CefR modulates transporters of beta-lactam intermediates preventing the loss of penicillins to the broth and increases cephalosporin production in Acremonium chrysogenum

Metabolic Engineering

Volumn 13, Issue 5, 2011, Pages 532-543

  Teijeira, F ^a   Ullán, R V ^a   Fernandez Aguado M ^b   Martin J F ^a,b  

^a Institute of Biotechnology INBIOTEC Parque Científico de León   (Spain)

^b UNIVERSITY OF LEÓN   (Spain)

Author keywords

Acremonium chrysogenum; Cephalosporin biosynthesis regulation; Cephalosporin transporters; Gene expression regulation; Regulatory protein

Indexed keywords

ACREMONIUM; BIOSYNTHETIC GENE; BIOSYNTHETIC PATHWAY; CEPHALOSPORIN BIOSYNTHESIS REGULATION; CEPHALOSPORIN C; CEPHALOSPORIN TRANSPORTERS; EPIMERIZATION; EXPRESSION LEVELS; NORTHERN BLOT ANALYSIS; NUCLEAR TARGETING; OVER-EXPRESSION; REGULATORY PROTEIN; STIMULATORY EFFECTS; TRANSFORMANTS;

BIOCHEMISTRY; BIOSYNTHESIS; CYTOLOGY; DRUG PRODUCTS; GENE EXPRESSION; GENE EXPRESSION REGULATION; PHYSIOLOGY; PROTEINS;

SEWAGE TREATMENT PLANTS;

ADICILLIN; BETA LACTAM; CEFEF PROTEIN; CEFM PROTEIN; CEFP PROTEIN; CEFR PROTEIN; CEPHALOSPORIN C; FUNGAL DNA; REGULATOR PROTEIN; UNCLASSIFIED DRUG;

ACREMONIUM; ACREMONIUM CHRYSGENUM; ARTICLE; DNA SEQUENCE; GENE CONTROL; GENE INACTIVATION; GENE OVEREXPRESSION; NONHUMAN; NORTHERN BLOTTING; NUCLEOTIDE SEQUENCE; OPEN READING FRAME; PRIORITY JOURNAL; SOUTHERN BLOTTING;

ACREMONIUM; CARRIER PROTEINS; CEPHALOSPORINS; FUNGAL PROTEINS; GENE KNOCKDOWN TECHNIQUES; PENICILLINS; PEROXISOMES;

ACREMONIUM CHRYSOGENUM;

EID: 80052030355     PISSN: 10967176     EISSN: 10967184     Source Type: Journal    
DOI: 10.1016/j.ymben.2011.06.004     Document Type: Article

References (63)

1. Aharonowitz Y., Cohen G., Martín J.F. Penicillin and cephalosporin biosynthetic genes: Structure, organization, regulation, and evolution. Annu. Rev. Microbiol. 1992, 46:461-495.
2. Andrade A.C., Van Nistelrooy J.G., Peery R.B., Skatrud P.L., De Waard M.A. The role of ABC transporters from Aspergillus nidulans in protection against cytotoxic agents and in antibiotic production. Mol. Genet. Genomics. 2000, 263:966-977.
3. Blanc V., Salah-Bey K., Folcher M., Thompson C.J. Molecular characterization and transcriptional analysis of a multidrug resistance gene cloned from the pristinamycin-producing organism. Streptomyces pristinaespiralis. Mol. Microbiol. 1995, 17:989-999.
4. Burger G., Strauss J., Scazzocchio C., Lang B.F. nirA, the pathway-specific regulatory gene of nitrate assimilation in Aspergillus nidulans, encodes a putative GAL4-type zinc finger protein and contains four introns in highly conserved regions. Mol. Cell. Biol 1991, 11:5746-5755.
5. Dotzlaf J.E., Yeh W.K. Copurification and characterization of deacetoxycephalosporin C synthetase/hydroxylase from Cephalosporium acremonium. J. Bacteriol. 1987, 169:1611-1618.
6. Dreyer J., Eichhorn H., Friedlin E., Kürnsteiner H., Kück U. 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.
7. Elander R.P. Industrial production of beta-lactam antibiotics. Appl. Microbiol. Biotechnol. 2003, 61:385-392.
8. Evers M.E., Trip H., van den Berg M.A., Bovenberg R.A., Driessen A.J. Compartmentalization and transport in beta-lactam antibiotics biosynthesis. Adv. Biochem. Eng. Biotechnol. 2004, 88:111-135.
9. Fierro F., Martín J.F., Kosalková K. Sulfur-containing Β-lactam antibiotics: Enzymes, genes and regulation of the biosynthesis. Microbial secondary metabolites: biosynthesis, genetics and regulation. 2002, 179-210. Research Signpost, Trivandrum. F. Fierro, J.F. Martín (Eds.).
10. García-Estrada C., Fierro F., Martín J.F. Evolution of fungal beta-lactam biosynthesis gene clusters. Current Research, Technology and Education Topics in Applied Microbiology and Microbial Biotechnology 2010, 577-588. Formatex Research Center, Vol 1. A.M. Vilas (Ed.).
11. Grkovic S., Brown M.H., Skurray R.A. Transcriptional regulation of multidrug efflux pumps in bacteria. Semin. Cell. Dev. Biol. 2001, 12:225-237.
12. Grkovic S., Brown M.H., Skurray R.A. Regulation of bacterial drug export systems. Microbiol. Mol. Biol. Rev. 2002, 66:671-701.
13. Gulshan K., Moye-Rowley W.S. Multidrug resistance in fungi. Eukaryot. Cell. 2007, 6:1933-1942.
14. Gutiérrez S., Díez B., Montenegro E., Martín J.F. Characterization of the Cephalosporium acremonium pcbAB gene encoding alpha-aminoadipyl-cysteinyl-valine synthetase, a large multidomain peptide synthetase: Linkage to the pcbC gene as a cluster of early cephalosporin biosynthetic genes and evidence of multiple functional domains. J. Bacteriol 1991, 173:2354-2365.
15. Gutiérrez S., Fierro F., Casqueiro J., Martín J.F. Gene organization and plasticity of the beta-lactam genes in different filamentous fungi. Antonie van Leeuwenhoek 1999, 75:81-94.
16. Gutiérrez S., Velasco J., Fernández F.J., Martín J.F. The cefG gene of Cephalosporium acremonium is linked to the cefEF gene and encodes a deacetylcephalosporin C acetyltransferase closely related to homoserine O-acetyltransferase. J. Bacteriol 1992, 174:3056-3064.
17. Gutiérrez S., Velasco J., Marcos A.T., Fernández F.J., Fierro F., Barredo J.L., Díez B., Martín J.F. Expression of the cefG gene is limiting for cephalosporin biosynthesis in Acremonium chrysogenum. Appl. Microbiol. Biotechnol. 1997, 48:606-614.
18. Harris D.M., Diderich J.A., van der Krogt Z.A., Luttik M.A., Raamsdonk L.M., Bovenberg R.A., van Gulik W.M., van Dijken J.P., Pronk J.T. Enzymic analysis of NADPH metabolism in beta-lactam-producing Penicillium chrysogenum: Presence of a mitochondrial NADPH dehydrogenase. Metab. Eng. 2006, 8:91-101.
19. Harris D.M., Westerlaken I., Schipper D., van der Krogt Z.A., Gombert A.K., Sutherland J., Raamsdonk L.M., van den Berg M.A., Bovenberg R.A., Pronk J.T., Daran J.M. Engineering of Penicillium chrysogenum for fermentative production of a novel carbamoylated cephem antibiotic precursor. Metab. Eng. 2009, 11:125-137.
20. Hickman R.K., McMurry L.M., Levy S.B. Overproduction and purification of the Tn10-specified inner membrane tetracycline resistance protein Tet using fusions to beta-galactosidase. Mol. Microbiol 1990, 4:1241-1251.
21. Hoff B., Schmitt E.K., Kück U. CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum. Mol. Microbiol. 2005, 56:1220-1233.
22. Jekosch K., Kück U. Glucose dependent transcriptional expression of the cre1 gene in Acremonium chrysogenum strains showing different levels of cephalosporin C production. Curr. Genet 2000, 37:388-395.
23. Jones E.W., Fink G.R. Regulation of amino acid and nucleotide biosynthesis in yeast. The Molecular Biology of the Yeast Saccharomyces: Metabolism and Gene Expression 1992, 181-299. Cold Spring Harbor Laboratory Press, New York. J.N. Strathern, E.W. Jones, J.R. Broach (Eds.).
24. Kleijn R.J., Liu F., van Winden W.A., van Gulik W.M., Ras C., Heijnen J.J. Cytosolic NADPH metabolism in penicillin-G producing and non-producing chemostat cultures of Penicillium chrysogenum. Metab. Eng. 2007, 9:112-123.
25. Kreisberg-Zakarin R., Borovok I., Yanko M., Aharonowitz Y., Cohen G. Recent advances in the structure and function of isopenicillin N synthase. Antonie van Leeuwenhoek 1999, 75:33-39.
26. Le T.B., Fiedler H..P.., den Hengst C..D., Ahn S.K., Maxwell A., Buttner M.J. Coupling of the biosynthesis and export of the DNA gyrase inhibitor simocyclinone in Streptomyces antibioticus. Mol. Microbiol. 2009, 72(6):1462-1474.
27. Lejon S., Ellis J., Valegård K. The last step in cephalosporin C formation revealed: Crystal structures of deacetylcephalosporin C acetyltransferase from Acremonium chrysogenum in complexes with reaction intermediates. J. Mol. Biol 2008, 377:935-944.
28. Liras P., Martín J.F. Gene clusters for beta-lactam antibiotics and control of their expression: Why have clusters evolved, and from where did they originate?. Int. Microbiol 2006, 9:9-19.
29. MacPherson S., Larochelle M., Turcotte B. A fungal family of transcriptional regulators: The zinc cluster proteins. Microbiol. Mol. Biol. Rev. 2006, 70:583-604.
30. Martín J.F. Alpha-aminoadipyl-cysteinyl-valine synthetases in beta-lactam producing organisms. From Abraham's discoveries to novel concepts of non-ribosomal peptide synthesis. J. Antibiot. (Tokyo) 2000, 53:1008-1021.
31. Martín 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.
32. Martín J.F., Demain A.L. Unraveling the methionine-cephalosporin puzzle in Acremonium chrysogenum. Trends Biotechnol. 2002, 20:12502-12507.
33. Martín J.F., Liras P. Organization and expression of genes involved in the biosynthesis of antibiotics and other secondary metabolites. Annu. Rev. Microbiol 1989, 43:173-206.
34. Martín J.F., Ullán R.V., García-Estrada C. Regulation and compartmentalization of Β-lactam biosynthesis. Microbiol Biotechnol 2010, 3:285-299.
35. Nasution U., van Gulik W.M., Ras C., Proell A., Heijnen J.J. A metabolome study of the steady-state relation between central metabolism, amino acid biosynthesis and penicillin production in Penicillium chrysogenum. Metab. Eng. 2008, 10:10-23.
36. Neyfakh A.A. Natural functions of bacterial multidrug transporters. Trends Microbiol. 1997, 5:309-313.
37. Nijland J.G., Kovalchuk A., van den Berg M.A., Bovenberg R.A., Driessen A.J. 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.
38. Olano C., Lombó F., Méndez C., Salas J.A. Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab. Eng. 2008, 10:281-292.
39. Palmer J.M., Keller NP Secondary metabolism in fungi: Does chromosomal location matter?. Curr. Opin. Microbiol. 2010, 13(4):431-436.
40. Plate I., Albertsen L., Lisby M., Hallwyl S.C.L., Feng Q., Seong C., Rothstein R., Sung P., Mortensen U.H. Rad52 is important for its nuclear localization in Saccharomyces cerevisiae. DNA Repair 2008, 7:57-66.
41. Punt P.J., Oliver R.P., Dingemanse M.A., Pouwels P.H., Van den Hondel.C.A. Transformation of Aspergillus based on the hygromycin B resistance marker from Escherichia coli. Gene 1987, 56:117-124.
42. Putman M., van Veen H.W., Konings W.N. Molecular properties of bacterial multidrug transporters. Microbiol. Mol. Biol. Rev. 2000, 64:672-693.
43. Samson S.M., Belagaje R., Blankenship D.T., Chapman J.L., Perry D., Skatrud P.L., VanFrank R.M., Abraham E.P., Baldwin J.E., Queener S.W. Isolation, sequence determination and expression in Escherichia coli of the isopenicillin N synthetase gene from Cephalosporium acremonium. Nature 1985, 318:191-194.
44. Samson S.M., Dotzlaf J.E., Slisz M.L., Becker G.W., van Frank R.M., Veal.L.E., Yeh.W-K., Miller J.E., Queener S.W., Ingolia T.D. Cloning and expression of the fungal expandase/hidroxylase gene involved in cephalosporin biosynthesis. Bio/Technology 1987, 5:1207-1214.
45. Schmitt E., Hoff B., Kück U. AcFKH1, a novel member of the forkhead family, associates with the RFX transcription factor CPCR1 in the cephalosporin C-producing fungus Acremonium chrysogenum. Gene 2004, 342:269-281.
46. Schmitt E.K., Hoff B., Kück U. Regulation of cephalosporin biosynthesis. Adv. Biochem. Eng. Biotechnol. 2004, 88:1-43.
47. Schmitt E.K., Kempken R., Kück U. Functional analysis of promoter sequences of cephalosporin C biosynthesis genes from Acremonium chrysogenum: Specific DNA-protein interactions and characterization of the transcription factor PacC. Mol. Genet. Genomics 2001, 265:508-518.
48. Schmitt E.K., Kück U. The fungal CPCR1 protein, which binds specifically to beta-lactam biosynthesis genes, is related to human regulatory factor X transcription factors. J. Biol. Chem 2000, 275:9348-9357.
49. Schofield C.J., Baldwin J.E., Byford M.F., Clifton I., Hajdu J., Hensgens C., Roach P. Proteins of the penicillin biosynthesis pathway. Curr. Opin. Struct. Biol. 1997, 7:857-864.
50. Shelest E. Transcription factors in fungi. FEMS Microbiol. Lett. 2008, 286:145-151.
51. Teijeira F., Ullán R.V., Guerra S.M., García-Estrada C., Vaca I., Martín J.F. The transporter CefM is essential for cephalosporin production. Biochem. J. 2009, 418:113-124.
52. Ullán R.V., Campoy S., Casqueiro J., Fernández F.J., Martín J.F. Deacetylcephalosporin C production in Penicillium chrysogenum by expression of the isopenicillin N epimerization, ring expansion, and acetylation genes. Chem. Biol. 2007, 14:329-339.
53. Ullán R.V., Casqueiro J., Bañuelos O., Fernández F.J., Gutiérrez S., Martín J.F. A novel epimerization system in fungal secondary metabolism involved in the conversion of isopenicillin N into penicillin N in Acremonium chrysogenum. J. Biol. Chem. 2002, 277:46216-46225.
54. Ullán R.V., Casqueiro J., Naranjo L., Vaca I., Martín J.F. Expression of cefD2 and he conversion of isopenicillin N into penicillin N by the two-component epimerase system are rate-limiting steps in cephalosporin biosynthesis. Mol. Genet. Genomics 2004, 272:562-570.
55. Ullán R.V., Godio R.P., Teijeira F., Vaca I., García-Estrada C., Feltrer R., Kosalková K., Martín J.F. RNA-silencing in Penicillium chrysogenum and Acremonium chrysogenum: Validation studies using beta-lactam genes expression. J. Microbiol. Methods 2008, 75:209-218.
56. Ullán R.V., Liu G., Casqueiro J., Gutiérrez S., Bañuelos O., Martín J.F. The cefT gene of Acremonium chrysogenum C10 encodes a multidrug efflux pump protein that significantly increases cephalosporin C production. Mol. Gen. Genomics 2002, 267:673-683.
57. Ullán R.V., Teijeira F., Guerra S.M., Vaca I., Martín J.F. Characterization of a novel peroxisome membrane protein essential for conversion of isopenicillin N into cephalosporin C. Biochem. J. 2010, 432:227-236.
58. Ullán R.V., Teijeira F., Martín J.F. Expression of the Acremonium chrysogenum cefT gene in Penicillum chrysogenum indicates that it encodes an hydrophilic beta-lactam transporter. Curr. Genet. 2008, 54:153-161.
59. van de Kamp M., Driessen A.J., Konings W.N. Compartmentalization and transport in beta-lactam antibiotic biosynthesis by filamentous fungi. Antonie van Leeuwenhoek 1999, 75:41-78.
60. Velasco J., Gutiérrez S., Casqueiro J., Fierro F., Campoy S., Martín J.F. Cloning and characterization of the gene cahB encoding a cephalosporin C acetylhydrolase from Acremonium chrysogenum. Appl. Microbiol. Biotechnol. 2001, 57:350-356.
61. Velasco J., Gutiérrez S., Fernández F.J., Marcos A.T., Arenósm C., Martín J.F. Exogenous methionine increases levels of mRNAs transcribed from pcbAB, pcbC, and cefEF genes, encoding enzymes of the cephalosporin biosynthetic pathway, in Acremonium chrysogenum. J. Bacteriol 1994, 176:985-991.
62. Willems A.R, Tahlan K., Taguchi T., Zhang K., Lee Z.Z., Ichinose K., Junop M.S., Nodwell J.R. Crystal structures of the Streptomyces coelicolor TetR-like protein ActR alone and in complex with actinorhodin or the actinorhodin biosynthetic precursor (S)-DNPA. Mol Biol. 2008, 376:1377-1387.
63. Zhang J., Demain A.L. ACV synthetase. Crit. Rev. Biotechnol. 1992, 12:245-260.