from different fungi. J. Bacteriol. 49, 19.PubMedGoogle Scholar
  23. Guthrie, E.P. and Chater, K.F. (1990) The level of a transcript required for production of a Streptomyces coelicolor antibiotic is conditionally dependent on a tRNA gene. J.Bacteriol. 172, 6189–6193.PubMedGoogle Scholar
  24. Holt, G. and Macdonald, K.D. (1968) Isolation of strains with increased penicillin yield after hybridization in Aspergillus nidulans. Nature 219, 636–637.PubMedCrossRefGoogle Scholar
  25. Holt, G., Edwards, G.F.S.T.L. and Macdonald, K.D. (1976) The genetics of mutants impaired in the biosynthesis of penicillin, in “Second International Symposium on the Genetics of Industrial Microorganisms” (MacDonäld, K.D., Ed.), pp. 199–211. Academic Press, London.Google Scholar
  26. Honlinger, C. and Kubicek, C.P. (1989) Regulation of δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine and isopenicillin N biosynthesis in Penicillium chrysogenum by the α-aminoadipate pool size. FEMS Microbiol. Lett. 65, 71–76.CrossRefGoogle Scholar
  27. Hynes, M.J. and Kelly, J.M. (1977) Pleiotropic mutants of Aspergillus nidulans altered in carbon metabolism. Mol.Gen.Genet. 150, 193–204.PubMedCrossRefGoogle Scholar
  28. Keller, N.P. and Adams, T.H. (1993) Isolation of an Aspergillus gene, verA, encoding a putative reductase activity in the sterigmatocystin/aflatoxin biosynthetic pathway. Seventeenth Fungal Genetics Conference, Asiloma Poster abstract.Google Scholar
  29. Kelly, J.M. and Hynes, M.J. (1977) Increased and decreased sensitivity to carbon catabolite repression of enzymes of acetate metabolism in mutants of Aspergillus nidulans. Molec. gen. Genet. 156, 87–92.PubMedCrossRefGoogle Scholar
  30. Kulmburg, P., Mathieu, M., Dowzer, C., Kelly, J. and Felenbok, B. (1993) Specific binding sites in the alcR and alcA promoters of the ethanol regulon for the CREA repressor mediating carbon catabolite repression in Aspergillus nidulans. Mol.Microbiol. 7, 847–857.PubMedCrossRefGoogle Scholar
  31. Landan, G., Cohen, G., Aharonowitz, Y., Shuali, Y., Graur, D. and Shiffman, D. (1990) Evolution of isopenicillin N synthase genes may have involved horizontal gene transfer. Mol.Biol.Evol. 7, 399–406.PubMedGoogle Scholar
  32. Lipmann, F. (1971) Attempts to map a process evolution of peptide biosynthesis. Science 173, 875–884.PubMedCrossRefGoogle Scholar
  33. Luengo, J.M., Revilla, G., Lopez-Nieto, M.J., Villanueva, J.R. and Martin, J.F. (1980) Inhibition and repression of homocitrate synthetase by lysine in Penicillium chrysogenum. J. Bacteriol. 144, 869–876.PubMedGoogle Scholar
  34. MacCabe, A.P., Riach, M.B.R., Unkles, S.E. and Kinghorn, J.R. (1990) The Aspergillus nidulans npeA locus consists of three contiguous genes required for penicillin biosynthesis. EMBO J. 9, 279–287.PubMedGoogle Scholar
  35. MacCabe, A.P., Van Liempt, H., Palissa, H., Unkles, S.E., Riach, M.B.R., Pfeifer, E., Von Doehren, H. and Kinghorn, J.R. (1991) δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine synthetase from Aspergillus nidulans Molecular characterization of the acvA gene encoding the first enzyme of the penicillin biosynthetic pathway. J. Biol. Chem. 266, 12646–12654.PubMedGoogle Scholar
  36. Makins, J.F., Holt, G. and Macdonald, K.D. (1983) The genetic location of three mutations impairing penicillin production in Aspergillus nidulans. J. gen. Microbiol. 129, 3027–3033.PubMedGoogle Scholar
  37. Malpartida, F. and Hopwood, D.A. (1984) Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature 309, 462–464.PubMedCrossRefGoogle Scholar
  38. Marahiel, M.A., Zuber, P., Czekay, G. and Losick, R. (1987) Identification of the promoter for a peptide antibiotic biosynthesis gene from Bacillus brevis and its regulation in Bacillus subtilis. J. Bacteriol. 169, 2215–2222.PubMedGoogle Scholar
  39. Martin, J.F. and Aharonowitz, Y. (1983) Regulation of biosynthesis of β-lactam antibiotics, in “Antibiotics Containing the Beta-Lactam structure I” (Demain, A.L. and Solomon, N.A., Eds.), pp. 229–254. Springer Verlag, Berlin.Google Scholar
  40. Martin, J.F. and Demain, A.L. (1980) Control of antibiotic biosynthesis. Microbiol.Rev. 44, 230–251.PubMedGoogle Scholar
  41. Martinez-Bianco, H., Reglero, A., Fernandez-Valverde, M., Ferrero, M.A., Moreno, M.A., Penalva, M.A. and Luengo, J.M. (1992) Isolation and characterization of the acetyl-CoA synthetase from Penicillium chrysogenum involvement of this enzyme in the biosynthesis of penicillins. J. Biol. Chem. 267, 5474–5481.Google Scholar
  42. Merrick, M.J. and Caten, C.E. (1975) The inheritance of penicillin titre in wild-type isolates of Aspergillus nidulans. J. gen. Microbiol. 86, 283–293.PubMedCrossRefGoogle Scholar
  43. Montenegro, E., Barredo, J.L., Gutierrez, S., Diez, B., Alvarez, E. and Martin, J.F. (1990) Cloning, characterization of the acyl-CoA:6-amino penicillanic acid acyltransferase gene of Aspergillus nidulans and linkage to the isopenicillin N synthase gene. Mol. Gen. Genet. 221, 322–330.PubMedCrossRefGoogle Scholar
  44. Penalva, M.A., Moya, A., Dopazo, J. and Ramon, D. (1990) Sequences of isopenicillin N synthetase genes suggest horizontal gene transfer from prokaryotes to eukaryotes. Proc. R. Soc. Lond. B 241, 164–169.CrossRefGoogle Scholar
  45. Pontecorvo, G., Roper, J.A., Hemmons, L.M., Macdonald, K.D. and Butron, A.W.J. (1953) The genetics of Aspergillus nidulans. Adv. Genet. 5, 141–238.PubMedCrossRefGoogle Scholar
  46. Ramon, D., Carramolino, L., Patino, C., Sanchez, F. and Penalva, M.A. (1987) Cloning and characterization of the isopenicillin N synthetase gene mediating the formation of the betalactam ring in Aspergillus nidulans. Gene 57, 171–181.PubMedCrossRefGoogle Scholar
  47. Samson, S.M., Belagaje, R., Blankenship, D.T., Chapman, J.L., Perry, D., Skatrud, P.L., Van Frank, R.M., Abraham, E.P., Baldwin, J.E., Queener, S.W. and Ingolia, T.D. (1985) Isolation, sequence determination and expression in Escherichia coli of the isopenicillin N synthetase gene from Cephalosporium acremonium. Nature 318, 191–194.PubMedCrossRefGoogle Scholar
  48. Shah, A.J., Tilburn, J., Adlard, M.W. and Arst, H.N., Jr. (1991) pH regulation of penicillin production in Aspergillus nidulans. FEMS Microbiol.Lett. 77, 209–212.CrossRefGoogle Scholar
  49. Simpson, I. and Caten, C.E. (1979) Induced quantitative variation for penicillin titre in clonal populations of Aspergillus nidulans. J. gen. Microbiol. 110, 1–12.PubMedCrossRefGoogle Scholar
  50. Simpson, I.N. and Caten, C.E. (1979) Recurrent mutation and selection for increased penicillin titre in Aspergillus nidulans. J. gen. Microbiol. 113, 209–217.PubMedCrossRefGoogle Scholar
  51. Smith, D.J., Burnham, M.K.R., Edwards, J., Earl, A.J. and Turner, G. (1990a) Cloning and heterologous expression of the penicillin biosynthetic gene cluster from Penicillium chrysogenum. Bio/Technology 8, 39–41.PubMedCrossRefGoogle Scholar
  52. Smith, D.J., Burnham, M.K.R., Bull, J.H., Hodgson, J.E., Ward, J.M., Browne, P., Brown, J., Barton, B., Earl, A.J. and Turner, G. (1990b) β-Lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes. EMBO J. 9, 741–747.PubMedGoogle Scholar
  53. Smith, D.J., Earl, A.J. and Turner, G. (1990c) The multifunctional peptide synthetase performing the first step of penicillin biosynthesis in Penicillium chrysogenum is a 421,073 dalton protein homologous to Bacillus brevis peptide synthetases. EMBO J. 9, 2743–2750.PubMedGoogle Scholar
  54. Somerson, N.L., Demain, A.L. and Nunheimer, T.D. (1961) Reversal of lysine inhibition of penicillin production by α-aminoadipic acid or adipic acid. Arch.Biochem.Biophys. 93, 238–241.CrossRefGoogle Scholar
  55. Tilburn, J., Scazzocchio, C., Taylor, G.G., Zabicky-Zissman, J.H., Lockington, R.A. and Davies, R.W. (1983) Transformation by integration in Aspergillus nidulans. Gene 26, 205–221.PubMedCrossRefGoogle Scholar
  56. Turgay, K., Krause, M. and Marahiel, M.A. (1992) Four homologous domains in the primary structure of GrsB are related to domains in a superfamily of adenylate-forming enzymes. Mol. Microbiol. 6, 529–546.PubMedCrossRefGoogle Scholar
  57. Van Liempt, H., Von Döhren, H. and Kleinkauf, H. (1989) δ-(L-aminoadipyl)-L-cysteinyl-D-valine synthetase from Aspergillus nidulans. The first enzyme in penicillin biosynthesis is a multifunctional peptide synthetase J. Biol.Chem. 264, 3680–3684.PubMedGoogle Scholar
  58. Weigel, B.J., Burgett, S.G., Chen, V.J., Skatrud, P.L., Frolik, C.A., Queener, S.W. and Ingolia, T.D. (1988) Cloning and expression in Escherichia coli of isopenicillin N synthetase genes from Streptomyces lipmanii and Aspergillus nidulans. J. Bacteriol. 170, 3817–3826.PubMedGoogle Scholar
  59. Xuei, X. and Skatrud, P. (1993) Electrophoretic molecular karyotypes of echinocandin B-producing strains of Aspergillus nidulans. Seventeenth Fungal Genetics Conference, Asilomar. Poster abstract.Google Scholar
  60. Yelton, M.M., Hamer, J.E. and Timberlake, W.E. (1984) Transformation of Aspergillus nidulans by using a trpC plasmid. Proc. Natl. Acad. Sci. USA 81, 1470–1474.PubMedCrossRefGoogle Scholar
  61. Zhang, J. and Demain, A.L. (1992) ACV synthetase. Critical Reviews in Biotechnology 12, 245–260.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • G. Turner
    • 1
  1. 1.Department of Molecular Biology and Biotechnology, Krebs Institute for Biomolecular ResearchUniversity of SheffieldSheffieldUK

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