Biosynthetic concepts for the production of β-lactam antibiotics in Penicillium chrysogenum

Biotechnology Journal

Volumn 7, Issue 2, 2012, Pages 225-236

  Weber, Stefan S ^a   Bovenberg, Roel A L ^a,b   Driessen, Arnold J M ^a  

^a UNIVERSITY OF GRONINGEN   (Netherlands)

^b DSM BIOTECHNOLOGY CENTER   (Netherlands)

Author keywords

Lactam; Metabolic engineering; Penicillium chrysogenum; Synthetic biology

Indexed keywords

ACID PRECURSORS; BIOSYNTHETIC GENE CLUSTER; FERMENTATIVE PRODUCTION; FILAMENTOUS FUNGI; GENES ENCODING; INDUSTRIAL PRODUCTION; PENICILLIUM CHRYSOGENUM; PEPTIDE PRODUCTS; RELATED COMPOUNDS; STRAIN IMPROVEMENT; SYNTHETIC BIOLOGY; TRANSCRIPTIONAL ANALYSIS;

AMINO ACIDS; BIOCHEMISTRY; BIOSYNTHESIS; FACTOR ANALYSIS; GENES; INDUSTRY; METABOLIC ENGINEERING; SEWAGE TREATMENT PLANTS; STRAIN; TRANSCRIPTION;

ANTIBIOTICS;

ADIPOYL 7 AMINOCEPHALOSPORANIC ACID; AMPICILLIN; BACTERIAL ENZYME; BETA LACTAM ANTIBIOTIC; CEPHALOSPORIN C; CEPHALOSPORIN DERIVATIVE; DIPOYL 7 AMINODEACETOXY CEPHALOSPORIN ACID; ISOPENICILLIN N ACYLTRANSFERASE; ISOPENICILLIN N SYNTHETASE; UNCLASSIFIED DRUG;

AMINO ACID ANALYSIS; ANTIBIOTIC BIOSYNTHESIS; ASPERGILLUS NIDULANS; BACTERIAL GENOME; BACTERIAL STRAIN; CELL COMPARTMENTALIZATION; CEPHALOSPORIUM ACREMONIUM; ENZYME ACTIVATION; FATTY ACID OXIDATION; FERMENTATION; GENE AMPLIFICATION; GENE CLUSTER; GENETIC ASSOCIATION; GENETIC ENGINEERING; GENETIC TRANSCRIPTION; GENOME ANALYSIS; HOMOLOGOUS RECOMBINATION; METABOLIC ENGINEERING; NONHUMAN; PENICILLIUM CHRYSOGENUM; PEPTIDE ANALYSIS; PICHIA ANGUSTA; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; SITE DIRECTED MUTAGENESIS; STREPTOMYCES CLAVULIGERUS; STRUCTURE ANALYSIS; TRANSCRIPTION REGULATION;

BETA-LACTAMS; METABOLIC ENGINEERING; PENICILLIUM CHRYSOGENUM; SYNTHETIC BIOLOGY;

FUNGI; PENICILLIUM CHRYSOGENUM;

EID: 84856586285     PISSN: 18606768     EISSN: 18607314     Source Type: Journal    
DOI: 10.1002/biot.201100065     Document Type: Review

References (101)

1. Fleming, A., The antibacterial action of a Penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 1929, 10, 226-236.
2. Clutterbuck, P. W., Lovell, R., Raistrick, H., Studies in the biochemistry of micro-organisms: The formation from glucose by members of the Penicillium chrysogenum series of a pigment, an alkali-soluble protein and penicillin-the antibacterial substance of Fleming. Biochem. J. 1932, 26, 1907-1918.
3. Carr, L. G., Skatrud, P. L., Scheetz, M. E. 2nd, Queener, S. W. et al., Cloning and expression of the isopenicillin N synthetase gene from Penicillium chrysogenum. Gene 1986, 48, 257-266.
4. Cohen, G., Argaman, A., Schreiber, R., Mislovati, M. et al., The thioredoxin system of Penicillium chrysogenum and its possible role in penicillin biosynthesis. J. Bacteriol. 1994, 176, 973-984.
5. Teng, M., Miller, M. J., Nicas, T. I., Grissom-Arnold, J. et al., Beta-lactamase inhibitors derived from N-tosyloxy-beta-lactams. Bioorg. Med. Chem. 1993, 1, 151-154.
6. Ingolia, T. D., Queener, S. W., Beta-lactam biosynthetic genes. Med. Res. Rev. 1989, 9, 245-264.
7. Gutierrez, S., Fierro, F., Casqueiro, J., Martin, J. F., Gene organization and plasticity of the beta-lactam genes in different filamentous fungi. Antonie Van Leeuwenhoek 1999, 75, 81-94.
8. van den Berg, M. A., Albang, R., Albermann, K., Badger, J. H. et al., Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum. Nat. Biotechnol. 2008, 26, 1161-1168.
9. Elander, R. P., Industrial production of beta-lactam antibiotics. Appl. Microbiol. Biotechnol. 2003, 61, 385-392.
10. Fierro, F., Barredo, J. L., Diez, B., Gutierrez, S. et al., The penicillin gene cluster is amplified in tandem repeats linked by conserved hexanucleotide sequences. Proc. Natl. Acad. Sci. USA 1995, 92, 6200-6204.
11. Feldmann, E., Schmiemann, V., Goedecke, W., Reichenberger, S. et al., DNA double-strand break repair in cell-free extracts from Ku80-deficient cells: implications for Ku serving as an alignment factor in non-homologous DNA end joining. Nucleic Acids Res. 2000, 28, 2585-2596.
12. Ramsden, D. A., Gellert, M., Ku protein stimulates DNA end joining by mammalian DNA ligases: a direct role for Ku in repair of DNA double-strand breaks. EMBO J. 1998, 17, 609-614.
13. Meyer, V., Arentshorst, M., El-Ghezal, A., Drews, A. C. et al., Highly efficient gene targeting in the Aspergillus niger kusA mutant. J. Biotechnol. 2007, 128, 770-775.
14. Snoek, I. S., van der Krogt, Z. A., Touw, H., Kerkman, R. et al., Construction of an hdfA Penicillium chrysogenum strain impaired in non-homologous end-joining and analysis of its potential for functional analysis studies. Fungal Genet. Biol. 2009, 46, 418-426.
15. Jami, M. S., Barreiro, C., Garcia-Estrada, C., Martin, J. F., Proteome analysis of the penicillin producer Penicillium chrysogenum: characterization of protein changes during the industrial strain improvement. Mol. Cell. Proteomics 2010, 9, 1182-1198.
16. Harris, D. M., van der Krogt, Z. A., Klaassen, P., Raamsdonk, L. M. et al., Exploring and dissecting genome-wide gene expression responses of Penicillium chrysogenum to phenylacetic acid consumption and penicillinG production. BMC Genomics 2009, 10, 75.
17. Banuelos, O., Casqueiro, J., Steidl, S., Gutierrez, S. et al., Subcellular localization of the homocitrate synthase in Penicillium chrysogenum. Mol. Genet. Genomics 2002, 266, 711-719.
18. Banuelos, O., Casqueiro, J., Fierro, F., Hijarrubia, M. J. et al., Characterization and lysine control of expression of the lys1 gene of Penicillium chrysogenum encoding homocitrate synthase. Gene 1999, 226, 51-59.
19. López-Nieto, M. J., Ramos, F. R., Luengo, J. M., Martin, J. F., Characterization of the biosynthesis in vivo of α-aminoadipyl-cysteinyl-valine in Penicillium chrysogenum. Appl Microbiol Biotechnol 1985, 22, 343-343-351.
20. van de Kamp, M., Schuurs, T. A., Vos, A., van der Lende, T. R. et al., Sulfur regulation of the sulfate transporter genes sutA and sutB in Penicillium chrysogenum. Appl. Environ. Microbiol. 2000, 66, 4536-4538.
21. Dobeli, H., Nuesch, J., Regulatory properties of O-acetyl-L-serine sulfhydrylase of Cephalosporium acremonium: Evidence of an isoenzyme and its importance in cephalosporin C biosynthesis. Antimicrob. Agents Chemother. 1980, 18, 111-117.
22. Nuesch, J., Heim, J., Treichler, H. J., The biosynthesis of sulfur-containing beta-lactam antibiotics. Annu. Rev. Microbiol. 1987, 41, 51-75.
23. Kubicek-Pranz, E. M., Kubicek, C. P., Production and biosynthesis of amino acids by fungi. In Arora, D.K., Elander, R.P., Mukerji, K.G. (Eds.), Handbook of applied mycology, fungal biotechnology, Marcel Dekker, New York 1991.
24. Aharonowitz, Y., Cohen, G., Martin, J. F., Penicillin and cephalosporin biosynthetic genes: structure, organization, regulation, and evolution. Annu. Rev. Microbiol. 1992, 46, 461-495.
25. van der Lende, T. R., van de Kamp, M., Berg, M., Sjollema, K. et al., delta-(L-alpha-Aminoadipyl)-L-cysteinyl-D-valine synthetase, that mediates the first committed step in penicillin biosynthesis, is a cytosolic enzyme. Fungal Genet. Biol. 2002, 37, 49-55.
26. Kleinkauf, H., Von Dohren, H., A nonribosomal system of peptide biosynthesis. Eur. J. Biochem. 1996, 236, 335-351.
27. Cooper, R. D., The enzymes involved in biosynthesis of penicillin and cephalosporin; their structure and function. Bioorg. Med. Chem. 1993, 1, 1-17.
28. Muller, W. H., van der Krift, T. P., Krouwer, A. J., Wosten, H. A. et al., Localization of the pathway of the penicillin biosynthesis in Penicillium chrysogenum. EMBO J. 1991, 10, 489-495.
29. Barredo, J. L., van Solingen, P., Diez, B., Alvarez, E. et al., Cloning and characterization of the acyl-coenzyme A: 6-aminopenicillanic-acid-acyltransferase gene of Penicillium chrysogenum. Gene 1989, 83, 291-300.
30. Luengo, J. M., Enzymatic synthesis of hydrophobic penicillins. J. Antibiot. (Tokyo) 1995, 48, 1195-1212.
31. Aplin, R. T., Baldwin, J. E., Roach, P. L., Robinson, C. V. et al., Investigations into the post-translational modification and mechanism of isopenicillin N:acyl-CoA acyltransferase using electrospray mass spectrometry. Biochem. J. 1993, 294, 357-363.
32. Garcia-Estrada, C., Vaca, I., Fierro, F., Sjollema, K. et al., The unprocessed preprotein form IATC103S of the isopenicillin N acyltransferase is transported inside peroxisomes and regulates its self-processing. Fungal Genet. Biol. 2008, 45, 1043-1052.
33. Macmorine, H. G., Some factors influencing the production of certain biosynthetic penicillins. Appl. Microbiol. 1957, 5, 386-391.
34. Cole, M., Formation of 6-aminopenicillanic acid, penicillins, and penicillin acylase by various fungi. Appl. Microbiol. 1966, 14, 98-104.
35. Lamas-Maceiras, M., Vaca, I., Rodriguez, E., Casqueiro, J. et al., Amplification and disruption of the phenylacetyl-CoA ligase gene of Penicillium chrysogenum encoding an aryl-capping enzyme that supplies phenylacetic acid to the isopenicillin N-acyltransferase. Biochem. J. 2006, 395, 147-155.
36. Koetsier, M. J., Jekel, P. A., van den Berg, M. A., Bovenberg, R. A. et al., Characterization of a phenylacetate-CoA ligase from Penicillium chrysogenum. Biochem. J. 2009, 417, 467-476.
37. Koetsier, M. J., Gombert, A. K., Fekken, S., Bovenberg, R. A. et al., The Penicillium chrysogenum aclA gene encodes a broad-substrate-specificity acyl-coenzyme A ligase involved in activation of adipic acid, a side-chain precursor for cephem antibiotics. Fungal Genet. Biol. 2010, 47, 33-42.
38. Subramani, S., Components involved in peroxisome import, biogenesis, proliferation, turnover, and movement. Physiol. Rev. 1998, 78, 171-188.
39. Meijer, W. H., Gidijala, L., Fekken, S., Kiel, J. A. et al., Peroxisomes are required for efficient penicillin biosynthesis in Penicillium chrysogenum. Appl. Environ. Microbiol. 2010, 76, 5702-5709.
40. Muller, W. H., Bovenberg, R. A., Groothuis, M. H., Kattevilder, F. et al., Involvement of microbodies in penicillin biosynthesis. Biochim. Biophys. Acta 1992, 1116, 210-213.
41. Gidijala, L., Kiel, J. A., Douma, R. D., Seifar, R. M. et al., An engineered yeast efficiently secreting penicillin. PLoS One 2009, 4, e8317.
42. Kiel, J. A., van der Klei, I. J., van den Berg, M. A., Bovenberg, R. A. et al., Overproduction of a single protein, Pc-Pex11p, results in 2-fold enhanced penicillin production by Penicillium chrysogenum. Fungal Genet. Biol. 2005, 42, 154-164.
43. Todde, V., Veenhuis, M., van der Klei, I. J., Autophagy: principles and significance in health and disease. Biochim. Biophys. Acta 2009, 1792, 3-13.
44. Bartoszewska, M., Kiel, J. A., Bovenberg, R. A., Veenhuis, M. et al., Autophagy deficiency promotes beta-lactam production in Penicillium chrysogenum. Appl. Environ. Microbiol. 2011, 77, 1413-1422.
45. van der Lende, T. R., Breeuwer, P., Abee, T., Konings, W. N. et al., Assessment of the microbody luminal pH in the filamentous fungus Penicillium chrysogenum. Biochim. Biophys. Acta 2002, 1589, 104-111.
46. Alvarez, E., Cantoral, J. M., Barredo, J. L., Diez, B. et al., Purification to homogeneity and characterization of acyl coenzyme A:6-aminopenicillanic acid acyltransferase of Penicillium chrysogenum. Antimicrob. Agents Chemother. 1987, 31, 1675-1682.
47. Evers, M. E., Trip, H., van den Berg, M. A., Bovenberg, R. A. et al., Compartmentalization and transport in beta-lactam antibiotics biosynthesis. Adv. Biochem. Eng. Biotechnol. 2004, 88, 111-135.
48. Diez, B., Gutierrez, S., Barredo, J. L., van Solingen, P. et al., The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J. Biol. Chem. 1990, 265, 16358-16365.
49. Kosalkova, K., Marcos, A. T., Fierro, F., Hernando-Rico, V. et al., A novel heptameric sequence (TTAGTAA) is the binding site for a protein required for high level expression of pcbAB, the first gene of the penicillin biosynthesis in Penicillium chrysogenum. J. Biol. Chem. 2000, 275, 2423-2430.
50. Tilburn, J., Sarkar, S., Widdick, D. A., Espeso, E. A. et al., The Aspergillus PacC zinc finger transcription factor mediates regulation of both acid- and alkaline-expressed genes by ambient pH. EMBO J. 1995, 14, 779-790.
51. Suarez, T., Penalva, M. A., Characterization of a Penicillium chrysogenum gene encoding a PacC transcription factor and its binding sites in the divergent pcbAB-pcbC promoter of the penicillin biosynthetic cluster. Mol. Microbiol. 1996, 20, 529-540.
52. Revilla, G., Lopez-Nieto, M. J., Luengo, J. M., Martin, J. F., Carbon catabolite repression of penicillin biosynthesis by Penicillium chrysogenum. J. Antibiot. (Tokyo) 1984, 37, 781-789.
53. Revilla, G., Ramos, F. R., Lopez-Nieto, M. J., Alvarez, E. et al., Glucose represses formation of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine and isopenicillin N synthase but not penicillin acyltransferase in Penicillium chrysogenum. J. Bacteriol. 1986, 168, 947-952.
54. Espeso, E. A., Tilburn, J., Arst, H. N. Jr., Penalva, M. A., pH regulation is a major determinant in expression of a fungal penicillin biosynthetic gene. EMBO J. 1993, 12, 3947-3956.
55. Gutierrez, S., Marcos, A. T., Casqueiro, J., Kosalkova, K. et al., Transcription of the pcbAB, pcbC and penDE genes of Penicillium chrysogenum AS-P-78 is repressed by glucose and the repression is not reversed by alkaline pHs. Microbiology 1999, 145, 317-324.
56. Haas, H., Marzluf, G. A., NRE, the major nitrogen regulatory protein of Penicillium chrysogenum, binds specifically to elements in the intergenic promoter regions of nitrate assimilation and penicillin biosynthetic gene clusters. Curr. Genet. 1995, 28, 177-183.
57. Bok, J. W., Keller, N. P., LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell. 2004, 3, 527-535.
58. Noma, K., Allis, C. D., Grewal, S. I., Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 2001, 293, 1150-1155.
59. Kosalkova, K., Garcia-Estrada, C., Ullan, R. V., Godio, R. P. et al., The global regulator LaeA controls penicillin biosynthesis, pigmentation and sporulation, but not roquefortine C synthesis in Penicillium chrysogenum. Biochimie 2009, 91, 214-225.
60. Fischer, R., Developmental biology. Sex and poison in the dark. Science 2008, 320, 1430-1431.
61. Bayram, O., Krappmann, S., Ni, M., Bok, J. W. et al., VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 2008, 320, 1504-1506.
62. Kato, N., Brooks, W., Calvo, A. M., The expression of sterigmatocystin and penicillin genes in Aspergillus nidulans is controlled by veA, a gene required for sexual development. Eukaryot. Cell. 2003, 2, 1178-1186.
63. Dreyer, J., Eichhorn, H., Friedlin, E., Kurnsteiner, H. et al., A homologue of the Aspergillus velvet gene regulates both cephalosporin C biosynthesis and hyphal fragmentation in Acremonium chrysogenum. Appl. Environ. Microbiol. 2007, 73, 3412-3422.
64. Sprote, P., Brakhage, A. A., The light-dependent regulator velvet A of Aspergillus nidulans acts as a repressor of the penicillin biosynthesis. Arch. Microbiol. 2007, 188, 69-79.
65. Hoff, B., Kamerewerd, J., Sigl, C., Mitterbauer, R. et al., Two components of a velvet-like complex control hyphal morphogenesis, conidiophore development, and penicillin biosynthesis in Penicillium chrysogenum. Eukaryot. Cell. 2010, 9, 1236-1250.
66. Theilgaard, H., van Den Berg, M., Mulder, C., Bovenberg, R. et al., Quantitative analysis of Penicillium chrysogenum Wis54-1255 transformants overexpressing the penicillin biosynthetic genes. Biotechnol. Bioeng. 2001, 72, 379-388.
67. Nijland, J. G., Ebbendorf, B., Woszczynska, M., Boer, R. et al., Nonlinear biosynthetic gene cluster dose effect on penicillin production by Penicillium chrysogenum. Appl. Environ. Microbiol. 2010, 76, 7109-7115.
68. Crawford, L., Stepan, A. M., McAda, P. C., Rambosek, J. A. et al., Production of cephalosporin intermediates by feeding adipic acid to recombinant Penicillium chrysogenum strains expressing ring expansion activity. Biotechnology (N.Y.) 1995, 13, 58-62.
69. Robin, J., Jakobsen, M., Beyer, M., Noorman, H. et al., Physiological characterisation of Penicillium chrysogenum strains expressing the expandase gene from Streptomyces clavuligerus during batch cultivations. Growth and adipoyl-7-aminodeacetoxycephalosporanic acid production. Appl. Microbiol. Biotechnol. 2001, 57, 357-362.
70. Robin, J., Bonneau, S., Schipper, D., Noorman, H. et al., Influence of the adipate and dissolved oxygen concentrations on the beta-lactam production during continuous cultivations of a Penicillium chrysogenum strain expressing the expandase gene from Streptomyces clavuligerus. Metab. Eng. 2003, 5, 42-48.
71. Schroen, C. G., VandeWiel, S., Kroon, P. J., DeVroom, E. et al., Equilibrium position, kinetics, and reactor concepts for the adipyl-7-ADCA-hydrolysis process. Biotechnol. Bioeng. 2000, 70, 654-661.
72. Monti, D., Carrea, G., Riva, S., Baldaro, E. et al., Characterization of an industrial biocatalyst: immobilized glutaryl-7-ACA acylase. Biotechnol. Bioeng. 2000, 70, 239-244.
73. Ullan, R. V., Campoy, S., Casqueiro, J., Fernandez, F. J. et al., Deacetylcephalosporin C production in Penicillium chrysogenum by expression of the isopenicillin N epimerization, ring expansion, and acetylation genes. Chem. Biol. 2007, 14, 329-339.
74. Harris, D. M., Westerlaken, I., Schipper, D., van der Krogt, Z. A. et al., Engineering of Penicillium chrysogenum for fermentative production of a novel carbamoylated cephem antibiotic precursor. Metab. Eng. 2009.
75. Nijland, J. G., Kovalchuk, A., van den Berg, M. A., Bovenberg, R. A. et al., Expression of the transporter encoded by the cefT gene of Acremonium chrysogenum increases cephalosporin production in Penicillium chrysogenum. Fungal Genet. Biol. 2008, 45, 1415-1421.
76. Kell, D. B., Peck, M. W., Rodger, G., Morris, J. G., On the permeability to weak acids and bases of the cytoplasmic membrane of Clostridium pasteurianum. Biochem. Biophys. Res. Commun. 1981, 99, 81-88.
77. Hillenga, D. J., Versantvoort, H., van der Molen, S., Driessen, A. et al., Penicillium chrysogenum takes up the penicillin G precursor phenylacetic acid by passive diffusion. Appl. Environ. Microbiol. 1995, 61, 2589-2595.
78. Krebs, H. A., Wiggins, D., Stubbs, M., Sols, A. et al., Studies on the mechanism of the antifungal action of benzoate. Biochem. J. 1983, 214, 657-663.
79. Plumridge, A., Hesse, S. J., Watson, A. J., Lowe, K. C. et al., The weak acid preservative sorbic acid inhibits conidial germination and mycelial growth of Aspergillus niger through intracellular acidification. Appl. Environ. Microbiol. 2004, 70, 3506-3511.
80. Piper, P., Mahe, Y., Thompson, S., Pandjaitan, R. et al., The pdr12 ABC transporter is required for the development of weak organic acid resistance in yeast. EMBO J. 1998, 17, 4257-4265.
81. Hazelwood, L. A., Tai, S. L., Boer, V. M., de Winde, J. H. et al., A new physiological role for Pdr12p in Saccharomyces cerevisiae: Export of aromatic and branched-chain organic acids produced in amino acid catabolism. FEMS Yeast Res. 2006, 6, 937-945.
82. Palmieri, L., Rottensteiner, H., Girzalsky, W., Scarcia, P. et al., Identification and functional reconstitution of the yeast peroxisomal adenine nucleotide transporter. EMBO J. 2001, 20, 5049-5059.
83. van Roermund, C. W., Elgersma, Y., Singh, N., Wanders, R. J. et al., The membrane of peroxisomes in Saccharomyces cerevisiae is impermeable to NAD(H) and acetyl-CoA under in vivo conditions. EMBO J. 1995, 14, 3480-3486.
84. Antonenkov, V. D., Mindthoff, S., Grunau, S., Erdmann, R. et al., An involvement of yeast peroxisomal channels in transmembrane transfer of glyoxylate cycle intermediates. Int. J. Biochem. Cell Biol. 2009, 41, 2546-2554.
85. Garcia-Estrada, C., Vaca, I., Lamas-Maceiras, M., Martin, J. F., In vivo transport of the intermediates of the penicillin biosynthetic pathway in tailored strains of Penicillium chrysogenum. Appl. Microbiol. Biotechnol. 2007, 76, 169-182.
86. Hillenga, D. J., Transport processes in penicillin biosynthesis. Thesis, University of Groningen, The Netherlands 1999.
87. Van den Berg, M. A., Bovenberg, R. A. L., Driessen, A. J. M., Konings, W. N. et al., Method for enhancing secretion of beta-lactam transport. WO 2001/32904.
88. Coque, J. J., Liras, P., Martin, J. F., Genes for a beta-lactamase, a penicillin-binding protein and a transmembrane protein are clustered with the cephamycin biosynthetic genes in Nocardia lactamdurans. EMBO J. 1993, 12, 631-639.
89. Martin, J. F., Casqueiro, J., Liras, P., Secretion systems for secondary metabolites: How producer cells send out messages of intercellular communication. Curr. Opin. Microbiol. 2005, 8, 282-293.
90. Ullan, R. V., Liu, G., Casqueiro, J., Gutierrez, S. et al., The cefT gene of Acremonium chrysogenum C10 encodes a putative multidrug efflux pump protein that significantly increases cephalosporin C production. Mol. Genet. Genomics 2002, 267, 673-683.
91. van den Berg, M. A., Westerlaken, I., Leeflang, C., Kerkman, R. et al., Functional characterization of the penicillin biosynthetic gene cluster of Penicillium chrysogenum Wisconsin54-1255. Fungal Genet. Biol. 2007, 44, 830-844.
92. Andrade, A. C., Van Nistelrooy, J. G., Peery, R. B., Skatrud, P. L. et al., The role of ABC transporters from Aspergillus nidulans in protection against cytotoxic agents and in antibiotic production. Mol. Gen. Genet. 2000, 263, 966-977.
93. Dassa, E., Bouige, P., The ABC of ABCS: a phylogenetic and functional classification of ABC systems in living organisms. Res. Microbiol. 2001, 152, 211-229.
94. Walker, J. E., Saraste, M., Runswick, M. J., Gay, N. J., Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1982, 1, 945-951.
95. Bairoch, A., PROSITE: a dictionary of sites and patterns in proteins. Nucleic Acids Res. 1992, 20, Suppl 2013-2018.
96. Kovalchuk, A., Driessen, A. J., Phylogenetic analysis of fungal ABC transporters. BMC Genomics 2010, 11, 177.
97. Gottesman, M. M., Fojo, T., Bates, S. E., Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer. 2002, 2, 48-58.
98. Balzi, E., Goffeau, A., Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 1995, 27, 71-76.
99. Pao, S. S., Paulsen, I. T., Saier, M. H. Jr., Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 1998, 62, 1-34.
100. Saier, M. H. Jr., Paulsen, I. T., Phylogeny of multidrug transporters. Semin. Cell Dev. Biol. 2001, 12, 205-213.
101. Sa-Correia, I., dos Santos, S. C., Teixeira, M. C., Cabrito, T. R. et al., Drug:H+ antiporters in chemical stress response in yeast. Trends Microbiol. 2009, 17, 22-31.