Aspects of Primary Carbon and Nitrogen Metabolism

Sven Krappmann

doi:10.1128/9781555815523.ch6

Chapter 6 : Aspects of Primary Carbon and Nitrogen Metabolism

Author: Sven Krappmann¹

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Affiliations: 1: Research Center for Infectious Diseases, Julius-Maximilians-University, Würzburg, Germany

Content Type: Monograph

Publication Year: 2009

Category: Clinical Microbiology; Fungi and Fungal Pathogenesis

Book DOI: 10.1128/9781555815523

Chapter DOI: 10.1128/9781555815523.ch6

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Abstract:

This chapter focuses on routes of carbon metabolism and nitrogen metabolism, on specific aspects of their regulation, and on insights specifically gained for Aspergillus fumigatus, by far the most pathogenic species among aspergilli and the main causative agent of aspergillosis. Fungi contribute significantly to the global recycling routes that result in turnover of elements like carbon or nitrogen, and aspergilli with their saprophytic life-style inhabit a prominent role in these processes. Genomic data from several Aspergillus species, among them A. fumigatus, have not revealed the existence of true virulence factors that would cause significant host damage; in fact, they clearly mirror the routine of degrading external polymers and assimilation of nutrients. Signal transduction pathways affecting the fungal response to varying environmental conditions are likely to contribute to its nutritional versatility, and identification of nutritional pathways supporting growth of Aspergillus in the ecological niche of a ‘‘susceptible host’’ could provide the capability to pinpoint fungus-specific virulence determinants and therefore targets of antifungal therapy. This is of course not limited to routes of carbon metabolism. The chapter also discusses the accumulated knowledge of nitrogen metabolism of A. fumigatus with respect to its pathogenicity.

Citation: Krappmann S. 2009. Aspects of Primary Carbon and Nitrogen Metabolism, p 63-74. In Latgé J, Steinbach W (ed), Aspergillus fumigatus and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch6

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Aspects of Primary Carbon and Nitrogen Metabolism

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Figure 1.

Metabolism as a virulence determinant of Aspergillus. This scheme illustrates the pathogen-host interaction as a variation of Aspergillus exploiting a specific environment. After infection by airborne conidia, the surrounding tissue has to be utilized to allow germination and hyphal growth, which eventually may result in a final outcome of disease. Nutritional versatility occupies a crucial role in this setting and therefore affects the aftermath of the pathogen-host encounter.

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Figure 1.

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Figure 2.

Routes of carbon metabolism to utilize fatty acids and amino acids. Various metabolic pathways are used by Aspergillus in utilizing carbon sources, including fatty acids and amino acids. (A) The former result in increased levels of acetyl-CoA and anaplerosis of the tricarbonic cycle (TCC) intermediate oxaloacetate via the glyoxalate bypass. The intermediate glyoxalate is formed by the action of an isocitrate lyase enzyme (AcuD; EC 4.1.3.1), which is dispensable in invasive aspergillosis ( Schöbel et al., 2007 ). (B) The methylcitrate cycle feeds from propionyl-CoA, which derives from isoleucine, valine, or methionine as products from protein degradation. Its condensation with the TCC intermediate oxaloacetate is catalyzed by methylcitrate synthetase activity (McsA; EC 6.2.1.17), an enzyme that is essential for invasive aspergillosis ( Ibrahim-Granet et al., 2008 ). Accordingly, A. fumigatus appears to utilize amino acids as a source for carbon and nitrogen.

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Figure 2.

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Figure 3.

Cross-pathway control signaling in Aspergillus. The schematic outline shows the core components and regulatory effects in the eIF2α kinase signaling cascade of fungal cross-pathway control. Nutritional stress, such as amino acid starvation, is perceived by the kinase CpcC, which in turn phosphorylates the α-subunit of eIF2. This results in lower rates of translation initiation but elevated expression of the transcription factor CpcA, mediated by two uORFs on the cpcA transcript. Accordingly, transcriptional reprogramming occurs to counter the initial stress condition. The presence of the cpcA gene is required for full virulence of A. fumigatus ( Krappmann et al., 2002 ), whereas a cpcCΔ deletant is as virulent as wild type ( Sasse et al., 2008 ).

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Figure 3.

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Figure 4.

Aspects of primary carbon and nitrogen metabolism that influence pathogenicity of Aspergillus. Several biosynthetic routes have been identified as required for aspergillosis, and a variety of regulatory circuits have been analyzed in this respect, too. However, distinct aspects of basic C or N metabolism have been scrutinized only to a limited extent, and the role of nutritional transporters has not been addressed thoroughly. See text for further details.

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Figure 4.

References

/content/book/10.1128/9781555815523.ch06

1. Amaar, Y. G., and, M. M. Moore. 1998. Mapping of the nitrate-assimilation gene cluster (crnA-niiA-niaD) and characterization of the nitrite reductase gene (niiA) in the opportunistic fungal pathogen Aspergillus fumigatus. Curr. Genet. 33: 206–215.

2. Bertram, P. G.,, J. H. Choi,, J. Carvalho,, W. Ai,, C. Zeng,, T. F. Chan, and, X. F. Zheng. 2000. Tripartite regulation of Gln3p by TOR, Ure2p, and phosphatases. J. Biol. Chem. 275: 35727–35733.

3. Bölker, M. 1998. Sex and crime: heterotrimeric G proteins in fungal mating and pathogenesis. Fungal Genet. Biol. 25: 143–156.

4. Boyce, J. D.,, P. A. Cullen, and, B. Adler. 2004. Genomic-scale analysis of bacterial gene and protein expression in the host. Emerg. Infect. Dis. 10: 1357–1362.

5. Brakhage, A. A., and, K. Langfelder. 2002. Menacing mold: the molecular biology of Aspergillus fumigatus. Annu. Rev. Microbiol. 56: 433–455.

6. Brakhage, A. A., and, B. Liebmann. 2005. Aspergillus fumigatus conidial pigment and cAMP signal transduction: significance for virulence. Med. Mycol. 43(Suppl. 1): S75–S82.

7. Brock, M.,, R. Fischer,, D. Linder, and, W. Buckel. 2000. Methylcitrate synthase from Aspergillus nidulans: implications for propionate as an antifungal agent. Mol. Microbiol. 35: 961–973.

8. Bromley, M.,, C. Gordon,, N. Rovira-Graells, and, J. Oliver. 2006. The Aspergillus fumigatus cellobiohydrolase B (cbhB) promoter is tightly regulated and can be exploited for controlled protein expression and RNAi. FEMS Microbiol. Lett. 264: 246–254.

9. Brown, J. S.,, A. Aufauvre-Brown,, J. Brown,, J. M. Jennings,, H. Arst, Jr., and, D. W. Holden. 2000. Signature-tagged and directed mutagenesis identify PABA synthetase as essential for Aspergillus fumigatus pathogenicity. Mol. Microbiol. 36: 1371–1380.

10. Caddick, M. X. 1994. Nitrogen metabolite repression. Prog. Ind. Microbiol. 29: 323–353.

11. Caddick, M. X.,, H. N. Arst, Jr.,, L. H. Taylor,, R. I. Johnson, and, A. G. Brownlee. 1986. Cloning of the regulatory gene areA mediating nitrogen metabolite repression in Aspergillus nidulans. EMBO J. 5: 1087–1090.

12. Caddick, M. X.,, D. Peters, and, A. Platt. 1994. Nitrogen regulation in fungi. Antonie Leeuwenhoek 65: 169–177.

13. Cardenas, M. E.,, N. S. Cutler,, M. C. Lorenz,, C. J. Di Como, and, J. Heitman. 1999. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13: 3271–3279.

14. Carsiotis, M., and, R. F. Jones. 1974. Cross-pathway regulation: tryptophan-mediated control of histidine and arginine biosynthetic enzymes in Neurospora crassa. J. Bacteriol. 119: 889–892.

15. Carsiotis, M.,, R. F. Jones, and, A. C. Wesseling. 1974. Cross-pathway regulation: histidine-mediated control of histidine, tryptophan, and arginine biosynthetic enzymes in Neurospora crassa. J. Bacteriol. 119: 893–898.

16. 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. 2006. Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot. Cell 5: 972–980.

17. d’Enfert, C.,, M. Diaquin,, A. Delit,, N. Wuscher,, J. P. Debeaupuis,, M. Huerre, and, J.-P. Latgé. 1996. Attenuated virulence of uridine-uracil auxotrophs of Aspergillus fumigatus. Infect. Immun. 64: 4401–4405.

18. Denning, D. W.,, M. J. Anderson,, G. Turner,, J.-P. Latgé, and, J. W. Bennett. 2002. Sequencing the Aspergillus fumigatus genome. Lancet Infect. Dis. 2: 251–253.

19. Diallinas, G. 2007. Aspergillus transporters, p. 301–320. In G. H. Goldman and, S. A. Osmani (ed.), The Aspergilli: Genomics, Medical Aspects, Biotechnology, and Research Methods. CRC Press, Boca Raton, FL.

20. 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.

21. Dowzer, C. E., and, J. M. Kelly. 1991. Analysis of the creA gene, a regulator of carbon catabolite repression in Aspergillus nidulans. Mol. Cell. Biol. 11: 5701–5709.

22. D’Souza, C. A., and, J. Heitman. 2001. Conserved cAMP signaling cascades regulate fungal development and virulence. FEMS Microbiol. Rev. 25: 349–364.

23. Ebel, F.,, M. Schwienbacher,, J. Beyer,, J. Heesemann,, A. A. Brakhage, and, M. Brock. 2006. Analysis of the regulation, expression, and localisation of the isocitrate lyase from Aspergillus fumigatus, a potential target for antifungal drug development. Fungal Genet. Biol. 43: 476–489.

24. Fitzgibbon, G. J.,, I. Y. Morozov,, M. G. Jones, and, M. X. Caddick. 2005. Genetic analysis of the TOR pathway in Aspergillus nidulans. Eukaryot. Cell 4: 1595–1598.

25. Garrad, R. C., and, J. K. Bhattacharjee. 1992. Lysine biosynthesis in selected pathogenic fungi: characterization of lysine auxotrophs and the cloned LYS1 gene of Candida albicans. J. Bacteriol. 174: 7379–7384.

26. Haines, J. 1995. Aspergillus in compost: straw man or fatal flaw. Biocycle 6: 32–35.

27. Hensel, M.,, H. N. Arst, Jr.,, A. Aufauvre-Brown, and, D. W. Holden. 1998. The role of the Aspergillus fumigatus areA gene in invasive pulmonary aspergillosis. Mol. Gen. Genet. 258: 553–557.

28. Hinnebusch, A. G. 1986. The general control of amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae. CRC Crit. Rev. Biochem. 21: 277–317.

29. Hinnebusch, A. G. 1997. Translational regulation of yeast GCN4. A window on factors that control initiator-tRNA binding to the ribosome. J. Biol. Chem. 272: 21661–21664.

30. Hoffmann, B.,, O. Valerius,, M. Andermann, and, G. H. Braus. 2001. Transcriptional autoregulation and inhibition of mRNA translation of amino acid regulator gene cpcA of filamentous fungus Aspergillus nidulans. Mol. Biol. Cell 12: 2846–2857.

31. Hondmann, D. H., and, J. Visser. 1994. Carbon metabolism. Prog. Ind. Microbiol. 29: 61–139.

32. Hull, E. P.,, P. M. Green,, H. N. Arst, Jr., and, C. Scazzocchio. 1989. Cloning and physical characterization of the L-proline catabolism gene cluster of Aspergillus nidulans. Mol. Microbiol. 3: 553–559.

33. Hynes, M. J. 2007. Gluconeogenic carbon metabolism, p. 129–142. In G. H. Goldman and, S. A. Osmani (ed.), The Aspergilli: Genomics, Medical Aspects, Biotechnology, and Research Methods. CRC Press, Boca Raton, FL.

34. Ibrahim-Granet, O.,, M. Dubourdeau,, J.-P. Latgé,, P. Ave,, M. Huerre,, A. A. Brakhage, and, M. Brock. 2008. Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis. Cell. Microbiol. 10: 134–148.

35. Johnstone, I. L.,, P. C. McCabe,, P. Greaves,, S. J. Gurr,, G. E. Cole,, M. A. Brow,, S. E. Unkles,, A. J. Clutterbuck,, J. R. Kinghorn, and, M. A. Innis. 1990. Isolation and characterisation of the crnA-niiA-niaD gene cluster for nitrate assimilation in Aspergillus nidulans. Gene 90: 181–192.

36. Klionsky, D. J. 2007. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8: 931–937.

37. Kniemeyer, O.,, F. Lessing,, O. Scheibner,, C. Hertweck, and, A. A. Brakhage. 2006. Optimisation of a 2-D gel electrophoresis protocol for the humanpathogenic fungus Aspergillus fumigatus. Curr. Genet. 49: 178–189.

38. Krappmann, S. 2006. Tools to study molecular mechanisms of Aspergillus pathogenicity. Trends Microbiol. 14: 356–364.

39. Krappmann, S. 2007. Pathogenicity determinants and allergens, p. 377–400. In G. H. Goldman and, S. A. Osmani (ed.), The Aspergilli: Genomics, Medical Aspects, Biotechnology, and Research Methods. CRC Press, Boca Raton, FL.

40. Krappmann, S.,, E. M. Bignell,, U. Reichard,, T. Rogers,, K. Haynes, and, G. H. Braus. 2004. The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen. Mol. Microbiol. 52: 785–799.

41. Kupfahl, C.,, T. Heinekamp,, G. Geginat,, T. Ruppert,, A. Hard,, H. Hof, and, A. A. Brakhage. 2006. Deletion of the gliP gene of Aspergillus 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.

42. Lafon, A.,, K. H. Han,, J. A. Seo,, J. H. Yu, and, C. d’Enfert. 2006. G-protein and cAMP-mediated signaling in aspergilli: a genomic perspective. Fungal Genet. Biol. 43: 490–502.

43. Latgé, J.-P. 1999. Aspergillus fumigatus and aspergillosis. Clin. Microbiol. Rev. 12: 310–350.

44. Latgé, J.-P. 2001. The pathobiology of Aspergillus fumigatus. Trends Microbiol. 9: 382–389.

45. Liebmann, B.,, S. Gattung,, B. Jahn, and, A. A. Brakhage. 2003. cAMP signaling in Aspergillus fumigatus is involved in the regulation of the virulence gene pksP and in defense against killing by macrophages. Mol. Genet. Genomics 269: 420–435.

46. Liebmann, B.,, T. W. Mühleisen,, M. Müller,, M. Hecht,, G. Weidner,, A. Braun,, M. Brock, and, A. A. Brakhage. 2004a. Deletion of the Aspergillus fumigatus lysine biosynthesis gene lysF encoding homoaconitase leads to attenuated virulence in a low-dose mouse infection model of invasive aspergillosis. Arch. Microbiol. 181: 378–383.

47. Liebmann, B.,, M. Müller,, A. Braun, and, A. A. Brakhage. 2004b. The cyclic AMP-dependent protein kinase A network regulates development and virulence in Aspergillus fumigatus. Infect. Immun. 72: 5193–5203.

48. Lorenz, M. C.,, J. A. Bender, and, G. R. Fink. 2004. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot. Cell 3: 1076–1087.

49. Lorenz, M. C., and, G. R. Fink. 2001. The glyoxylate cycle is required for fungal virulence. Nature 412: 83–86.

50. Mabey, J. E.,, M. J. Anderson,, P. F. Giles,, C. J. Miller,, T. K. Attwood,, N. W. Paton,, E. Bornberg-Bauer,, G. D. Robson,, S. G. Oliver, and, D. W. Denning. 2004. CADRE: the Central Aspergillus Data RE-pository. Nucleic Acids Res. 32: D401–D405.

51. Maerker, C,, M. Rohde,, A. A. Brakhage, and, M. Brock. 2005. Methylcitrate synthase from Aspergillus fumigatus. Propionyl-CoA affects polyketide synthesis, growth and morphology of conidia. FEBS J. 272: 3615–3630.

52. Marzluf, G. A. 1997. Genetic regulation of nitrogen metabolism in the fungi. Microbiol. Mol. Biol. Rev. 61: 17–32.

53. May, G. S.,, T. Xue,, D. P. Kontoyiannis, and, M. C. Gustin. 2005. Mitogen activated protein kinases of Aspergillus fumigatus. Med. Mycol. 43(Suppl. 1): S83–S86.

54. Mogensen, J.,, H. B. Nielsen,, G. Hofmann, and, J. Nielsen. 2006. Transcription analysis using high-density micro-arrays of Aspergillus nidulans wild-type and creA mutant during growth on glucose or ethanol. Fungal Genet. Biol. 43: 593–603.

55. Munoz-Elias, E. J., and, J. D. McKinney. 2005. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat. Med. 11: 638–644.

56. Muthuvijayan, V., and, M. R. Marten. 2004. In silico reconstruction of nutrient-sensing signal transduction pathways in Aspergillus nidulans. In Silico Biol. 4: 605–631.

57. Natarajan, K.,, M. R. Meyer,, B. M. Jackson,, D. Slade,, C. Roberts,, A. G. Hinnebusch, and, M. J. Marton. 2001. Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol. Cell. Biol. 21: 4347–4368.

58. Nierman, W. C.,, G. May,, H. S. Kim,, M. J. Anderson,, D. Chen, and, D. W. Denning. 2005a. What the Aspergillus genomes have told us. Med. Mycol. 43(Suppl. 1): S3–S5.

59. 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,, N. Fedorova,, T. V. Feldblyum,, 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. Lafon,, J.-P. Largé,, 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. 2005b. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438: 1151–1156.

60. Nishida, H., and, M. Nishiyama. 2000. What is characteristic of fungal lysine synthesis through the α-aminoadipate pathway? J. Mol. Evol. 51: 299–302.

61. Nordstrom, U. M. 1974. Bark degradation by Aspergillus fumigatus. Growth studies. Can. J. Microbiol. 20: 283–298.

62. Oliver, B. G.,, J. C. Panepinto,, D. S. Askew, and, J. C. Rhodes. 2002a. cAMP alteration of growth rate of Aspergillus fumigatus and Aspergillus niger is carbon-source dependent. Microbiology 148: 2627–2633.

63. Oliver, B. G,, J. C. Panepinto,, J. R. Fortwendel,, D. L. Smith,, D. S. Askew, and, J. C. Rhodes. 2002b. Cloning and expression of pkaC and pkaR, the genes encoding the cAMP-dependent protein kinase of Aspergillus fumigatus. Mycopathologia 154: 85–91.

64. Onodera, J., and, Y. Ohsumi. 2005. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J. Biol. Chem. 280: 31582–31586.

65. Pain, A.,, J. Woodward,, M. A. Quail,, M. J. Anderson,, R. Clark,, M. Collins,, N. Fosker,, A. Fraser,, D. Harris,, N. Larke,, L. Murphy,, S. Humphray,, S. O’Neil,, M. Pertea,, C. Price,, E. Rabbinowitsch,, M. A. Rajandream,, S. Salzberg,, D. Saunders,, K. Seeger,, S. Sharp,, T. Warren,, D. W. Denning,, B. Barrell, and, N. Hall. 2004. Insight into the genome of Aspergillus fumigatus: analysis of a 922 kb region encompassing the nitrate assimilation gene cluster. Fungal Genet. Biol. 41: 443–453.

66. Paisley, D.,, G. D. Robson, and, D. W. Denning. 2005. Correlation between in vitro growth rate and in vivo virulence in Aspergillus fumigatus. Med. Mycol. 43: 397–401.

67. Panepinto, J. C.,, B. G. Oliver,, T. W. Amlung,, D. S. Askew, and, J. C. Rhodes. 2002. Expression of the Aspergillus fumigatus rheb homologue, rhbA, is induced by nitrogen starvation. Fungal Genet. Biol. 36: 207–214.

68. Panepinto, J. C.,, B. G. Oliver,, J. R. Fortwendel,, D. L. Smith,, D. S. Askew, and, J. C. Rhodes. 2003. Deletion of the Aspergillus fumigatus gene encoding the Ras-related protein RhbA reduces virulence in a model of invasive pulmonary aspergillosis. Infect. Immun. 71: 2819–2826.

69. Purnell, D. M. 1973. The effects of specific auxotrophic mutations on the virulence of Aspergillus nidulans for mice. Mycopathol. Mycol. Appl. 50: 195–203.

70. Reyes, G.,, A. Romans,, C. K. Nguyen, and, G. S. May. 2006. Novel mitogen-activated protein kinase MpkC of Aspergillus fumigatus is required for utilization of polyalcohol sugars. Eukaryot. Cell 5: 1934–1940.

71. Rhodes, J. C. 2006. Aspergillus fumigatus: growth and virulence. Med. Mycol. 44(Suppl. 1): S77–S81.

72. Rhodes, J. C.,, B. G. Oliver,, D. S. Askew, and, T. W. Amlung. 2001. Identification of genes of Aspergillus fumigatus up-regulated during growth on endothelial cells. Med. Mycol. 39: 253–260.

73. Richie, D. L.,, K. K. Fuller,, J. Fortwendel,, M. D. Miley,, J. W. McCarthy,, M. Feldmesser,, J. C. Rhodes, and, D. S. Askew. 2007. Unexpected link between metal ion deficiency and autophagy in Aspergillus fumigatus. Eukaryot. Cell 6: 2437–2447.

74. Roman, E.,, D. M. Arana,, C. Nombela,, R. Alonso-Monge, and, J. Pla. 2007. MAP kinase pathways as regulators of fungal virulence. Trends Microbiol. 15: 181–190.

75. Rubin-Bejerano, I.,, I. Fraser,, P. Grisafi, and, G. R. Fink. 2003. Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans. Proc. Natl. Acad. Sci. USA 100: 11007–11012.

76. Ruijter, G. J., and, J. Visser. 1997. Carbon repression in aspergilli. FEMS Microbiol. Lett. 151: 103–114.

77. Sandhu, D. K.,, R. S. Sandhu,, Z. U. Khan, and, V. N. Damodaran. 1976. Conditional virulence of a p-aminobenzoic acid-requiring mutant of Aspergillus fumigatus. Infect. Immun. 13: 527–532.

78. Santos, R.,, A. A. Firmino,, C. M. de Sá, and, C. R. Felix. 1996. Keratinolytic activity of Aspergillus fumigatus Fresenius. Curr. Microbiol. 33: 364–370.

79. Sasse, C.,, E. M. Bignell,, M. Hasenberg,, K. Haynes,, M. Gunzer,, G. H. Braus, and, S. Krappmann. 2008. Basal expression of the Aspergillus fumigatus transcriptional activator CpcA is sufficient to support pulmonary aspergillosis. Fungal Genet. Biol. 45: 693–704.

80. Schöbel, F.,, O. Ibrahim-Granet,, P. Ave,, J.-P. Latgé,, A. A. Brakhage, and, M. Brock. 2007. Aspergillus fumigatus does not require fatty acid metabolism via isocitrate lyase for development of invasive aspergillosis. Infect. Immun. 75: 1237–1244.

81. Schoberle, T., and, G. S. May. 2007. Fungal genomics: a tool to explore central metabolism of Aspergillus fumigatus and its role in virulence. Adv. Genet. 57: 263–283.

82. Shamji, A. F.,, F. G. Kuruvilla, and, S. L. Schreiber. 2000. Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins. Curr. Biol. 10: 1574–1581.

83. Spikes, S.,, R. Xu,, C. K. Nguyen,, G. Chamilos,, D. P. Kontoyiannis,, R. H. Jacobson,, D. E. Ejzykowicz,, L. Y. Chiang,, S. G. Filler, and, G. S. May. 2008. Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J. Infect. Dis. 197: 479–486.

84. 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. 2007. Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot. Cell 6: 1562–1569.

85. Tang, C. M.,, J. M. Smith,, H. N. Arst, Jr., and, D. W. Holden. 1994. Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis. Infect. Immun. 62: 5255–5260.

86. Tekaia, F., and, J.-P. Latgé. 2005. Aspergillus fumigatus: saprophyte or pathogen? Curr. Opin. Microbiol. 8: 385–392.

87. Valenzuela, L.,, C. Aranda, and, A. Gonzalez. 2001. TOR modulates GCN4-dependent expression of genes turned on by nitrogen limitation. J. Bacteriol. 183: 2331–2334.

88. Wei, H.,, K. Vienken,, R. Weber,, S. Bunting,, N. Requena, and, R. Fischer. 2004. A putative high affinity hexose transporter, hxtA, of Aspergillus nidulans is induced in vegetative hyphae upon starvation and in ascogenous hyphae during cleistothecium formation. Fungal Genet. Biol. 41: 148–156.

89. Wek, R. C.,, H. Y. Jiang, and, T. G. Anthony. 2006. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34: 7–11.

90. Wiles, A. M.,, F. Naider, and, J. M. Becker. 2006. Transmembrane domain prediction and consensus sequence identification of the oligopeptide transport family. Res. Microbiol. 157: 395–406.

91. Wilson, R. A., and, H. N. Arst, Jr. 1998. Mutational analysis of AREA, a transcriptional activator mediating nitrogen metabolite repression in Aspergillus nidulans and a member of the “streetwise” GATA family of transcription factors. Microbiol. Mol. Biol. Rev. 62: 586–596.

92. Xu, J. R. 2000. MAP kinases in fungal pathogens. Fungal Genet. Biol. 31: 137–152.

93. Xue, T.,, C. K. Nguyen,, A. Romans, and, G. S. May. 2004. A mitogen-activated protein kinase that senses nitrogen regulates conidial germination and growth in Aspergillus fumigatus. Eukaryot. Cell 3: 557–560.

94. Yang, W.,, W. S. Kim,, A. Fang, and, A. L. Demain. 2003. Carbon and nitrogen source nutrition of fumagillin biosynthesis by Aspergillus fumigatus. Curr. Microbiol. 46: 275–279.

95. Zaas, A. K., and, W. J. Steinbach. 2007. Mammalian models of aspergillosis, p. 401–412. In G. H. Goldman and, S. A. Osmani (ed.), The Aspergilli: Genomics, Medical Aspects, Biotechnology, and Research Methods. CRC Press, Boca Raton, FL.

96. Zabriskie, T. M., and, M. D. Jackson. 2000. Lysine biosynthesis and metabolism in fungi. Nat. Prod. Rep. 17: 85–97.