Applied Microbiology and Biotechnology

, Volume 93, Issue 2, pp 467–472 | Cite as

Biosynthesis and function of gliotoxin in Aspergillus fumigatus

  • Daniel H. Scharf
  • Thorsten Heinekamp
  • Nicole Remme
  • Peter Hortschansky
  • Axel A. Brakhage
  • Christian Hertweck
Mini-Review

Abstract

Gliotoxin (GT) is the prototype of the epidithiodioxopiperazine (ETP)-type fungal toxins. GT plays a critical role in the pathobiology of Aspergillus fumigatus. It modulates the immune response and induces apoptosis in different cell types. The toxicity has been attributed to the unusual intramolecular disulfide bridge, which is the functional motif of all ETPs. Because of the extraordinary structure and activity of GT, this fungal metabolite has been the subject of many investigations. The biosynthesis of GT involves unprecedented reactions catalysed by recently discovered enzymes. Here, we summarize the recent progress in elucidating the GT biosynthetic pathway and its role in virulence.

Keywords

Aspergillus fumigatus Non-ribosomal peptide biosynthesis Gliotoxin ETP toxins 

Notes

Acknowledgement

Financial support by the DFG funded JSMC and ILRS is gratefully acknowledged.

References

  1. Allen G, Bromley M, Kaye SJ, Keszenman-Pereyra D, Zucchi TD, Price J, Birch M, Oliver JD, Turner G (2011) Functional analysis of a mitochondrial phosphopantetheinyl transferase (PPTase) gene pptB in Aspergillus fumigatus. Fungal Genet Biol 48:456–464CrossRefGoogle Scholar
  2. Balibar CJ, Walsh CT (2006) GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin. Biochemistry 45:15029–15038CrossRefGoogle Scholar
  3. Bell MR, Johnson JR, Wildi BS, Woodward RB (1958) The structure of gliotoxin. J Am Chem Soc 80:1001–1001CrossRefGoogle Scholar
  4. Ben-Ami R, Lewis RE, Leventakos K, Kontoyiannis DP (2009) Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites. Blood 114:5393–5399CrossRefGoogle Scholar
  5. Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Kirby KA, Keller NP (2006) GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect Immun 74:6761–6768CrossRefGoogle Scholar
  6. Bu’Lock JD, Leigh C (1975) Biosynthesis of gliotoxin. J Chem Soc Chem Commun: 628–629Google Scholar
  7. Cramer RA Jr, Gamcsik MP, Brooking RM, Najvar LK, Kirkpatrick WR, Patterson TF, Balibar CJ, Graybill JR, Perfect JR, Abraham SN, Steinbach WJ (2006) Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot Cell 5:972–980CrossRefGoogle Scholar
  8. Davis C, Carberry S, Schrettl M, Singh I, Stephens JC, Barry SM, Kavanagh K, Challis GL, Brougham D, Doyle S (2011) The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol 18:542–552CrossRefGoogle Scholar
  9. Forseth RR, Fox EM, Chung D, Howlett BJ, Keller NP, Schroeder FC (2011) Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. J Am Chem Soc 133:9678–9681CrossRefGoogle Scholar
  10. Gardiner DM, Howlett BJ (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248:241–248CrossRefGoogle Scholar
  11. Gardiner DM, Cozijnsen AJ, Wilson LM, Pedras MS, Howlett BJ (2004) The sirodesmin biosynthetic gene cluster of the plant pathogenic fungus Leptosphaeria maculans. Mol Microbiol 53:1307–1318CrossRefGoogle Scholar
  12. Gardiner DM, Waring P, Howlett BJ (2005) The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology 151:1021–1032CrossRefGoogle Scholar
  13. Joosten V, van Berkel WJ (2007) Flavoenzymes. Curr Opin Chem Biol 11:195–202CrossRefGoogle Scholar
  14. Kirby GW, Patrick GL, Robins DJ (1978) cyclo-(l-Phenylalanyl-l-seryl) as an intermediate in the biosynthesis of gliotoxin. J Chem Soc Perkin Trans I: 1336–1338Google Scholar
  15. Kirby GW, Rao GV, Robins DJ (1988) New co-metabolites of gliotoxin in Gliocladium virens. J Chem Soc Perkin Trans I: 301–304Google Scholar
  16. Kroll M, Arenzana-Seisdedos F, Bachelerie F, Thomas D, Friguet B, Conconi M (1999) The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome. Chem Biol 6:689–698CrossRefGoogle Scholar
  17. Kupfahl C, Heinekamp T, Geginat G, Ruppert T, Hartl A, Hof H, Brakhage AA (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 62:292–302CrossRefGoogle Scholar
  18. Kupfahl C, Michalka A, Lass-Florl C, Fischer G, Haase G, Ruppert T, Geginat G, Hof H (2008) Gliotoxin production by clinical and environmental Aspergillus fumigatus strains. Int J Med Microbiol 298:319–327CrossRefGoogle Scholar
  19. Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri KV, Kontoyiannis DP, Prince RA (2005a) Detection of gliotoxin in experimental and human aspergillosis. Infect Immun 73:635–637CrossRefGoogle Scholar
  20. Lewis RE, Wiederhold NP, Lionakis MS, Prince RA, Kontoyiannis DP (2005b) Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center. J Clin Microbiol 43:6120–6122CrossRefGoogle Scholar
  21. Li B, Walsh CT (2011) Streptomyces clavuligerus HlmI is an intramolecular disulfide-forming dithiol oxidase in holomycin biosynthesis. Biochemistry 50:4615–4622CrossRefGoogle Scholar
  22. McDonagh A, Fedorova ND, Crabtree J, Yu Y, Kim S, Chen D, Loss O, Cairns T, Goldman G, Armstrong-James D, Haynes K, Haas H, Schrettl M, May G, Nierman WC, Bignell E (2008) Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Path 4:e1000154CrossRefGoogle Scholar
  23. Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, Berriman M, Abe K, Archer DB, Bermejo C, Bennett J, Bowyer P, Chen D, Collins M, Coulsen R, Davies R, Dyer PS, Farman M, Fedorova N, Fedorova N, Feldblyum TV, Fischer R, Fosker N, Fraser A, Garcia JL, Garcia MJ, Goble A, Goldman GH, Gomi K, Griffith-Jones S, Gwilliam R, Haas B, Haas H, Harris D, Horiuchi H, Huang J, Humphray S, Jimenez J, Keller N, Khouri H, Kitamoto K, Kobayashi T, Konzack S, Kulkarni R, Kumagai T, Lafon A, Latge JP, Li W, Lord A, Lu C, Majoros WH, May GS, Miller BL, Mohamoud Y, Molina M, Monod M, Mouyna I, Mulligan S, Murphy L, O’Neil S, Paulsen I, Penalva MA, Pertea M, Price C, Pritchard BL, Quail MA, Rabbinowitsch E, Rawlins N, Rajandream MA, Reichard U, Renauld H, Robson GD, Rodriguez de Cordoba S, Rodriguez-Pena JM, Ronning CM, Rutter S, Salzberg SL, Sanchez M, Sanchez-Ferrero JC, Saunders D, Seeger K, Squares R, Squares S, Takeuchi M, Tekaia F, Turner G, Vazquez de Aldana CR, Weidman J, White O, Woodward J, Yu JH, Fraser C, Galagan JE, Asai K, Machida M, Hall N, Barrell B, Denning DW (2005) Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438:1151–1156CrossRefGoogle Scholar
  24. Orciuolo E, Stanzani M, Canestraro M, Galimberti S, Carulli G, Lewis R, Petrini M, Komanduri KV (2007) Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis. J Leukocyte Biol 82:839–848CrossRefGoogle Scholar
  25. Pardo J, Urban C, Galvez EM, Ekert PG, Muller U, Kwon-Chung J, Lobigs M, Mullbacher A, Wallich R, Borner C, Simon MM (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 174:509–519CrossRefGoogle Scholar
  26. Patron NJ, Waller RF, Cozijnsen AJ, Straney DC, Gardiner DM, Nierman WC, Howlett BJ (2007) Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol Biol 7:174CrossRefGoogle Scholar
  27. Reeves EP, Messina CG, Doyle S, Kavanagh K (2004) Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella. Mycopathologia 158:73–79CrossRefGoogle Scholar
  28. Salinas AE, Wong MG (1999) Glutathione S-transferases—a review. Curr Med Chem 6:279–309Google Scholar
  29. Scharf DH, Remme N, Heinekamp T, Hortschansky P, Brakhage AA, Hertweck C (2010) Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. J Am Chem Soc 132:10136–10141CrossRefGoogle Scholar
  30. Scharf DH, Remme N, Habel A, Chankhamjon P, Scherlach K, Heinekamp T, Hortschansky P, Brakhage AA, Hertweck C (2011) A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis. J Am Chem Soc 133:12322–12325CrossRefGoogle Scholar
  31. Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O’Brien J, Nolan A, Stephens J, Fenelon O, Doyle S (2010) Self-protection against gliotoxin—a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Path 6:e1000952CrossRefGoogle Scholar
  32. Spikes S, Xu R, Nguyen CK, Chamilos G, Kontoyiannis DP, Jacobson RH, Ejzykowicz DE, Chiang LY, Filler SG, May GS (2008) Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J Infect Dis 197:479–486CrossRefGoogle Scholar
  33. Stanzani M, Orciuolo E, Lewis R, Kontoyiannis DP, Martins SL, St John LS, Komanduri KV (2005) Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. Blood 105:2258–2265CrossRefGoogle Scholar
  34. Sugui JA, Pardo J, Chang YC, Zarember KA, Nardone G, Galvez EM, Mullbacher A, Gallin JI, Simon MM, Kwon-Chung KJ (2007) Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell 6:1562–1569CrossRefGoogle Scholar
  35. Sugui JA, Kim HS, Zarember KA, Chang YC, Gallin JI, Nierman WC, Kwon-Chung KJ (2008) Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils. PLoS One 3:e2655CrossRefGoogle Scholar
  36. Suhadolnik RJ, Chenoweth RG (1958) Biosynthesis of gliotoxin: I.1 Incorporation of phenylalanine-1- and −2-C14. J Am Chem Soc 80:4391–4392CrossRefGoogle Scholar
  37. Wang C, Wesener SR, Zhang H, Cheng YQ (2009) An FAD-dependent pyridine nucleotide-disulfide oxidoreductase is involved in disulfide bond formation in FK228 anticancer depsipeptide. Chem Biol 16:585–593CrossRefGoogle Scholar
  38. Waring P, Beaver J (1996) Gliotoxin and related epipolythiodioxopiperazines. Gen Pharmacol 27:1311–1316CrossRefGoogle Scholar
  39. Winstead JA, Suhadolnik RJ (1960) Biosynthesis of gliotoxin: II.1,2 Further studies on the incorporation of carbon-14 and tritium-labeled precursors. J Am Chem Soc 82:1644–1647CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Daniel H. Scharf
    • 1
    • 2
  • Thorsten Heinekamp
    • 1
  • Nicole Remme
    • 1
    • 2
  • Peter Hortschansky
    • 1
  • Axel A. Brakhage
    • 1
    • 2
  • Christian Hertweck
    • 1
    • 2
  1. 1.Departments of Molecular and Applied Microbiology and Biomolecular ChemistryLeibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute (HKI)JenaGermany
  2. 2.Friedrich Schiller University JenaJenaGermany

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