Genomic loci for this biosynthetic pathway

Cluster Type From To
The following clusters are from record BGC0000361.1:
Cluster 1NRP1617

BGC0000361, gliotoxin biosynthetic gene cluster from Aspergillus fumigatus. Locus 1. Full MIBiG entry.

Chemical compounds

Compound: Gliotoxin
PubChem ID: 6223
SMILES string: Copy to clipboard
Molecular formula: C13H14N2O4S2
Average molecular mass: 326.385 Da
Molecular activity: Antibacterial, Antifungal, Antioxidant, Cytotoxic, Inhibitor

Class-specific details

Biosynthetic class(es):
NRP
Other (cyclic)
Thioesterase type:
Unknown
Release / cyclization type:
Unknown

Nonribosomal peptide synthetases:
gliP (AAW03307.1)
Module 0
A specificity: Phenylalanine
Evidence for specificity: Activity assay
C domain subtype: N/A
Module 1
A specificity: Serine
Evidence for specificity: Activity assay
C domain subtype: DCL
Module 2
A specificity: Unknown
Evidence for specificity: Unknown
C domain subtype: LCL

Gene cluster description

gliotoxin (BGC0000361). Gene Cluster 1. Biosynthetic class = NRP. GenBank AAHF01000006, positions 1054011-1054627. Click on genes for more information.

Legend:

biosynthetic genes
transport-related genes
regulatory genes
other genes

General MIBiG information on this cluster

Complete gene cluster sequence?complete
Evidence for cluster-compound connection:Knock-out studies
MIxS-compliance:Unknown
Comments:The gli cluster contains an additional experimentally verified gene (gliH; EAL88826) which is essential for gliotoxin biosynthesis (Schrettl et al. 2010- PMID 20548963). gliH occurs after gliT in the gli cluster. Bismethylgliotoxin is also formed via the action of the gli cluster, plus one additional gene on chromosome 2 (gliotoxin bis-thiomethyltransferase; AFUA_2g11120; Dolan et al. 2014; PMID 25126990).
Contact for this cluster:Sean Doyle (Maynooth University)

Literature references

1. Wang DN et al. (2014) GliA in Aspergillus fumigatus is required for its tolerance to gliotoxin and affects the amount of extracellular and intracellular gliotoxin. Med Mycol 52(5):506-18. doi: 10.1093/mmy/myu007. Epub 2014 May 20.
2. Dolan SK et al. (2014) Regulation of nonribosomal peptide synthesis: bis-thiomethylation attenuates gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol 21(8):999-1012. doi: 10.1016/j.chembiol.2014.07.006.
3. O'Keeffe G et al. (2014) RNA-seq reveals the pan-transcriptomic impact of attenuating the gliotoxin self-protection mechanism in Aspergillus fumigatus. BMC Genomics 15:894. doi: 10.1186/1471-2164-15-894.
4. Scharf DH et al. (2014) Opposed effects of enzymatic gliotoxin N- and S-methylations. J Am Chem Soc 136(33):11674-9. doi: 10.1021/ja5033106. Epub 2014 Aug
5. Scharf DH et al. (2013) Epidithiodiketopiperazine biosynthesis: a four-enzyme cascade converts glutathione conjugates into transannular disulfide bridges. Angew Chem Int Ed Engl 52(42):11092-5. doi: 10.1002/anie.201305059.
6. Scharf DH et al. (2012) Epidithiol formation by an unprecedented twin carbon-sulfur lyase in the gliotoxin pathway. Angew Chem Int Ed Engl 51(40):10064-8. doi: 10.1002/anie.201205041.
7. Scharf DH et al. (2011) A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis. J Am Chem Soc 133(32):12322-5. doi: 10.1021/ja201311d. Epub 2011 Jul
8. Davis C et al. (2011) The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol 18(4):542-52. doi: 10.1016/j.chembiol.2010.12.022.
9. Schrettl M et al. (2010) Self-protection against gliotoxin--a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog 6(6):e1000952. doi: 10.1371/journal.ppat.1000952.
10. Scharf DH et al. (2010) Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. J Am Chem Soc 132(29):10136-41. doi: 10.1021/ja103262m.
11. Spikes S et al. (2008) Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J Infect Dis 197(3):479-86. doi: 10.1086/525044.
12. Sugui JA et al. (2007) Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell 6(9):1562-9. doi: 10.1128/EC.00141-07. Epub 2007 Jun 29.
13. Balibar CJ, Walsh CT. (2006) GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin. Biochemistry 45(50):15029-38. doi: 10.1021/bi061845b.
14. Kupfahl C et al. (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(1):292-302. doi: 10.1111/j.1365-2958.2006.05373.x.
15. Cramer RA Jr et al. (2006) Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot Cell 5(6):972-80. doi: 10.1128/EC.00049-06.
16. Gardiner DM, Howlett BJ. (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248(2):241-8. doi: 10.1016/j.femsle.2005.05.046.