1887

Chapter 15 : Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis

Authors: Robert A. Cramer, Jr.1, E. Keats Shwab2, Nancy P. Keller3
VIEW AFFILIATIONS HIDE AFFILIATIONS
Affiliations: 1: Dept. of Veterinary Molecular Biology, Montana State University–Bozeman, Bozeman, MT 59718; 2: Dept. of Plant Pathology and Dept. of Medical Microbiology and Immunology, University of Wisconsin–Madison, Madison, WI 53706; 3: Dept. of Plant Pathology and Dept. of Medical Microbiology and Immunology, University of Wisconsin–Madison, Madison, WI 53706
Content Type: Monograph
Publication Year: 2009

Category: Clinical Microbiology; Fungi and Fungal Pathogenesis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Preview Magnify
Zoom in
Zoomout

Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815523/9781555814380_Chap15-1.gif /docserver/preview/fulltext/10.1128/9781555815523/9781555814380_Chap15-2.gif

Abstract:

With respect to fungal pathogenesis and virulence, fungal secondary metabolites are primary virulence factors in several fungus-plant interactions. This chapter explores the current state of knowledge on the production of secondary metabolites by the opportunistic human pathogen Aspergillus fumigatus. Several types of secondary metabolites have been isolated from A. fumigatus in vitro cultures, including fumitremorgins, verruculogen, fumigaclavines, fumagillin, helvolic acid, and gliotoxin, among other, less-studied compounds. Importantly, gliotoxin has been detected in the serum of patients with invasive pulmonary aspergillosis (IPA) and in experimental murine models of IPA. Overexpression of the nonribosomal peptide synthetase (NRPS) ftmA in A. fumigatus AF293.1 and A. nidulans resulted in accumulation of brevianamide F, the likely precursor of fumitremorgin biosynthesis. Like many other A. fumigatus-produced secondary metabolites, the potential role of helvolic acid in aspergillosis is unknown. Production of secondary metabolites is an energetically costly process involving many enzymatic steps. In fungi, signals generated in response to the environment are typically relayed through DNA-binding Cys2His2 zinc-finger proteins, including CreA for carbon signaling, AreA for nitrogen signaling, and PacC for pH signaling. Insight into signaling pathways linking growth, development, and secondary metabolism came from a key study in A. nidulans showing heterotrimeric G-protein activation simultaneously inhibits sporulation and production of the mycotoxin sterigmatocystin while promoting vegetative growth. Fungal secondary metabolites are important biomolecules with significant biological activities.

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-1,webId=/content/author/10.1128/9781555815523.ch15-1,properties={foaf_givenname=Robert A., foaf_name=Robert A. Cramer, Jr., foaf_surname=Cramer, Jr., pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-2,webId=/content/author/10.1128/9781555815523.ch15-2,properties={foaf_givenname=E. Keats, foaf_name=E. Keats Shwab, foaf_surname=Shwab, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-3,webId=/content/author/10.1128/9781555815523.ch15-3,properties={foaf_givenname=Nancy P., foaf_name=Nancy P. Keller, foaf_surname=Keller, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff3]]}]]
Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
/content/10.1128/9781555815523.ch15.ch15fig01
Figure 1.
Secondary metabolites produced by A. fumigatus. Chemical structures were obtained from the PubChem project http://pubchem.ncbi.nlm.nih.gov/
10.1128/9781555815523/f0186-01_thmb.gif
10.1128/9781555815523/f0186-01.gif
Image of Figure 1.
Figure 1.

Secondary metabolites produced by A. fumigatus. Chemical structures were obtained from the PubChem project http://pubchem.ncbi.nlm.nih.gov/

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555815523.ch15.ch15fig02
Figure 2.
Regulation of a hypothetical secondary metabolite gene cluster. This figure illustrates modes of regulation of production for a hypothetical secondary metabolite based on known regulatory mechanisms for gliotoxin, aflatoxin, sterigmatocystin, and others. A cluster-specific regulatory gene located within the cluster is activated by LaeA and in turn activates expression of the rest of the cluster genes, leading to biosynthesis of the metabolite product, which then may act to promote expression of the cluster in a positive feedback mechanism. Cluster expression is repressed by the chromatin-modifying proteins ClrD, HepA, and HdaA. G-protein signaling activates PKA, which suppresses metabolite production by inhibiting expression of laeA and the in-cluster transcription factor gene and also by inactivation of its protein product via phosphorylation. Environmental signals, such as carbon and nitrogen sources, pH, and light, may alter production of this metabolite through the actions of proteins such as CreA, PacC, AreA, and VeA.
10.1128/9781555815523/f0191-01_thmb.gif
10.1128/9781555815523/f0191-01.gif
Image of Figure 2.
Figure 2.

Regulation of a hypothetical secondary metabolite gene cluster. This figure illustrates modes of regulation of production for a hypothetical secondary metabolite based on known regulatory mechanisms for gliotoxin, aflatoxin, sterigmatocystin, and others. A cluster-specific regulatory gene located within the cluster is activated by LaeA and in turn activates expression of the rest of the cluster genes, leading to biosynthesis of the metabolite product, which then may act to promote expression of the cluster in a positive feedback mechanism. Cluster expression is repressed by the chromatin-modifying proteins ClrD, HepA, and HdaA. G-protein signaling activates PKA, which suppresses metabolite production by inhibiting expression of laeA and the in-cluster transcription factor gene and also by inactivation of its protein product via phosphorylation. Environmental signals, such as carbon and nitrogen sources, pH, and light, may alter production of this metabolite through the actions of proteins such as CreA, PacC, AreA, and VeA.

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555815523.ch15
1. Abe, I.,, K. Naito,, Y. Takagi, and, H. Noguchi. 2001. Molecular cloning, expression, and site-directed mutations of oxidosqualene cy-clase from Cephalosporium caerulens. Biochim. Biophys. Acta 1522: 67– 73.
2. Allen, J. D.,, A. van Loevezijn,, J. M. Lakhai,, M. van der Valk,, O. van Tellingen,, G. Reid,, J. H. Schellens,, G. J. Koomen, and, A. H. Schinkel. 2002. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol. Cancer Ther. 1: 417– 425.
3. Amitani, R.,, G. Taylor,, E. N. Elezis,, C. Llewellyn-Jones,, J. Mitchell,, F. Kuze,, P. J. Cole, and, R. Wilson. 1995. Purification and characterization of factors produced by Aspergillus fumigatus which affect human ciliated respiratory epithelium. Infect. Immun. 63: 3266– 3271.
4. Bailey, L. 1953. Effect of fumagillin upon Nosema apis (Zander). Nature 171: 212– 213.
5. Balibar, C. J., and, C. T. Walsh. 2006. GliP, a multimodular non-ribosomal peptide synthetase in Aspergillus fumigatus, makes the di-ketopiperazine scaffold of gliotoxin. Biochemistry 45: 15029– 15038.
6. Beaver, J. P., and, P. Waring. 1994. Lack of correlation between early intracellular calcium ion rises and the onset of apoptosis in thy-mocytes. Immunol. Cell. Biol. 72: 489– 499.
7. Belkacemi, L.,, R. C. Barton,, V. Hopwood, and, E. G. Evans. 1999. Determination of optimum growth conditions for gliotoxin production by Aspergillus fumigatus and development of a novel method for gliotoxin detection. Med. Mycol. 37: 227– 233.
8. Bennett, J. W.,, F. A. Fernholz, and, L. S. Lee. 1978. Effect of light on aflatoxins, anthraquinones, and sclerotia in Aspergillus flavus and A. parasiticus. Mycologia 70: 104– 116.
9. Bennett, J. W.,, J. J. Dunn, and, C. I. Goldsman. 1981. Influence of white light on production of aflatoxins and anthraquinones in As-pergillus parasiticus. Appl. Environ. Microbiol. 41: 488– 491.
10. Bennett, J. W., and, R. Bentley. 1989. What’s in a name? Microbial secondary metabolism. Adv. Appl. Microbiol. 34: 1– 28.
11. Bernardo, P. H.,, N. Brasch,, C. L. Chai, and, P. Waring. 2003. A novel redox mechanism for the glutathione-dependent reversible uptake of a fungal toxin in cells. J. Biol. Chem. 278: 46549– 46555.
12. Bernier, S. G.,, N. Taghizadeh,, C. D. Thompson,, W. F. Westlin, and, G. Hannig. 2005. Methionine aminopeptidases type I and type II are essential to control cell proliferation. J. Cell. Biochem. 95: 1191– 1203.
13. Bok, J. W., and, N. P. Keller. 2004. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3: 527– 535.
14. Bok, J. W.,, S. A. Balajee,, K. A. Marr,, D. Andes,, K. F. Nielsen,, J. C. Frisvad, and, N. P. Keller. 2005. LaeA, a regulator of morphogenetic fungal virulence factors. Eukaryot. Cell 4: 1574– 1582.
15. Bok, J. W.,, D. Chung,, S. A. Balajee,, K. A. Marr,, D. Andes,, K. F. Nielsen,, J. C. Frisvad,, K. A. Kirby, and, N. P. Keller. 2006a. GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect. Immun. 74: 6761– 6768.
16. Bok, J. W.,, D. Hoffmeister,, L. A. Maggio-Hall,, R. Murillo,, J. D. Glasner, and, N. P. Keller. 2006b. Genomic mining for Aspergillus natural products. Chem. Biol. 13: 31– 37.
17. Bok, J. W.,, D. Noordermeer,, S. P. Kale, and, N. P. Keller. 2006c. Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol. Microbiol. 61: 1636– 1645.
18. Bradford, H. F.,, P. J. Norris, and, C. C. Smith. 1990. Changes in transmitter release patterns in vitro induced by tremorgenic mycotoxins. J. Environ. Pathol. Toxicol. Oncol. 10: 17– 30.
19. Brakhage, A. A.,, A. Andrianopoulos,, M. Kato,, S. Steidl,, M. A. Davis,, N. Tsukagoshi, and, M. J. Hynes. 1999. HAP-like CCAAT-binding complexes in filamentous fungi: implications for biotechnology. Fungal Genet. Biol. 27: 243– 252.
20. Brodhagen, M., and, N. P. Keller. 2006. Signaling pathways connecting mycotoxin production and sporulation. Mol. Plant Pathol. 7: 285– 301.
21. Brown, D. W.,, J. H. Yu,, H. S. Kelkar,, M. Fernandes,, T. C. Nesbitt,, N. P. Keller,, T. H. Adams, and, T. J. Leonard. 1996. Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in As-pergillus nidulans. Proc. Natl. Acad. Sci. USA 93: 1418– 1422.
22. Butchko, R. A.,, T. H. Adams, and, N. P. Keller. 1999. Aspergillus nidulans mutants defective in stc gene cluster regulation. Genetics 153: 715– 720.
23. Calvo, A. M.,, R. A. Wilson,, J. W. Bok, and, N. P. Keller. 2002. Relationship between secondary metabolism and fungal development. Microbiol. Mol. Biol. Rev. 66: 447– 459.
24. Chang, P. K.,, J. W. Cary,, D. Bhatnagar,, T. E. Cleveland,, J. W. Bennett,, J. E. Linz,, C. P. Woloshuk, and, G. A. Payne. 1993. Cloning of the Aspergillus parasiticus apa-2 gene associated with the regulation of aflatoxin biosynthesis. Appl. Environ. Microbiol. 59: 3273– 3279.
25. Chang, P. K.,, J. Yu,, D. Bhatnagar, and, T. E. Cleveland. 2000. Characterization of the Aspergillus parasiticus major nitrogen regulatory gene, areA. Biochim. Biophys. Acta 1491: 263– 266.
26. Chang, S. Y.,, E. C. McGary, and, S. Chang. 1989. Methionine aminopeptidase gene of Escherichia coli is essential for cell growth. J. Bacteriol. 171: 4071– 4072.
27. Clevstrom, G.,, H. Ljunggren,, S. Tegelstrom, and, K. Tideman. 1983. Production of aflatoxin by an Aspergillus flavus isolate cultured under a limited oxygen supply. Appl. Environ. Microbiol. 46: 400– 405.
28. Cohen, D. J.,, R. Loertscher,, M. F. Rubin,, N. L. Tilney,, C. B. Carpenter, and, T. B. Strom. 1984. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann. Intern. Med. 101: 667– 682.
29. Cole, R. J.,, J. W. Kirksey,, J. W. Dorner,, D. M. Wilson,, J. C. Johnson, Jr.,, A. N. Johnson,, D. M. Bedell,, J. P. Springer,, K. K. Chexal,, J. C. Clardy, and, R. H. Cox. 1977. Mycotoxins produced by Aspergillus fumigatus species isolated from molded silage. J. Agric. Food Chem. 25: 826– 830.
30. Coyle, C. M., and, D. G. Panaccione. 2005. An ergot alkaloid biosynthesis gene and clustered hypothetical genes from Aspergillus fumigatus. Appl. Environ. Microbiol. 71: 3112– 3118.
31. Cramer, R. A., Jr.,, M. P. Gamcsik,, R. M. Brooking,, L. K. Najvar,, W. R. Kirkpatrick,, T. F. Patterson,, C. J. Balibar,, J. R. Graybill,, J. R. Perfect,, S. N. Abraham, and, W. J. Steinbach. 2006a. Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot. Cell 5: 972– 980.
32. Cramer, R. A., Jr.,, J. E. Stajich,, Y. Yamanaka,, F. S. Dietrich,, W. J. Steinbach, and, J. R. Perfect. 2006b. Phylogenomic analysis of non-ribosomal peptide synthetases in the genus Aspergillus. Gene 383: 24– 32.
33. De Las Penas, A.,, S. J. Pan,, I. Castano,, J. Alder,, R. Cregg, and, B. P. Cormack. 2003. Virulence-related surface glycoproteins in the yeast pathogen Candida glabrata are encoded in subtelomeric clusters and subject to RAP1- and SIR-dependent transcriptional silencing. Genes Dev. 17: 2245– 2258.
34. Domergue, R.,, I. Castano,, A. De Las Penas,, M. Zupancic,, V. Lock-atell,, J. R. Hebel,, D. Johnson, and, B. P. Cormack. 2005. Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308: 866– 870.
35. Dowzer, C. E., and, J. M. Kelly. 1989. Cloning of the creA gene from Aspergillus nidulans: a gene involved in carbon catabolite repression. Curr. Genet. 15: 457– 459.
36. Dummer, J. S.,, A. Hardy,, A. Poorsattar, and, M. Ho. 1983. Early infections in kidney, heart, and liver transplant recipients on cy-closporine. Transplantation 36: 259– 267.
37. Duran, R. M.,, J. W. Cary, and, A. M. Calvo. 2007. Production of cyclopiazonic acid, aflatrem, and aflatoxin by Aspergillus flavus is regulated by veA, a gene necessary for sclerotial formation. Appl. Microbiol. Biotechnol. 73: 1158– 1168.
38. Ehrlich, K. C.,, B. G. Montalbano, and, J. W. Cary. 1999. Binding of the C6-zinc cluster protein, AflR, to the promoters of aflatoxin pathway biosynthesis genes in Aspergillus parasiticus. Gene 230: 249– 257.
39. Eichner, R. D., and, A. Mullbacher. 1984. Hypothesis: fungal toxins are involved in aspergillosis and AIDS. Aust. J. Exp. Biol. Med. Sci. 62: 479– 484.
40. Eichner, R. D.,, M. Al Salami,, P. R. Wood, and, A. Mullbacher. 1986. The effect of gliotoxin upon macrophage function. Int. J. Immu-nopharmacol. 8: 789– 797.
41. Ellis, W. O.,, J. P. Smith,, B. K. Simpson,, H. Ramaswamy, and, G. Doyon. 1994. Growth of and aflatoxin production by Aspergillus flavus in peanuts stored under modified atmosphere packaging (MAP) conditions. Int. J. Food Microbiol. 22: 173– 187.
42. Fairhead, C., and, B. Dujon. 2006. Structure of Kluyveromyces lactis subtelomeres: duplications and gene content. FEMS Yeast Res. 6: 428– 441.
43. Fernandes, M.,, N. P. Keller, and, T. H. Adams. 1998. Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol. Microbiol. 28: 1355– 1365.
44. Fox, E. M.,, D. M. Gardiner,, N. P. Keller, and, B. J. Howlett. 2008. A Zn(II)2Cys6 DNA binding protein regulates the sirodesmin PL biosynthetic gene cluster in Leptosphaeria maculans. Fungal Genet. Biol. 45: 671– 682.
45. Freitas-Junior, L. H.,, R. Hernandez-Rivas,, S. A. Ralph,, D. Montiel-Condado,, O. K. Ruvalcaba-Salazar,, A. P. Rojas-Meza,, L. Mancio-Silva,, R. J. Leal-Silvestre,, A. M. Gontijo,, S. Shorte, and, A. Scherf. 2005. Telomeric heterochromatin propagation and histone acety-lation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121: 25– 36.
46. Fukuda, T.,, M. Boeckh,, K. A. Guthrie,, D. K. Mattson,, S. Owens,, A. Wald,, B. M. Sandmaier,, L. Corey,, R. F. Storb, and, K. A. Marr. 2004. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol. Blood Marrow Transplant. 10: 494– 503.
47. Gallagher, R. T., and, G. C. Latch. 1977. Production of the tremor-genic mycotoxins verruculogen and fumitremorgin B by Penicillium piscarium Westling. Appl. Environ. Microbiol. 33: 730– 730.
48. Gardiner, D. M., and, B. J. Howlett. 2005. Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol. Lett. 248: 241– 241.
49. Gardiner, D. M.,, R. S. Jarvis, and, B. J. Howlett. 2005a. The ABC transporter gene in the sirodesmin biosynthetic gene cluster of Lep-tosphaeria maculans is not essential for sirodesmin production but facilitates self-protection. Fungal Genet. Biol. 42: 257– 257.
50. Gardiner, D. M.,, P. Waring, and, B. J. Howlett. 2005b. The epipoly-thiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology 151: 1021– 1021.
51. Garimella, T. S.,, D. D. Ross, and, K. S. Bauer. 2004. Liquid chro-matography method for the quantitation of the breast cancer resistance protein ABCG2 inhibitor fumitremorgin C and its chemical analogues in mouse plasma and tissues. J. Chromatogr. B 807: 203– 203.
52. Griffith, E. C,, Z. Su,, B. E. Turk,, S. Chen,, Y. H. Chang,, Z. Wu,, K. Biemann, and, J. O. Liu. 1997. Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem. Biol. 4: 461– 461.
53. Griffith, E. C,, Z. Su,, S. Niwayama,, C. A. Ramsay,, Y. H. Chang, and, J. O. Liu. 1998. Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Natl. Acad. Sci. USA 95: 15183– 15183.
54. Grow, W. B.,, J. S. Moreb,, D. Roque,, K. Manion,, H. Leather,, V. Reddy,, S. A. Khan,, K. J. Finiewicz,, H. Nguyen,, C. J. Clancy,, P. S. Mehta, and, J. R. Wingard. 2002. Late onset of invasive Aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplant. 29: 15– 15.
55. Halme, A.,, S. Bumgarner,, C. Styles, and, G. R. Fink. 2004. Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast. Cell 116: 405– 405.
56. Han, K. H.,, J. A. Seo, and, J. H. Yu. 2004. Regulators of G-protein signalling in Aspergillus nidulans: RgsA downregulates stress response and stimulates asexual sporulation through attenuation of GanB (Ga) signalling. Mol. Microbiol. 53: 529– 529.
57. Hartwig, A., and, A. Przelecka. 1971. Nucleic acids in intestine of Apis mellifica infected with Nosema apis and treated with fumagillin DCH: cytochemical and autoradiographic studies. J. Invertebr. Pathol. 18: 331– 331.
58. Hewitt, W. L. 1967. Penicillin—historical impact on infection control. Ann. N. Y. Acad. Sci. 145: 212– 212.
59. Hicks, J. K.,, J. H. Yu,, N. P. Keller, and, T. H. Adams. 1997. Aspergillus sporulation and mycotoxin production both require inactivation of the FadA G alpha protein-dependent signaling pathway. EMBO J. 16: 4916– 4916.
60. Hoffmeister, D., and, N. P. Keller. 2007. Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat. Prod. Rep. 24: 393– 393.
61. Horn, D., and, J. D. Barry. 2005. The central roles of telomeres and subtelomeres in antigenic variation in African trypanosomes. Chromosome Res. 13: 525– 525.
62. Hurne, A. M.,, C. L. Chai,, K. Moerman, and, P. Waring. 2002. Influx of calcium through a redox-sensitive plasma membrane channel in thymocytes causes early necrotic cell death induced by the epipoly-thiodioxopiperazine toxins. J. Biol. Chem. 277: 31631– 31631.
63. Hynes, M. J. 1975. Studies on the role of the areA gene in the regulation of nitrogen catabolism in Aspergillus nidulans. Aust. J. Biol. Sci. 28: 301– 313.
64. Ingber, D.,, T. Fujita,, S. Kishimoto,, K. Sudo,, T. Kanamaru,, H. Brem, and, J. Folkman. 1990. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348: 555– 557.
65. Johnson, J. R.,, W. F. Bruce, and, J. D. Dutcher. 1943. Gliotoxin, the antibiotic principle of Gliocladium fimbriatum. Production, physical and biological properties. J. Am. Chem. Soc. 65: 2005– 2009.
66. Kale, S. P.,, J. W. Cary,, N. Hollis,, J. R. Wilkinson,, D. Bhatnagar,, J. Yu,, T. E. Cleveland, and, J. W. Bennett. 2007. Analysis of aflatoxin regulatory factors in serial transfer-induced non-aflatoxigenic As-pergillus parasiticus. Food Addit. Contam. 24: 1061– 1069.
67. Kato, N.,, W. Brooks, and, A. M. Calvo. 2003. The expression of sterigmatocystin and penicillin genes in Aspergillus nidulans is controlled by veA, a gene required for sexual development. Eukaryot. Cell 2: 1178– 1186.
68. Katznelson, H., and, C. A. Jamieson. 1952. Control of nosema disease of honeybees with fumagillin. Science 115: 70– 71.
69. Kawaguchi, A.,, H. Kobayashi, and, S. Okuda. 1973. Cyclization of 2,3-oxidosqualene with microsomal fraction of Cephalosporium ca-erulens. Chem. Pharm. Bull. 21: 577– 583.
70. Keller, N.,, J. Bok,, D. Chung,, R. M. Perrin, and, E. K. Shwab. 2006. LaeA, a global regulator of Aspergillus toxins. Med. Mycol. 44 (Suppl.): 83– 85.
71. Keller, N. P., and, T. M. Hohn. 1997. Metabolic pathway gene clusters in filamentous fungi. Fungal Genet. Biol. 21: 17– 29.
72. Keller, N. P.,, G. Turner, and, J. W. Bennett. 2005. Fungal secondary metabolism: from biochemistry to genomics. Nat. Rev. Microbiol. 3: 937– 947.
73. Khoufache, K.,, O. Puel,, N. Loiseau,, M. Delaforge,, D. Rivollet,, A. Coste,, C. Cordonnier,, E. Escudier,, F. Botterel, and, S. Bretagne. 2007. Verruculogen associated with Aspergillus fumigatus hyphae and conidia modifies the electrophysiological properties of human nasal epithelial cells. BMC Microbiol. 7: 5.
74. Kim, K. H.,, Y. R. Cho,, M. I. Rota,, R. A. Cramer, Jr., and, C. B. Lawrence. 2007. Functional analysis of the Alternaria brassicicola non-ribosomal peptide synthetase gene AbNPS2 reveals a role in conidial cell wall construction. Mol. Plant Pathol. 8: 23– 39.
75. Knaus, H. G.,, O. B. McManus,, S. H. Lee,, W. A. Schmalhofer,, M. Garcia-Calvo,, L. M. Helms,, M. Sanchez,, K. Giangiacomo,, J. P. Reuben,, A. B. Smith III, et al. 1994. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry 33: 5819– 5828.
76. Kroll, M.,, F. Arenzana-Seisdedos,, F. Bachelerie,, D. Thomas,, B. Fri-guet, and, M. Conconi. 1999. The secondary fungal metabolite glio-toxin targets proteolytic activities of the proteasome. Chem. Biol. 6: 689– 698.
77. Kupfahl, C.,, T. Heinekamp,, G. Geginat,, T. Ruppert,, A. Hartl,, H. Hof, and, A. A. Brakhage. 2006. Deletion of the gliP gene of As-pergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model. Mol. Microbiol. 62: 292– 302.
78. Kupfahl, C.,, A. Michalka,, C. Lass-Florl,, G. Fischer,, G. Haase,, T. Ruppert,, G. Geginat, and, H. Hof. 2008. Gliotoxin production by clinical and environmental Aspergillus fumigatus strains. Int. J. Med. Microbiol. 298: 319– 327.
79. Kupfahl, C.,, T. Ruppert,, A. Dietz,, G. Geginat, and, H. Hof. 2007. Candida species fail to produce the immunosuppressive secondary metabolite gliotoxin in vitro. FEMS Yeast Res. 7: 986– 992.
80. Land, C. J.,, K. Hult,, R. Fuchs,, S. Hagelberg, and, H. Lundstrom. 1987. Tremorgenic mycotoxins from Aspergillus fumigatus as a possible occupational health problem in sawmills. Appl. Environ. Microbiol. 53: 787– 790.
81. Land, C. J.,, H. Lundstrom, and, S. Werner. 1993. Production of tre-morgenic mycotoxins by isolates of Aspergillus fumigatus from sawmills in Sweden. Mycopathologia 124: 87– 93.
82. Landan, G.,, G. Cohen,, Y. Aharonowitz,, Y. Shuali,, D. Graur, and, D. Shiffman. 1990. Evolution of isopenicillin N synthase genes may have involved horizontal gene transfer. Mol. Biol. Evol. 7: 399– 406.
83. Larsen, T. O.,, J. Smedsgaard,, K. F. Nielsen,, M. A. Hansen,, R. A. Samson, and, J. C. Frisvad. 2007. Production of mycotoxins by As-pergillus lentulus and other medically important and closely related species in section Fumigati. Med. Mycol. 45: 225– 232.
84. Lee, B. N.,, S. Kroken,, D. Y. T. Chou,, B. Robbertse,, O. C. Yoder, and, B. G. Turgeon. 2005. Functional analysis of all nonribosomal peptide synthetases in Cochliobolus heterostrophus reveals a factor, NPS6, involved in virulence and resistance to oxidative stress. Eu-karyot. Cell 4: 545– 555.
85. Lewis, R. E.,, N. P. Wiederhold,, J. Chi,, X. Y. Han,, K. V. Komanduri,, D. P. Kontoyiannis, and, R. A. Prince. 2005a. Detection of gliotoxin in experimental and human aspergillosis. Infect. Immun. 73: 635– 637.
86. Lewis, R. E.,, N. P. Wiederhold,, M. S. Lionakis,, R. A. Prince, and, D. P. Kontoyiannis. 2005b. Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center. J. Clin. Microbiol. 43: 6120– 6122.
87. Li, X., and, Y. H. Chang. 1995. Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases. Proc. Natl. Acad. Sci. USA 92: 12357– 12361.
88. Litzka, O.,, P. Papagiannopolous,, M. A. Davis,, M. J. Hynes, and, A. A. Brakhage. 1998. The penicillin regulator PENR1 of Aspergillus nidulans is a HAP-like transcriptional complex. Eur. J. Biochem. 251: 758– 767.
89. Lopes Bezerra, L. M., and, S. G. Filler. 2004. Interactions of Aspergillus fumigatus with endothelial cells: internalization, injury, and stimulation of tissue factor activity. Blood 103: 2143– 2149.
90. Macdonald, J. C., and, G. P. Slater. 1975. Biosynthesis of gliotoxin and mycelianamide. Can. J. Biochem. 53: 475– 478.
91. Maiya, S.,, A. Grundmann,, S. M. Li, and, G. Turner. 2006. The fum-itremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. ChemBioChem 7: 1062– 1069.
92. Marr, K. A.,, R. A. Carter,, M. Boeckh,, P. Martin, and, L. Corey. 2002. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 100: 4358– 4366.
93. Martin, J. F. 2000. Molecular control of expression of penicillin biosynthesis genes in fungi: regulatory proteins interact with a bidirectional promoter region. J. Bacteriol. 182: 2355– 2362.
94. Meyers, D. M.,, G. Obrian,, W. L. Du,, D. Bhatnagar, and, G. A. Payne. 1998. Characterization of aflJ, a gene required for conversion of pathway intermediates to aflatoxin. Appl. Environ. Microbiol. 64: 3713– 3717.
95. Mitchell, C. G.,, J. Slight, and, K. Donaldson. 1997. Diffusible component from the spore surface of the fungus Aspergillus fumigatus which inhibits the macrophage oxidative burst is distinct from gli-otoxin and other hyphal toxins. Thorax 52: 796– 801.
96. Mullbacher, A., and, R. D. Eichner. 1984. Immunosuppression in vitro by a metabolite of a human pathogenic fungus. Proc. Natl. Acad. Sci. USA 81: 3835– 3837.
97. Mullbacher, A.,, P. Waring, and, R. D. Eichner. 1985. Identification of an agent in cultures of Aspergillus fumigatus displaying anti-phagocytic and immunomodulating activity in vitro. J. Gen. Micro-biol. 131: 1251– 1258.
98. Mullbacher, A.,, D. Hume,, A. W. Braithwaite,, P. Waring, and, R. D. Eichner. 1987. Selective resistance of bone marrow-derived hemopoietic progenitor cells to gliotoxin. Proc. Natl. Acad. Sci. USA 84: 3822– 3825.
99. Nierman, W. C.,, A. Pain,, M. J. Anderson,, J. R. Wortman,, H. S. Kim,, J. Arroyo,, M. Berriman,, K. Abe,, D. B. Archer,, C. Bermejo,, J. Bennett,, P. Bowyer,, D. Chen,, M. Collins,, R. Coulsen,, R. Davies,, P. S. Dyer,, M. Farman,, N. Fedorova,, T. V. Feldblum,, R. Fischer,, N. Fosker,, A. Fraser,, J. L. Garcia,, M. J. Garcia,, A. Goble,, G. H. Goldman,, K. Gomi,, S. Griffith-Jones,, R. Gwilliam,, B. Haas,, H. Haas,, D. Harris,, H. Horiuchi,, J. Huang,, S. Humphray,, J. Jimenez,, N. Keller,, H. Khouri,, K. Kitamoto,, T. Kobayashi,, S. Konzack,, R. Kulkarni,, T. Kumagai,, A. Lafton,, J. P. Large,, W. Li,, A. Lord,, C. Lu,, W. H. Majoros,, G. S. May,, B. L. Miller,, Y. Mohamoud,, M. Molina,, M. Monod,, I. Mouyna,, S. Mulligan,, L. Murphy,, S. O’Neil,, I. Paulsen,, M. A. Penalva,, M. Pertea,, C. Price,, B. L. Pritchard,, M. A. Quail,, E. Rabbinowitsch,, N. Rawlins,, M. A. Rajandream,, U. Reichard,, H. Renauld,, G. D. Robson,, S. Rodriguez de Cordoba,, J. M. Rodriguez-Pena,, C. M. Ronning,, S. Rutter,, S. L. Salzberg,, M. Sanchez,, J. C. Sanchez-Ferrero,, D. Saunders,, K. Seeger,, R. Squares,, S. Squares,, M. Takeuchi,, F. Tekaia,, G. Turner,, C. R. Vazquez de Aldana,, J. Weidman,, O. White,, J. Woodward,, J. H. Yu,, C. Fraser,, J. E. Galagan,, K. Asai,, M. Machida,, N. Hall,, B. Barrell, and, D. W. Denning. 2005. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438: 1151– 1151.
100. Nishida, S.,, L. S. Yoshida,, T. Shimoyama,, H. Nunoi,, T. Kobayashi, and, S. Tsunawaki. 2005. Fungal metabolite gliotoxin targets flav-ocytochrome b558 in the activation of the human neutrophil NADPH oxidase. Infect. Immun. Tb-. 235– 244.
101. O’Brian, G. R.,, D. R. Georgianna,, J. R. Wilkinson,, J. Yu,, H. K. Abbas,, D. Bhatnagar,, T. E. Cleveland,, W. Nierman, and, G. A. Payne. 2007. The effect of elevated temperature on gene transcription and aflatoxin biosynthesis. Mycologia 99: 232– 232.
102. Okuda, S.,, S. Iwasaki,, K. Tsuda,, Y. Sano,, T. Hata,, S. Udagawa,, Y. Nakayama, and, H. Yamaguchi. 1964. The structure of helvolic acid. Chem. Pharm. Bull. (Tokyo) 12: 121– 121.
103. Okuda, S.,, Y. Nakayama, and, K. Tsuda. 1966. Studies on micro-bial products. I. Helvolic acid and related compounds. I. β-desacetoxyhelvolic acid and helvolinic acid. Chem. Pharm. Bull. (Tokyo) 14: 436– 436.
104. Orciuolo, E.,, M. Stanzani,, M. Canestraro,, S. Galimberti,, G. Carulli,, R. Lewis,, M. Petrini, and, K. V. Komanduri. 2007. Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis. J. Leukoc. Biol. 82: 839– 839.
105. Osbourn, A. E. 2001. Tox-boxes, fungal secondary metabolites, and plant disease. Proc. Natl. Acad. Sci. USA 98: 14187– 14187.
106. Pahl, H. L.,, B. Krauss,, K. Schulze-Osthoff,, T. Decker,, E. B. Traenck-ner,, M. Vogt,, C. Myers,, T. Parks,, P. Warring,, A. Muhlbacher,, A. P. Czernilofsky, and, P. A. Baeuerle. 1996. The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-ĸB. J. Exp. Med. 183: 1829– 1829.
107. Panaccione, D. G., and, C. M. Coyle. 2005. Abundant respirable ergot alkaloids from the common airborne fungus Aspergillus fumigatus. Appl. Environ. Microbiol. 71: 3106– 3106.
108. Pardo, J.,, C. Urban,, E. M. Galvez,, P. G. Ekert,, U. Muller,, J. Kwon-Chung,, M. Lobigs,, A. Mullbacher,, R. Wallich,, C. Borner, and, M. M. Simon. 2006. The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice. J. Cell Biol. 174: 509– 509.
109. Payne, G. A., and, M. P. Brown. 1998. Genetics and physiology of aflatoxin biosynthesis. Annu. Rev. Phytopathol. 36: 329– 329.
110. Pedley, K. F., and, J. D. Walton. 2001. Regulation of cyclic peptide biosynthesis in a plant pathogenic fungus by a novel transcription factor. Proc. Natl. Acad. Sci. USA 98: 14174– 14174.
111. Perfect, J. R., and, D. T. Durack. 1985. Effects of cyclosporine in experimental cryptococcal meningitis. Infect. Immun. 50: 22– 22.
112. Perrin, R.,, N. Federova,, J.-W. Bok,, J. Wortman,, R. A. Cramer, Jr.,, H. Kim,, W. Nierman, and, N. Keller. 2007. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 3: e50.
113. Price, M. S.,, J. Yu,, W. C. Nierman,, H. S. Kim,, B. Pritchard,, C. A. Jacobus,, D. Bhatnagar,, T. E. Cleveland, and, G. A. Payne. 2006. The aflatoxin pathway regulator AflR induces gene transcription inside and outside of the aflatoxin biosynthetic cluster. FEMS Micro-biol. Lett. 255: 275– 275.
114. Proctor, R. H.,, T. M. Hohn,, S. P. McCormick, and, A. E. Desjardins. 1995. tri6 encodes an unusual zinc finger protein involved in regulation of trichothecene biosynthesis in Fusarium sporotrichioides. Appl. Environ. Microbiol. 61: 1923– 1923.
115. Rabindran, S. K.,, D. D. Ross,, L. A. Doyle,, W. Yang, and, L. M. Green-berger. 2000. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res. 60: 47– 47.
116. Ralph, S. A., and, A. Scherf. 2005. The epigenetic control of antigenic variation in Plasmodium falciparum. Curr. Opin. Microbiol. 8: 434– 434.
117. Rehmeyer, C,, W. Li,, M. Kusaba,, Y. S. Kim,, D. Brown,, C. Staben,, R. Dean, and, M. Farman. 2006. Organization of chromosome ends in the rice blast fungus, Magnaporthe oryzae. Nucleic Acids Res. 34: 4685– 4701.
118. Ribaud, P.,, C. Chastang,, J. P. Large,, L. Baffroy-Lafitte,, N. Parquet,, A. Devergie,, H. Esperou,, F. Selimi,, V. Rocha,, H. Esperou,, F. Selimi,, V. Rocha,, F. Derouin,, G. Socie, and, E. Gluckman. 1999. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin. Infect. Dis. 28: 322– 322.
119. Robyr, D.,, Y. Suka,, I. Xenarios,, S. K. Kurdistani,, A. Wang,, N. Suka, and, M. Grunstein. 2002. Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109: 437– 446.
120. Rodriguez, P. L., and, L. Carrasco. 1992. Gliotoxin: inhibitor of poliovirus RNA synthesis that blocks the viral RNA polymerase 3Dpol. J. Virol. 66: 1971– 1971.
121. Rohlfs, M.,, M. Albert,, N. P. Keller, and, F. Kempken. 2007. Secondary chemicals protect mould from fungivory. Biol. Lett. 3: 523– 523.
122. Roze, L. V.,, R. M. Beaudry,, N. P. Keller, and, J. E. Linz. 2004. Regulation of aflatoxin synthesis by FadA/cAMP/protein kinase A signaling in Aspergillus parasiticus. Mycopathologia 158: 219– 219.
123. Roze, L. V.,, R. M. Beaudry,, A. E. Arthur,, A. M. Calvo, and, J. E. Linz. 2007. Aspergillus volatiles regulate aflatoxin synthesis and asexual sporulation in Aspergillus parasiticus. Appl. Environ. Microbiol. 73: 7268– 7268.
124. Schindler, A. F.,, J. G. Palmer, and, W. V. Eisenberg. 1967. Aflatoxin production by Aspergillus flavus as related to various temperatures. Appl. Microbiol. 15: 1006– 1006.
125. Seo, J. A., and, J. H. Yu. 2006. The phosducin-like protein PhnA is required for Gβγ-mediated signaling for vegetative growth, developmental control, and toxin biosynthesis in Aspergillus nidulans. Eu-karyot. Cell 5: 400– 400.
126. Shah, D. T., and, B. Larsen. 1991. Clinical isolates of yeast produce a gliotoxin-like substance. Mycopathologia 116: 203– 203.
127. Shah, D. T.,, D. D. Glover, and, B. Larsen. 1995. In situ mycotoxin production by Candida albicans in women with vaginitis. Gynecol. Obstet. Investig. 39: 67– 67.
128. Shimizu, K., and, N. P. Keller. 2001. Genetic involvement of a cAMP-dependent protein kinase in a G protein signaling pathway regulating morphological and chemical transitions in Aspergillus nidulans. Genetics 157: 591– 591.
129. Shimizu, K.,, J. K. Hicks,, T. P. Huang, and, N. P. Keller. 2003. Pka, Ras and RGS protein interactions regulate activity of AflR, a Zn(II)2Cys6 transcription factor in Aspergillus nidulans. Genetics 165: 1095– 1095.
130. Shwab, E. K.,, J. W. Bok,, M. Tribus,, J. Galehr,, S. Graessle, and, N. P. Keller. 2007. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 6: 1656– 1656.
131. Sin, N.,, L. Meng,, M. Q. Wang,, J. J. Wen,, W. G. Bornmann, and, C. M. Crews. 1997. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc. Natl. Acad. Sci. USA 94: 6099– 6099.
132. Spilsbury, J. F., and, S. Wilkinson. 1961. The isolation of festuclavine and two new clavine alkaloids from Aspergillus fumigatus Fres. J. Chem. Soc. 5: 2085– 2091.
133. Sprote, P., and, A. A. Brakhage. 2007. The light-dependent regulator velvet A of Aspergillus nidulans acts as a repressor of the penicillin biosynthesis. Arch. Microbiol. 188: 69– 79.
134. Stanimirovic, Z.,, J. Stevanovic,, V. Bajic, and, I. Radovic. 2007. Evaluation of genotoxic effects of fumagillin by cytogenetic tests in vivo. Mutat. Res. 628: 1– 10.
135. Stanzani, M.,, E. Orciuolo,, R. Lewis,, D. P. Kontoyiannis,, S. L. Martins,, L. S. St. John, and, K. V. Komanduri. 2005. Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. Blood 105: 2258– 2265.
136. Stinnett, S. M.,, E. A. Espeso,, L. Cobeno,, L. Araujo-Bazan, and, A. M. Calvo. 2007. Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light. Mol. Microbiol. 63: 242– 255.
137. Stollerman, G. H. 1993. The global impact of penicillin: then and now. Mt. Sinai J. Med. 60: 112– 119.
138. Sugui, J. A.,, J. Pardo,, Y. C. Chang,, K. A. Zarember,, G. Nardone,, E. M. Galvez,, A. Mullbacher,, J. I. Gallin,, M. M. Simon, and, K. J. Kwon-Chung. 2007a. Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosup-pressed with hydrocortisone. Eukaryot. Cell 6: 1562– 1569.
139. Sugui, J. A.,, J. Pardo,, Y. C. Chang,, A. Müllbacher,, K. A. Zarember,, E. M. Galvez,, L. Brinster,, P. Zerfas,, J. I. Gallin,, M. M. Simon, and, K. J. Kwon-Chung. 2007b. Role of laeA in the regulation of alb1, gliP, conidial morphology, and virulence in Aspergillus fumigatus. Eukaryot. Cell 6: 1552– 1561.
140. Sutton, P.,, N. R. Newcombe,, P. Waring, and, A. Mullbacher. 1994. In vivo immunosuppressive activity of gliotoxin, a metabolite produced by human pathogenic fungi. Infect. Immun. 62: 1192– 1198.
141. Suzuki, S.,, K. Kikkawa, and, M. Yamazaki. 1984. Abnormal behavioral effects elicited by a neurotropic mycotoxin, fumitremorgin A in mice. J. Pharmacobiodyn. 7: 935– 942.
142. Tag, A.,, J. Hicks,, G. Garifullina,, C. Ake, Jr.,, T. D. Phillips,, M. Ber-emand, and, N. Keller. 2000. G-protein signalling mediates differential production of toxic secondary metabolites. Mol. Microbiol. 38: 658– 665.
143. Tilburn, J.,, S. Sarkar,, D. A. Widdick,, E. A. Espeso,, M. Orejas,, J. Mungroo,, M. A. Penalva, and, H. N. Arst, Jr. 1995. The Aspergillus PacC zinc finger transcription factor mediates regulation of both acid- and alkaline-expressed genes by ambient pH. EMBO J. 14: 779– 790.
144. Todd, R. B., and, A. Andrianopoulos. 1997. Evolution of a fungal regulatory gene family: the Zn(II)2Cys6 binuclear cluster DNA binding motif. Fungal Genet. Biol. 21: 388– 405.
145. Trown, P. W., and, J. A. Bilello. 1972. Mechanism of action of gli-otoxin: elimination of activity by sulfhydryl compounds. Anti-microb. Agents Chemother. 2: 261– 266.
146. Tsitsigiannis, D. I.,, T. M. Kowieski,, R. Zarnowski, and, N. P. Keller. 2004. Endogenous lipogenic regulators of spore balance in Aspergillus nidulans. Eukaryot. Cell 3: 1398– 1411.
147. Tsitsigiannis, D. I., and, N. P. Keller. 2006. Oxylipins act as determinants of natural product biosynthesis and seed colonization in Aspergillus nidulans. Mol. Microbiol. 59: 882– 892.
148. Tsitsigiannis, D. I., and, N. P. Keller. 2007. Oxylipins as developmental and host-fungal communication signals. Trends Microbiol. 15: 109– 118.
149. Tsunawaki, S.,, L. S. Yoshida,, S. Nishida,, T. Kobayashi, and, T. Shi-moyama. 2004. Fungal metabolite gliotoxin inhibits assembly of the human respiratory burst NADPH oxidase. Infect. Immun. 72: 3373– 3382.
150. Unsold, I. A., and, S. M. Li. 2005. Overproduction, purification and characterization of FgaPT2, a dimethylallyltryptophan synthase from Aspergillus fumigatus. Microbiology 151: 1499– 1505.
151. van Loevezijn, A.,, J. D. Allen,, A. H. Schinkel, and, G. J. Koomen. 2001. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg. Med. Chem. Lett. 11: 29– 29.
152. Ward, C,, E. R. Chilvers,, M. F. Lawson,, J. G. Pryde,, S. Fujihara,, S. N. Farrow,, C. Haslett, and, A. G. Rossi. 1999. NF-KB activation is a critical regulator of human granulocyte apoptosis in vitro. J. Biol. Chem. 274: 4309– 4309.
153. Waring, P.,, N. Newcombe,, M. Edel,, Q. H. Lin,, H. Jiang,, A. Sjaarda,, T. Piva, and, A. Mullbacher. 1994. Cellular uptake and release of the immunomodulating fungal toxin gliotoxin. Toxicon 32: 491– 491.
154. Waring, P.,, A. Sjaarda, and, Q. H. Lin. 1995. Gliotoxin inactivates alcohol dehydrogenase by either covalent modification or free radical damage mediated by redox cycling. Biochem. Pharmacol. 49: 1195– 1201.
155. Watanabe, A.,, K. Kamei,, T. Sekine,, M. Waku,, K. Nishimura,, M. Miyaji,, K. Tatsumi, and, T. Kuriyama. 2004. Effect of aeration on gliotoxin production by Aspergillus fumigatus in its culture filtrate. Mycopathologia 157: 245– 245.
156. Weindling, R., and, O. H. Emerson. 1936. The isolation of a toxic substance from the culture filtrate of Trichoderma. Phytopathology 31: 991– 991.
157. Whittington, R., and, M. L. Winston. 2003. Effects of Nosema bombi and its treatment fumagillin on bumble bee (Bombus occidentalis) colonies. J. Invertebr. Pathol. 84: 54– 54.
158. Williams, T. I. 1952. Some chemical properties of helvolic acid. Biochem. J. 51: 538– 538.
159. Willingale, J.,, K. P. Perera, and, P. G. Mantle. 1983. An intermediary role for the tremorgenic mycotoxin TR-2 in the biosynthesis of ver-ruculogen. Biochem. J. 214: 991– 993.
160. Woloshuk, C. P.,, K. R. Foutz,, J. F. Brewer,, D. Bhatnagar,, T. E. Cleveland, and, G. A. Payne. 1994. Molecular characterization of aflR, a regulatory locus for aflatoxin biosynthesis. Appl. Environ. Microbiol. 60: 2408– 2414.
161. Yamazaki, M.,, H. Fujimoto, and, T. Kawasaki. 1980. Chemistry of tremorogenic metabolites. I. Fumitremorgin A from Aspergillus fumigatus. Chem. Pharm. Bull. (Tokyo) 28: 245– 254.
162. Yamazaki, M.,, S. Suzuki, and, N. Ozaki. 1983. Biochemical investigation on the abnormal behaviors induced by fumitremorgin A, a tremorgenic mycotoxin to mice. J. Pharmacobiodyn. 6: 748– 751.
163. Yamazaki, M., and, S. Suzuki. 1986. Toxicology of tremorgenic my-cotoxins, fumitremorgin A and B. Dev. Toxicol. Environ. Sci. 12: 273– 282.
164. Yoshida, L. S.,, S. Abe, and, S. Tsunawaki. 2000. Fungal gliotoxin targets the onset of superoxide-generating NADPH oxidase of human neutrophils. Biochem. Biophys. Res. Commun. 268: 716– 723.
165. Yu, J. H.,, R. A. Butchko,, M. Fernandes,, N. P. Keller,, T. J. Leonard, and, T. H. Adams. 1996. Conservation of structure and function of the aflatoxin regulatory gene aflR from Aspergillus nidulans and A. flavus. Curr. Genet. 29: 549– 555.
166. Yu, J. H., and, N. Keller. 2005. Regulation of secondary metabolism in filamentous fungi. Annu. Rev. Phytopathol. 43: 437– 458.

Tables

Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-1,webId=/content/author/10.1128/9781555815523.ch15-1,properties={foaf_givenname=Robert A., foaf_name=Robert A. Cramer, Jr., foaf_surname=Cramer, Jr., pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-2,webId=/content/author/10.1128/9781555815523.ch15-2,properties={foaf_givenname=E. Keats, foaf_name=E. Keats Shwab, foaf_surname=Shwab, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815523.ch15-3,webId=/content/author/10.1128/9781555815523.ch15-3,properties={foaf_givenname=Nancy P., foaf_name=Nancy P. Keller, foaf_surname=Keller, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815523.ch15-aff3]]}]]
Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
/content/10.1128/9781555815523.ch15.ch15tab01
Table 1.
Pathogenesis studies of gliotoxin-deficient A. fumigatus strains in murine models of IPA
Generic image for table
Table 1.

Pathogenesis studies of gliotoxin-deficient A. fumigatus strains in murine models of IPA

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15

Back to top
This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error