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Skeletal formula of gliotoxin
Space-filling model of the gliotoxin molecule
IUPAC name
3D model (JSmol)
ECHA InfoCard 100.163.992
Molar mass 326.4 g/mol
Appearance white to light yellow solid
Density 1.75 g/ml
Solubility in DMSO soluble
Safety data sheet MSDS from Fermentek
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Gliotoxin is a sulfur-containing mycotoxin that belongs to a class of naturally occurring 2,5-diketopiperazines[1] produced by several species of fungi, especially those of marine origin. It is the most prominent member of the epipolythiopiperazines, a large class of natural products featuring a diketopiperazine with di- or polysulfide linkage. These highly bioactive compounds have been the subject of numerous studies aimed at new therapeutics.[2] Gliotoxin was originally isolated from Gliocladium fimbriatum, and was named accordingly. It is an epipolythiodioxopiperazine metabolite.


The compound is produced by human pathogens such as Aspergillus fumigatus,[3] and also by species of Trichoderma, and Penicillium. Gliotoxin has also been reported from yeasts of the genus Candida,[4] but results from other studies have cast doubt on the production of this metabolite by Candida fungi.[5][6]..

Mechanism of action[edit]

Gliotoxin is suspected to be an important virulence factor in Aspergillus fungus. Gliotoxin possesses immunosuppressive properties that may suppress and cause apoptosis in certain cells of the immune system, including neutrophils, eosinophils, granulocytes, macrophages, and thymocytes.[7] Specifically, neutrophils exposed to gliotoxin release less reactive oxygen species (ROS) and complete fewer phagocytic activities.[8] Gliotoxin is also believed to interfere with T-cell activation.[9] Additionally, gliotoxin acts as an inhibitor of farnesyl transferase. It noncompetitively inhibits the chymotrypsin-like activity of the 20S proteasome.[7]

In vivo gliotoxin displays anti-inflammatory activity. It was investigated as an antibiotic and antifungal in the 1940s and as an antiviral agent.[7] Gliotoxin inactivates many different enzymes, including nuclear factor-κB (NF-κB), NADPH oxidase, and glutaredoxin. The inhibition of NF-κB leads prevents cytokine release and induction of the inflammatory response.[10]

The immunosuppressive properties of gliotoxin are due to the disulfide bridge within its structure. Interactions occur between sulfur molecules that make up the disulfide bridge and thiol groups contained in cysteine residues. Gliotoxin acts by blocking thiol residues in the cell membrane.[7] Gliotoxin also activates a member of the Bcl-2 family called Bak in order to mediate cell apoptosis. Activated Bak then causes the release of ROS, which form pores within the mitochondrial membrane. These pores allow the release of cytochrome C and AIF, which initiate apoptosis within the cell.[9]


In Aspergillus fumigatus, the enzymes needed for gliotoxin biosynthesis are encoded in 13 genes within the gli gene cluster. When this gene cluster is activated, these enzymes mediate the production of gliotoxin from serine and phenylalanine residues.[10]

Enzymes Involved in Biosynthesis (in order of activity) [10]

GliZ: transcription factor that regulates expression of gli gene cluster
GliP: facilitates formation of cyclo-phenylalanyl-serine intermediate from serine and
phenylalanine residues
GliC: adds hydroxyl group to the alpha carbon of the phenylalanine residue in the
cyclo-phenylalanyl-serine intermediate
GliG: glutathione S-transferase (GST) that adds two glutathione molecules forming a
bis-glutathionylated intermediate
GliK: gamma-glutamyl transferase that removes gamma-glutamyl moieties from
glutathione additions
GliN: adds a methyl group to nitrogen to form the dithiol gliotoxin intermediate
GliT: oxidoreductase that mediates closure of the disulfide-bridge
Conversion of dithiol gliotoxin to gliotoxin by the enzyme GliT.
GliA: Major Facilitator Superfamily transporter that secretes gliotoxin across cell membrane
Enzymes GliJ, GliI, GliF, and GliH are necessary for biosynthesis, but their exact function is unknown.

Regulation of Biosynthesis

Some gliotoxin molecules are not secreted by GliA and remain in the cell. This intracellular gliotoxin activates the transcription factor GliZ, facilitating gli gene cluster expression, and an enzyme called GtmA. GtmA acts as a negative regulator for gliotoxin biosynthesis by adding methyl groups to the two sulfur residues on the dithiol gliotoxin intermediate. These additions prevent the formation of the disulfide bridge by GliT, inhibiting gliotoxin formation.[10]

Exposure and health effects[edit]

Environmental Exposure

Exposure to fungal species that secrete gliotoxin is common because airborne Aspergillus fungal spores are ubiquitous in many environments. Regular environmental exposure does not typically cause illness, but can cause serious infections in immunosuppressed individuals or those suffering from chronic respiratory illnesses. Infections caused by Aspergillus fungus are called aspergillosis. There are many types of aspergillosis, but infections typically affect the lungs or the sinuses.[11]

Gliotoxin is hypothesized to be an important virulence factor in Aspergillus fumigatus.[10] Experiments have demonstrated that gliotoxin is isolated in the highest concentrations from Aspergillus fumigates in comparison to other Aspergillus species. This species of fungi is the most common cause of aspergillosis in humans. Gliotoxin is also the only toxin that has been isolated from the sera of patients suffering from invasive aspergillosis. These results suggest a link between gliotoxin secretion and fungal pathogenicity.[12]

While not enough data exists to definitively tie chronic gliotoxin exposure to the development of cancer, chronic exposure to other immunosuppressive agents has been linked to the development of lymphomas and mammary tumors. Individuals taking immunosuppressive medications or with previous or current exposure to chemotherapy radiation are at higher risk for the development of these tumors.[13]

Clinical Exposure

Gliotoxin is toxic if swallowed or inhaled, and can cause skin and eye irritation if exposure occurs to these areas. The oral LD50 of gliotoxin is 67 mg/kg. Acute symptoms of gliotoxin start rapidly after ingestion. [14]


  1. ^ Borthwick AD (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews. 112 (7): 3641–3716. doi:10.1021/cr200398y. PMID 22575049.
  2. ^ Jiang, C.-S.; Muller, W. E. G.; Schroder, H. C.; Guo, Y.-W., "Disulfide- and Multisulfide-Containing Metabolites from Marine Organisms", Chem. Rev. 2012, 112, 2179-2207. doi:10.1021/cr200173z
  3. ^ Scharf DH, Heinekamp T, Remme N, Hortschansky P, Brakhage AA, Hertweck C (2012). "Biosynthesis and function of gliotoxin in Aspergillus fumigatus". Appl Microbiol Biotechnol. 93 (2): 467–72. doi:10.1007/s00253-011-3689-1. PMID 22094977.
  4. ^ Shah, Darshana T.; Larsen, Bryan (1991). "Clinical isolates of yeast produce a gliotoxin-like substance". Mycopathologia. 116 (3): 203–8. doi:10.1007/BF00436836. PMID 1724551.
  5. ^ Kupfahl C, Ruppert T, Dietz A, Geginat G, Hof H (2007). "Candida species fail to produce the immunosuppressive secondary metabolite gliotoxin in vitro". FEMS Yeast Res. 7 (6): 986–92. doi:10.1111/j.1567-1364.2007.00256.x. PMID 17537180.
  6. ^ Kosalec I, Puel O, Delaforge M, Kopjar N, Antolovic R, Jelic D, Matica B, Galtier P, Pepeljnjak S (2010). "Isolation and cytotoxicity of low-molecular-weight metabolites of Candida albicans". Front Biosci. 13 (13): 6893–904. doi:10.2741/3197. PMID 18508703.
  7. ^ a b c d McDougall, J. K. (1969). "Antiviral action of gliotoxin". Archiv für die gesamte Virusforschung. 27 (2–4): 255. doi:10.1007/BF01249648.
  8. ^ Kwon-Chung, Kyung J.; Sugui, Janyce A. (2009). "What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus?". Medical Mycology. 47: S97–103. doi:10.1080/13693780802056012. PMC 2729542. PMID 18608908.
  9. ^ a b Pardo, Julian; Urban, Christin; Galvez, Eva M.; Ekert, Paul G.; Müller, Uwe; Kwon-Chung, June; Lobigs, Mario; Müllbacher, Arno; Wallich, Reinhard; Borner, Christoph; Simon, Markus M. (2006). "The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillusfumigatus virulence in mice". The Journal of Cell Biology. 174 (4): 509–19. doi:10.1083/jcb.200604044. PMC 2064257. PMID 16893972.
  10. ^ a b c d e Dolan, Stephen K.; o'Keeffe, Grainne; Jones, Gary W.; Doyle, Sean (2015). "Resistance is not futile: Gliotoxin biosynthesis, functionality and utility". Trends in Microbiology. 23 (7): 419–28. doi:10.1016/j.tim.2015.02.005. PMID 25766143.
  11. ^ The Aspergillosis Website . (n.d.). Aspergillus & Aspergillosis Website. Retrieved May 08, 2017, from
  12. ^ Dagenais, T. R. T.; Keller, N. P. (2009). "Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis". Clinical Microbiology Reviews. 22 (3): 447–65. doi:10.1128/cmr.00055-08. PMC 2708386. PMID 19597008.
  13. ^[full citation needed]
  14. ^

Further reading[edit]

  • Identification of an agent in cultures of Aspergillus fumigatus displaying anti-phagocytic and immunomodulating activity in vitro: A. Müllbacher, et al.; J. Gen. Microbiol. 131, 1251 (1985)
  • Clinical Isolates of yeast produce a gliotoxin-like substance". D. Shah and B. Larsen; Mycopatholgia 116: 203-208,(1991)
  • "Mechanism of gliotoxin action and factors mediating gliotoxin sensitivity". R.W. Jones & J.G. Hancock; J. Gen. Microbiol. 134: 2067-2075 (1988)
  • Gliotoxin stimulates Ca2+ release from intact rat liver mitochondria: M. Schweizer & C. Richter; Biochemistry 33, 13401 (1994)
  • Gliotoxin–bane or boon?.Scharf DH, Brakhage AA, Mukherjee PK. Environmental Microbiology. 18(4): 1096-1109 (2016).

External links[edit]

  • Puri, Alka; Ahmad, Ajaz; Panda, Bibhu Prasad (2009). "Development of an HPTLC-based diagnostic method for invasive aspergillosis". Biomedical Chromatography: n/a. doi:10.1002/bmc.1382.