Antonie van Leeuwenhoek

, Volume 65, Issue 3, pp 227–243 | Cite as

Expression of genes and processing of enzymes for the biosynthesis of penicillins and cephalosporins

  • Juan F. Martín
  • Santiago Gutiérrez
  • Francisco J. Fernández
  • Javier Velasco
  • Francisco Fierro
  • Ana T. Marcos
  • Katarina Kosalkova


The genespcbAB,pcbC andpenDE encoding the enzymes (α-aminoadipyl-cysteinyl-valine synthetase, isopenicillin N synthase and isopenicillin N acyltransferase, respectively) involved in the biosynthesis of penicillin have been cloned fromPenicillium chrysogenum andAspergillus nidulans. They are clustered in chromosome I (10.4 Mb) ofP. chrysogenum, in chromosome II ofPenicillium notatum (9.6 Mb) and in chromosome VI (3.0 Mb) ofA. nidulans. Each gene is expressed as a single transcript from separate promoters. Enzyme regulation studies and gene expression analysis have provided useful information to understand the control of genes involved in penicillin biosynthesis. The enzyme isopenicillin N acyltransferase encoded by thepenDE gene is synthesized as a 40 kDa protein that is (self)processed into two subunits of 29 and 11 kDa. Both subunits appear to be required for acyl-CoA 6-APA acyltransferase activity. The isopenicillin N acyltransferase was shown to be located in microbodies, whereas the isopenicillin N synthase has been reported to be present in vesicles of the Golgi body and in the cell wall. A mutant in the carboxyl-terminal region of the isopenicillin N acyltransferase lacking the three final amino acids of the enzymes was not properly located in the microbodies and failed to synthesize penicillin in vivo. InC. acremonium the genes involved in cephalosporin biosynthesis are separated in at least two clusters. Cluster I (pcbAB-pcbC) encodes the first two enzymes (α-aminoadipyl-cysteinyl valine synthetase and isopenicillin N synthase) of the cephalosporin pathway which are very similar to those involved in penicillin biosynthesis. Cluster II (cefEF-cefG), encodes the last three enzymatic activities (deacetoxycephalosporin C synthetase/hydroxylase and deacetylcephalosporin C acetyltransferase) of the cephalosporin pathway. It is unknown, at this time, if thecefD gene encoding isopenicillin epimerase is linked to any of these two clusters. Methionine stimulates cephalosporin biosynthesis in cultures of three different strains ofA. chrysogenum. Methionine increases the levels of enzymes (isopenicillin N synthase and deacetylcephalosporin C acetyltransferase) expressed from genes (pcbC andcefG respectively) which are separated in the two different clusters of cephalosporin biosynthesis genes. This result suggests that both clusters of genes have regulatory elements which are activated by methionine. Methionine-supplemented cells showed higher levels of transcripts of thepcbAB,pcbC,cefEF genes and to a lesser extent ofcefG than cells grown in absence of methionine. The levels of thecefG transcript were very low as compared to those ofpcbAB,pcbC andcefEF. The induction by methionine of transcription of the four cephalosporin biosynthesis genes and the known effect of this amino acid on differentiation ofA. chrysogenum indicates that methionine exerts a pleiotropic effect that regulates coordinately cephalosporin biosynthesis and differentiation.

Key words

Penicillin and cephalosporin biosynthesis pcbAB genes pcbC genes penDE genes cefEF genes cefG genes transcription analysis protein processing regulation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aharonowitz Y, Bergmeyer J, Cantoral JM, Cohen G, Demain AL, Fink U, Kinghorn J, Kleinkauf H, MacCabe A, Palissa H, Pfeifer E, Schwecke T, Van Liempt H, von Döhren H, Wolfe S & Zhang J (1993) δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine synthetase, the multienzyme integrating the four primary reactions in β-lactam biosynthesis, as a model peptide synthetase. Biotechnol. 11: 807–810Google Scholar
  2. Alvarez E, Cantoral JM, Barredo JL, Díez B & Martín JF (1987) Purification to homegeneity and characterization of acyl coenzyme A:6-aminopenicillanic acid acyltransferase ofP. chrysogenum. Antimicrob. Agents Chemother. 31: 1675–1682PubMedGoogle Scholar
  3. Alvarez E, Meesschaert B, Montenegro E, Gutiérrez S, Díez B, Barredo JL & Martín JF (1993) The isopenicillin N acyltransferase ofP. chrysogenum has isopenicillin N amidohydrolase, 6-aminopenicillanic acid acyltransferase and penicillin amidase activities, all of which are encoded by the singlepenDE gene. Eur. J. Biochem. 215: 323–332PubMedGoogle Scholar
  4. Aplin RT, Baldwin JE, Cole SCJ, Sutherland JD & Tobin MB (1993) On the production of α,β-hetrodimeric acyl-coenzyme A:isopenicillin N acyltransferase ofPenicillium chrysogenum: Studies using a recombinant source. FEBS Lett. 319: 166–170PubMedGoogle Scholar
  5. Baker RE & Masison DC (1990) Isolation of the gene encoding theSaccharomyces cerevisiae centromere-binding protein CP1. Mol. Cell Biol. 10: 2458–2467PubMedGoogle Scholar
  6. Baldwin JE, Keeping JW, Singh PD & Vallejo CA (1981) Cell-free conversion of isopenicillin N into deacetoxycephalosporin C byCephalosporium acremonium mutant M-0198. Biochem. J. 194: 649–651PubMedGoogle Scholar
  7. Baldwin JE, Bird JW, Field RA, O'Callaghan NM & Schofield CJ (1990) Isolation and partial characterisation of ACV synthetase fromCephalosporium acremonium andStreptomyces clavuligerus. J. Antibiot. 43: 1055–1057PubMedGoogle Scholar
  8. Ballance DJ (1986) Sequences important for gene expression in filamentous fungi. Yeast 2: 229–236PubMedGoogle Scholar
  9. Barredo JL, Cantoral JM, Alvarez E, Díez B & Martín JF (1989a) Cloning, sequence analysis and transcriptional study of the isopenicillin N synthase ofPenicillium chrysogenum AS-P-78. Mol. Gen. Genet. 216: 91–98PubMedGoogle Scholar
  10. Barredo JL, Van Solingen P, Díez B, Alvarez E, Cantoral JM, Kattevilder A, Smaal EB, Groenen MAM, Veenstra AE & Martín JF (1989b) Cloning and characterization of acyl-CoA:6-APA acyltransferase gene ofPenicillium chrysogenum. Gene 83: 291–300PubMedGoogle Scholar
  11. Cai M & Davis RW (1990) Yeast centromere binding protein CBF1, of the helix-loop-loop protein family, is required for chromosome stability and methionine prototrophy. Cell 61: 437–446PubMedGoogle Scholar
  12. Cantoral JM, Gutiérrez S, Fierro F, Gil-Espinosa S, Van Liempt H & Martín JF (1993) Biochemical characterization and molecular genetics of nine mutants ofPenicillium chrysogenum impaired in penicillin biosynthesis. J. Biol. Chem. 268: 737–744PubMedGoogle Scholar
  13. Carr LG, Skatrud PL, Scheetz ME, Queener SW & Ingolia TD (1986) Cloning and expression of isopenicillin N synthetase gene fromPenicillium chrysogenum. Gene 48: 257–266PubMedGoogle Scholar
  14. Castro JM, Liras P, Láiz L & Martín JF (1988) Purification and characterization of the isopenicillin N synthase ofStreptomyces lactamdurans. J. Gen. Microbiol. 134: 133–141PubMedGoogle Scholar
  15. Coque JJR, Martín JF, Calzada JG & Liras P (1991a) The cephamycin biosynthetic genespcbAB, encoding a large multidomain peptide synthetase, andpcbC ofNocardia lactamdurans are clustered together in an organization different from the same genes inAcremonium chrysogenum andPenicillium chrysogenum. Mol. Microbiol. 5: 1125–1133PubMedGoogle Scholar
  16. Coque JJR, Liras P & Martín JF (1993a) Characterization and expression inStreptomyces lividans ofcefD andcefE gene fromNocardia lactamdurans: The organization of the cephamycin gene cluster differs from that inStreptomyces clavuligerus. Mol. Gen. Genet. 236: 453–458PubMedGoogle Scholar
  17. Coque JJR, Liras P & Martín JF (1993b) Gene for a β-lactamase, a penicillin-binding protein and a transmembrane protein are clustered with the cephamycin biosynthetic genes inNocardia lactamdurans. EMBO J. 12: 631–639PubMedGoogle Scholar
  18. Dayhoff MO, Barker WC & Hardman JK (1976) Atlas of protein sequencing and structure. In: Demain AL (Ed) Atlas of Protein Sequencing and Structure, Vol 5 (pp 53–66). National Biomedical Research Foundation, Washington DCGoogle Scholar
  19. Demain AL (1983) Biosynthesis of β-lactam antibiotics. In: Demain AL & Salomon NA (Eds) Antibiotics Containing the β-Lactam Structure, Vol I (pp 189–228). Springer-Verlag, BerlinGoogle Scholar
  20. Demain AL & Wolfe S (1987) Biosynthesis of cephalosporins. Dev. Ind. Microbiol. 27: 175–182Google Scholar
  21. Díez B, Barredo JL, Alvarez E, Cantoral JM, Van Solingen P, Groenen MAM, Veenstra AE & Martín JF (1989) Two genes involved in penicillin biosynthesis are linked in a 5.1 kbSalI fragment in the genome ofPenicillium chrysogenum. Mol. Gen. Genet. 218: 572–576PubMedGoogle Scholar
  22. Díez B, Gutiérrez S, Barredo JL, Van Solingen P, Van der Voort LHM & Martín JF (1990) The cluster of penicillin biosynthetic genes. Identification and characterization of thepcbAB gene encoding the α-aminoadipyl-cysteinyl-valine synthetase and linkage to thepcbC andpenDE genes. J. Biol. Chem. 265: 16358–16365PubMedGoogle Scholar
  23. Drew SW, Winstanley DJ & Demain AL (1976) Effect of norleucine on mycelial fragmentation inCephalosporium acremonium. Appl. Environ. Microbiol. 31: 143–145PubMedGoogle Scholar
  24. Fierro F, Gutiérrez S, Díez B & Martín JF (1993) Resolution of four large chromosomes in penicillin-producing filamentous fungi: the penicillin gene cluster is located on chromosome II (9.6 mb) inPenicillium notatum and chromosome I (10.4 mb) inPenicillium chrysogenum. Mol. Gen. Genet. 241: 573–579PubMedGoogle Scholar
  25. Gutiérrez S, Díez B, Alvarez E, Barredo JL & Martín JF (1991a) Expression of thepenDE gene ofPenicillium chrysogenum encoding isopenicillin N acyltransferase inCephalosporium acremonium: Production of benzylpenicillin by the transformants. Mol. Gen. Genet. 225: 56–64PubMedGoogle Scholar
  26. Gutiérrez S, Díez B, Montenegro E & Martín JF (1991b) Characterization of theCephalosporium acremonium pcbAB gene encoding α-aminoadipyl-cysteinyl-valine synthetase, a large multidomain peptide synthetase: Linkage to thepcbC gene as a cluster of early cephalosporin-biosynthetic genes and evidence of multiple functional domains. J. Bacteriol. 173: 2354–2365PubMedGoogle Scholar
  27. Gutiérrez S, Velasco J, Fernández FJ & Martín JF (1992) ThecefG gene ofCephalosporium acremonium is linked to thecefEF gene and encodes a deacetylcephalosporin C acetyltransferase closely related to homoserine O-acetyltransferase. J. Bacteriol. 174: 3056–3064PubMedGoogle Scholar
  28. Hardie DG, Dewart KB, Aitken A & McCarthy AD (1985) Amino acid sequence around the reactive serine residue of the thioesterase domain of rabbit fatty acid synthase. Biochem. Biophys. Acta 828: 380–382PubMedGoogle Scholar
  29. Hönlinger C & Kubicek CP (1989a) Metabolism and compartmentation of α-aminoadipic acid in penicillin-producing strains ofPenicillium chrysogenum. Biochim. Biophys. Acta 993: 204–211Google Scholar
  30. Hönlinger C & Kubicek CP (1989b) Regulation of δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine and isopenicillin N biosynthesis inPenicillium chrysogenum by the α-aminoadipate pool size. FEMS Microbiol. Lett. 65: 71–76Google Scholar
  31. Komatsu K-I, Mizuno M & Kodaira R (1975) Effect of methionine on cephalosporin C and penicillin N production by a mutant ofCephalosporium acremonium. J. Antibiot. 28: 881–888PubMedGoogle Scholar
  32. Korck C, Mountain HA & Byström AS (1991) Cloning, nucleotide sequence, and regulation of MET14, the gene encoding the APS kinase ofSaccharomyces cerevisiae. Mol. Gen. Genet. 229: 96–108PubMedGoogle Scholar
  33. Kovacevic S, Tobin MB and Miller JR (1990) The β-lactam biosynthesis genes for isopenicillin N epimerase and deacetoxy-cephalosporin C synthetase are expressed from a single transcript inStreptomyces clavuligerus. J. Bacteriol. 172: 3952–3958PubMedGoogle Scholar
  34. Kurzàtkowski W, Palissa H, Van Liempt H, von Döhren H, Kleinkauf H, Wolf WP & Kurylowicz W (1991) Localization of isopenicillin N synthase inPenicillium chrysogenum PQ-96. Appl. Microbiol. Biotechnol. 35: 517–520Google Scholar
  35. Luengo JM, Revilla G, Villanueva JR & Martín JF (1980) Inhibition and repression of homocitrate synthase by lysine inPenicillium chrysogenum. J. Bacteriol. 144: 869–876PubMedGoogle Scholar
  36. MacCabe AP, Riach MBR, Unkles SE & Kinghorn JR (1990) TheAspergillus nidulans npeA locus consists of the three contiguous genes required for penicillin biosynthesis. EMBO J. 9: 279–287PubMedGoogle Scholar
  37. MacCabe AP, Van Liempt H, Palissa H, Unkles SE, Riach MBR, Pfeifer E, von Döhren H & Kinghorn JR (1991) δ-(L-α-Aminoadipyl)-L-cysteinyl-D-valine synthetase fromAspergillus nidulans. J. Biol. Chem. 266: 12646–12654PubMedGoogle Scholar
  38. Martín JF (1992) Clusters of genes for the biosynthesis of antibiotics: Regulatory genes and overproduction of pharmaceuticals. J. Ind. Microbiol. 9: 73–90PubMedGoogle Scholar
  39. Martín JF & Aharonowitz Y (1983) Regulation of biosynthesis of β-lactam antibiotics. In: Demain AL & Solomon NA (Eds) Antibiotics Containing the Beta-Lactam Structure I (pp 229–254). Springer-Verlag, Berlin, HeidelbergGoogle Scholar
  40. Martín JF & Gutiérrez S (1992) Molecular genetics of fungal secondary metabolites. In: Kinghorn JR & Turner G (Eds) Applied Molecular Genetics of Filamentous Fungi (pp 214–252) Blackie and Son Ltd, GlasgowGoogle Scholar
  41. Martín JF & Liras P (1989a) Enzymes involved in penicillin, cephalosporin and cephamycin biosynthesis. In: Fiechter A (Ed) Advances Biochemical Engineering/Biotechnology, Vol 39 (pp 153–187). Springer Verlag, Berlín, HeidelbergGoogle Scholar
  42. Martín JF & Liras P (1989b) Organization and expression of genes involved in the biosynthesis of antibiotics and other secondary metabolites. Ann. Rev. Microbiol. 43: 173–206Google Scholar
  43. Martín JF, Díez B, Alvarez E, Barredo JL & Cantoral JM (1987) Development of a transformation system inPenicillium chrysogenum. Cloning of genes involved in penicillin biosynthesis. In: Alacevic M, Hranueli D & Toman Z (Eds) Genetics of Industrial Microorganisms (pp 297–308). Pliva, ZagrebGoogle Scholar
  44. Martín JF, Ingolia TD & Queener SW (1991) Molecular genetics of penicillin and cephalosporin antibiotic biosynthesis. In: Leong S & Berka RM (Eds) Molecular Industrial Mycology. Systems and Applications for Filamentous Fungi (pp 149–196). Marcel Dekker, Inc., New YorkGoogle Scholar
  45. Martín JF, Gutiérrez S, Montenegro E, Coque JJR, Fernández FJ, Velasco J, Gil S, Fierro F, Calzada JG, Cardoza RE & Liras P (1992) Genes, enzymes and control of the production of β-lactam antibiotics. In: Ladisch MR & Bose A (Eds) Harnessing Biotechnology for the 21st Century. Proceedings of the Ninth International Biotechnology Symposium (pp 131–137). American Chemical Society, Washington DCGoogle Scholar
  46. Mathison L, Soliday C, Stepan T, Aldrich T & Rambosek J (1993) Cloning, characterization, and use in strain improvement of theCephalosporium acremonium genecefG encoding acetyltransferase. Curr. Genet. 23: 33–41PubMedGoogle Scholar
  47. Matsuda A, Sugiura H, Matsuyama K, Matsumoto H, Ichikawa S & Komatsu K-I (1992) Molecular cloning of aceylt coenzyme A:deacetylcephalosporin C O-acetyltransferase cDNA fromAcremonium chrysogenum: Sequence and expression of catalytic activity in yeast. Biochem. Biophys. Res. Comm. 182: 995–1001PubMedGoogle Scholar
  48. Matsuyama K, Matsumoto H, Matsuda A, Sugiura H, Komatsu K-I & Ichikawa S (1992) Purification of acetyl coenzyme A:deacetylacephalosporin CO-acetyltransferase fromAcremonium chrysogenum. Biosci. Biotech. Biochem. 56: 1410–1412Google Scholar
  49. Mellor J, Jiang W, Funk M, Rathjen J, Barnes CA, Hinz T, Hegemann JH & Philippsen P (1990) CPF1, a yeast protein which functions in centromeres and promoters. EMBO J. 9: 4017–4026PubMedGoogle Scholar
  50. Montenegro E, Barredo JL, Gutiérrez S, Díez B, Alvarez E & Martín JF (1990) Cloning, characterization of the acyl-CoA:6-amino penicillanic acid acyltransferase gene ofAspergillus nidulans and linkage to the isopenicillin N synthase gene. Mol. Gen. Genet. 221: 322–330PubMedGoogle Scholar
  51. Montenegro E, Fierro F, Fernández FJ, Gutiérrez S & Martín JF (1992) Resolution of chromosomes III and VI ofAspergillus nidulans by pulsed-field gel electrophoresis shows hat the penicillin biosynthetic pathway genespcbAB,pcbC, andpenDE are clustered on chromosome VI (3.0 megabases). J. Bacteriol. 174: 7063–7067PubMedGoogle Scholar
  52. Müller WH, Van der Krft TP, Krouwer AJJ, Wösten HAB, Van der Voort LHM, Smaal EB & Verkleij AJ (1991) Localization of the pathway of the penicillin biosynthesis inPenicillium chrysogenum. EMBO J. 10: 489–495PubMedGoogle Scholar
  53. Müller WH, Bovenberg RAL, Groothuis MH, Kattevilder F, Smaal EB, Van der Voort LHM & Verkleij AJ (1992) Involvement of microbodies in penicillin biosynthesis. Biochim. Biophys. Acta 1116: 210–213PubMedGoogle Scholar
  54. Murre C, McCaw PS & Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding,daughterless, MyoD, andmyc proteins. Cell 56: 777–783PubMedGoogle Scholar
  55. Naggert J, Witkowski A, Mikkelsen J & Smith S (1988) Molecular cloning and sequencing of a cDNA encoding the thioesterase domain of the rat fatty acid synthetase. J. Biol. Chem. 263: 1146–1150PubMedGoogle Scholar
  56. Nash CH & Huber FM (1971) Antibiotic synthesis and morphological differentiation ofCephalosporium acremonium. Appl. Microbiol. 22: 6–10PubMedGoogle Scholar
  57. Nüesch J, Heim J & Treichler H-J (1987) The biosynthesis of sulfurcontaining β-lactam antibiotics. Ann. Rev. Microbiol. 41: 51–57Google Scholar
  58. Poulose AJ, Rogers L & Kolattukudy PE (1981) Primary structure of a chymotyptic peptide containing the ‘active serine’ of the thioesterase domain of fatty acid synthetase. Biochem. Biophys. Res. Comm. 103: 377–383PubMedGoogle Scholar
  59. Queener SW & Neuss N (1982) The biosynthesis of beta-lactam antibiotics. In: Morin RB & Gorman M (Eds) Chemistry and Biology of Beta-Lactam Antibiotics, Vol 3 (pp 1–82). Academic Press, New YorkGoogle Scholar
  60. Ramón D, Carramolino L, Patino C, Sánchez F & Peñalva MA (1987) Cloning and characterization of the isopenicillin N synthetase gen mediating the formation of the β-lactam ring inAspergillus nidulans. Gene 57: 171–181CrossRefPubMedGoogle Scholar
  61. Ramos FR, López-Nieto MJ & Martín JF (1985) Isopenicillin N synthetase ofPenicillium chrysogenum, an enzyme that converts δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N. Antimicrob. Agents Chemother. 27: 380–387PubMedGoogle Scholar
  62. Ramos FR, López-Nieto MJ & Martín JF (1986) Coordinate increase of isopenicillin N synthetase, isopenicillin N epimerase and deacetoxycephalosporin C synthetase in a high cephalosporin-producing mutant ofAcremonium chrysogenum and simultaneous loss of the three enzymes in a non-producing mutant. FEMS Microbiol. Lett. 35: 123–127Google Scholar
  63. Ramsdem M, McQuade BA, Saunders K, Turner MK & Hafford S (1989) Characterization of a loss-of-function mutation in the isopenicillin N synthase gene ofAcremonium chrysogenum. Gene 85: 267–273PubMedGoogle Scholar
  64. Randhawa ZI, Naggert J, Blacher RW & Smith S (1987) Amino acid sequence of the serine active-site region of the medium-chain S-acyl fatty acid synthetase thioester hydrolase from rat mammary gland. Eur. J. Biochem. 162: 577–581PubMedGoogle Scholar
  65. Revilla G, Ramos FR, López-Nieto MJ, Alvarez E & Martín JF (1986) Glucose represses formation of δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine and isopenicillin N synthase but not penicillin acyltransferase inPenicillium chrysogenum. J. Bacteriol. 168: 947–952PubMedGoogle Scholar
  66. Samson SM, Belagaje R, Blankenship DT, Champman JL, Perry D, Skatrud PL, Van Frank RM, Abraham EP, Baldwin JE, Queener SW & Ingolia TD (1985) Isolation, sequence determination and expression inE. coli of the isopenicillin N synthetase fromCephalosporium acremonium. Nature 318: 191–194PubMedGoogle Scholar
  67. Samson SM, Chapman JL, Belagaje P, Queener SW & Ingolia TD (1987a) Analysis of the role of cysteine residues in isopenicillin N synthetase activity by site-directed mutagenesis. Proc. Natl. Acad. Sci. USA 84: 5705–5709PubMedGoogle Scholar
  68. Samson SM, Dotzlaf JE, Slisz ML, Becker GW, Van Frank RM, Veal LE, Yeh WK, Miller JR, Queener SW & Ingolia TD (1987b) Cloning and expression of the fungal expandase/hydroxylase gene involved in cephalosporin biosynthesis. Biotechnol. 5: 1207–1216Google Scholar
  69. Sawada Y, Konomi T, Solomon NA & Demain AL (1980) Increase in activity of β-lactam synthetases after growth ofCephalosporium acremonium with methionine or norleucine. FEMS Microbiol. Lett. 9: 281–284Google Scholar
  70. Siewinski M, Kuropatwa M & Szewczuk A (1984) Phenylaklylsulfonyl derivatives as covalent inhibitors of penicillin amidase. Z. Physiol. Chem. 365: 829–837Google Scholar
  71. Skatrud PL & Queener SW (1989) An electrophoretic molecular karyotype for an industrial strain ofCephalosporium acremonium. Gene 78: 331–338PubMedGoogle Scholar
  72. Smith DJ, Burnham MKR, Bull JH, Hodgson JE, Ward JM, Browne P, Brown J, Barton B, Earl AJ & Turner G (1990a) β-Lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes. EMBO J. 9: 741–747PubMedGoogle Scholar
  73. Smith DJ, Burnham MKR, Edwards J, Earl AJ & Turner G (1990b) Cloning and heterologous expression of the penicillin biosynthetic gene cluster fromPenicillium chrysogenum. Biotechnol. 8: 39–41Google Scholar
  74. Smith AW, Collis K, Ramsden M, Fox HM & Peberdy JE (1991) Chromosome rearrangements in improved cephalosporin C producing strains ofAcremonium chrysogenum. Curr. Genet. 19: 235–237PubMedGoogle Scholar
  75. Somerson NL, Demain AL & Nunheimer TD (1961) Reversal of lysine inhibition of penicillin production by α-aminoadipic acid. Arch. Biochem. Biophys. 93: 238–241Google Scholar
  76. Thomas D, Cherest H & Surdin-Kerjan Y (1989) Elements involved in S-adenosylmethionine-mediated regulation of theSaccharomyces cerevisiae MET25 gene. Mol. Cell Biol. 9: 3292–3298PubMedGoogle Scholar
  77. Tobin MB, Kovacevic S, Madduri K, Hoskins JA, Skatrud PL, Vining LC, Stuttard C & Miller JR (1991) Localization of lysine ε-aminotransferase (lat) and δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase (pcbAB) genes inStreptomyces clavuligerus and production of lysine ε-aminotransferase activity inEscherichia coli. J. Bacteriol. 173: 6223–6229PubMedGoogle Scholar
  78. Tobin MB, Baldwin JE, Cole SCJ, Miller JR, Skatrud PL & Sutherland D (1993) The requirement for subunit interaction in the production ofPencillium chrysogenum acyl-coenzyme A:isopenicillin N acyltransferase inEscherichia coli. Gene 132: 199–206PubMedGoogle Scholar
  79. Turgay K, Krause M & Marahiel MA (1992) Four homologous domains in the primary structure of GrsB are related to domains in a superfamily of adenylate forming enzymes. Mol. Microbiol. 6: 529–546PubMedGoogle Scholar
  80. Veenstra AE, Van Solingen P, Huninga-Murrling H, Koekman BP, Groenen MAM, Smaal EB, Kattevilder A, Alvarez E, Barredo JL & Martín JF (1989) Cloning of penicillin biosynthetic genes. In: Hershberger CL, Queener SW & Hegeman G (Eds) Genetics and Molecular Biology of Industrial Microoganisms (pp 262–269). American Society for Microbiology, Washington DCGoogle Scholar
  81. Velasco J, Gutiérrez S, Fernández FJ, Marcos AT, Arenós C & Martín JF (1994) Exogenous methionine increases levels of mRNAs transcribed frompcbAB,pcbC, andcefEF gene, encoding enzymes of the cephalosporin biosynthetic pathway, inAcremonium chrysogenum. J. Bacteriol. 176, in pressGoogle Scholar
  82. Vogel K, Hörz W & Hinnen A (1989) The two positively acting regulatory proteins PHO2 and PHO4 physically interact with PHO5 upstream activation regions. Mol. Cell Biol. 9: 2050–2057PubMedGoogle Scholar
  83. Whiteman PA, Abraham EP, Baldwin JW, Fleming MD, Schofield CJ, Sutherland JD & Willis AC (1990) Acyl-coenzyme A:6-aminopenicillanic acid acyltransferase fromPenicillium chrysogenum andAspergillus nidulans. FEMS Lett. 262: 342–344Google Scholar
  84. Yuan Z, Liu W & Hammes GG (1988) Molecular cloning and sequencing of DNA complementary to chicken liver fatty acid synthase mRNA. Proc. Natl. Acad. Sci. USA 85: 6328–6331PubMedGoogle Scholar
  85. Zanca DM & Martín JF (1983) Carbon catabolite regulation of the conversion of penicillin N into cephalosporin C. J. Antibiot. 36: 700–708PubMedGoogle Scholar
  86. Zhang J-Y, Banko G, Wolfe S & Demain AL (1987) Methionine induction of ACV synthetase inCephalosporium acremonium. J. Ind. Microbiol. 2: 251–255Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Juan F. Martín
    • 1
  • Santiago Gutiérrez
    • 1
  • Francisco J. Fernández
    • 1
  • Javier Velasco
    • 1
  • Francisco Fierro
    • 1
  • Ana T. Marcos
    • 1
  • Katarina Kosalkova
    • 1
  1. 1.Area of Microbiology, Department of Ecology, Genetics and Microbiology, Faculty of BiologyUniversity of LeónLeónSpain

Personalised recommendations