Gliotoxin

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Gliotoxin
Skeletal formula of gliotoxin
Space-filling model of the gliotoxin molecule
Names
IUPAC name
(3R,6S,10aR)-6-Hydroxy-3-(hydroxymethyl)-2-methyl-2,3,6,10-tetrahydro-5aH-3,10a-epidithiopyrazino[1,2-a]indole-1,4-dione
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
ECHA InfoCard
 100.163.992 Edit this at Wikidata
UNII
  • InChI=1S/C13H14N2O4S2/c1-14-10(18)12-5-7-3-2-4-8(17)9(7)15(12)11(19)13(14,6-16)21-20-12/h2-4,8-9,16-17H,5-6H2,1H3/t8-,9-,12+,13+/m0/s1 checkY
    Key: FIVPIPIDMRVLAY-RBJBARPLSA-N checkY
  • InChI=1S/C13H14N2O4S2/c1-14-10(18)12-5-7-3-2-4-8(17)9(7)15(12)11(19)13(14,6-16)21-20-12/h2-4,8-9,16-17H,5-6H2,1H3/t8-,9-,12+,13+/m0/s1
    Key: FIVPIPIDMRVLAY-RBJBARPLBT
  • Key: FIVPIPIDMRVLAY-RBJBARPLSA-N
  • O=C1N([C@@]2(SS[C@@]14N(C2=O)[C@H]3C(=C\C=C/[C@@H]3O)/C4)CO)C
Properties
C13H14N2O4S2
Molar mass 326.39 g·mol−1
Appearance White to light yellow solid
Density 1.75 g/ml
Solubility in DMSO soluble
Hazards
Safety data sheet (SDS) MSDS from Fermentek
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Gliotoxin is a

Gliocladium fimbriatum, and was named accordingly. It is an epipolythiodioxopiperazine metabolite that is one of the most abundantly produced metabolites in human invasive Aspergillosis (IA).[3]

Occurrence

The compound is produced by

Candida,[5] but results from other studies have cast doubt on the production of this metabolite by Candida fungi.[6][7] Gliotoxin is not produced by nonpathogenic A. fischeri although A.fischeri contains a gene cluster that is homologous to the gliotoxin gene cluster found in the pathogenic A. fumigatus.[8] Gliotoxin contributes to the pathogenicity of opportunistic fungi by suppressing the immune system response of its host.[9] Gliotoxin additionally possesses fungicidal and bacteriostatic properties, which indicates that it likely plays an important self defense role against bacteria and other fungi for the fungi that produce gliotoxin.[10] Exposure of A. fumigatus to exogenous gliotoxin resulted in aberrant protein expression, especially in those strains that lacked the self-protection protein GliT.[11] There is additional evidence for differential gliotoxin sensitivities amongst fungi including Aspergillus flavus, Fusarium graminearum, and Aspergillus oryzae.[11]

Discovery

Gliotoxin was first described in 1936 by Weindling and Emerson as a metabolic product from the fungus Trichoderma lignorum. However, afterwards Weindling reported that the fungus had been misidentified based on the advice of C. Thom and M. Timonin, and that the compound instead was isolated from Gliocladium finbriatum.[12] Contention remains on whether the fungus used by Weindling was G. finbriatum or a species of Trichoderma.[12] The chemical structure of gliotoxin was resolved in 1958 by Bell et al. by treatment of gliotoxin on alkaline alumina.[13] Bell and colleagues were able to determine through their structural analyses that the attachment of the disulfide bridge could not occur at any positions other than 3 and 11. This led to the elucidation that gliotoxin was an anhydropeptide related to the amino acids serine and phenylalanine. Additionally, they found that it was noteworthy that the α-carbon atoms of the cooperating α-thio-α-amino acids must have the same configuration.[13]

Mechanism of action

Gliotoxin is suspected to be an important

20S proteasome.[14]

inflammatory response.[17]

The immunosuppressive properties of gliotoxin are due to the

cytochrome C and AIF, which initiate apoptosis within the cell.[16]

Biosynthesis

In

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.[17] The function of some genes contained within the gli gene cluster remain to be elucidated.[18]

Enzymes Involved in Biosynthesis (in order of activity)[17][18]

Biosynthetic pathway of gliotoxin Ye et al. (2021)
GliZ: transcription factor that regulates expression of gli gene cluster
GliP: non-ribosomal peptide synthetase that facilitates formation of cyclo-phenylalanyl-serine intermediate from serine and phenylalanine residues
GliC:
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
GliJ: Cys-Gly carboxypeptidase that removes carboxyl moieties from glutathione additions
GliI:
aminotransferase
that removes amino moieties from glutathione additions
GliF:
hydroxyl group
to the benzene residue and facilitates ring closure
GliN/GliM: N-methyltransferase/O-methyltransferase that adds a methyl group to nitrogen to form the dithiol gliotoxin intermediate utilizing s-adenosyl methionine (SAM) in the reaction
GliT:
disulfide-bridge
GliA:
Major Facilitator Superfamily
transporter that secretes gliotoxin across cell membrane
The exact roles of the enzymes GliC, GliF, GliM, and GliN and the steps in the biosynthetic pathway of these enzymes are still not completely understood in the biosynthesis of gliotoxin.[18]

Regulation of Biosynthesis

Some gliotoxin molecules are not secreted by GliA and remain in the cell. This

negative regulator for gliotoxin biosynthesis by adding methyl groups to the two sulfur residues on the dithiol gliotoxin intermediate to form bisdethilobis(methylthio)-gliotoxin (BmGT).[18] These additions prevent the formation of the disulfide bridge by GliT, inhibiting gliotoxin formation, while BmGT is significantly less toxic than gliotoxin.[17][18]

It is thought that GliA, GtmA, and GliT provide mechanisms for self-protection against gliotoxin toxicity for the fungi that produce and

excrete gliotoxin.[18] GliA is a transporter involved in the secretion of gliotoxin, and it has been found that depletion of the GliA protein would result in cell death in A. fumigatus and significantly increase A. fumigatus sensitivity to gliotoxin.[18] GtmA catalyzes the addition of methyl groups to the sulfur residues of dithiol gliotoxin to form nontoxic BmGT, which reduces the toxicity load on the fungi while also downregulating further expression of the gli cluster and attenuating gliotoxin biosynthesis.[17] GliT is required for the formation of the disulfide bridge to create active gliotoxin, but it is also suggested that it plays a role in self-protection against gliotoxin toxicity. In A. fumigatus with the deletion of the GliT gene, there was found to be an accumulation of dithiol gliotoxin, which contributed to hypersensitivity to exogenous gliotoxin. These regulatory controls on the biosynthesis of gliotoxin are thought to provide mechanisms for novel strategies of gliotoxin toxicity prevention.[18]

Chemical synthesis

The first

Triton B at room temperature produced the alcohol 3 in 88% overall yield. It is expected that there would be a trans-opening of the epoxide ring for 2, so the resulting epimers would differ in the relative configuration of the thioacetal bridge and the alcoholic group depending on the orientation of compounds 1 and 2 in the transition state. It was theorized that the orientation of 1 and 2 that produced the alcohol 3 would be unfavorable in non-polar
solvents. Thus, desired stereochemistry was assigned to the alcohol 3, and this compound was used in the further synthesis.

First total synthesis of gliotoxin Fukuyama & Kishi (1976)

The alcohol 3 was then converted into the acetate 4 via acetic anhydride-pyridine at room temperature with an overall yield of 90%. The acetate was then converted to the hydroxymethyl derivative 5 in three steps (1. TFA/room temperature; 2. ClCO2Et/Et3N-CH2Cl2/room temperature; 3. NaBH4/CH3OH-CH2Cl2/0 °C. Mesylation of 5 (MsCl/CH3OH-Et3N-CH2Cl2/0 °C), followed by lithium chloride treatment in DMF and hydrolysis (NaOCH3/CH3OH-CH2Cl2/room temperature) give the chloride 6 at a 95% overall yield. Adding phenyllithium slowly to a mixture of 6 and chloromethyl benzyl ether in excess in THF at 78 °C gave the benzylgliotoxin adduct 7 at 45% yield. Next, boron trichloride treatment of 7 in in methylene chloride at 0 °C yielded the gliotoxin anisaldehyde adduct 8 at 50% yield. Finally, acid oxidation of 8 followed by perchloric acid treatment in methylene chloride at room temperature yielded d,l-gliotoxin in a 65% yield. Spectroscopic analysis (NMR, ir, uv, MS) and TLC comparison showed that the synthetic substance was identical to natural gliotoxin.

Exposure and health effects

Environmental exposure

Exposure to fungal species that secrete gliotoxin is common because airborne

sinuses.[20]

Gliotoxin is hypothesized to be an important

pathogenicity.[21]

While not enough data exists to definitively tie chronic gliotoxin exposure to the development of cancer, chronic exposure to other

immunosuppressive medications or with previous or current exposure to chemotherapy radiation are at higher risk for the development of these tumors.[22]

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.[22]

Strategies for toxicity prevention

Understanding the mechanisms behind the toxicity of gliotoxin can open new possibilities for the use of gliotoxin therapeutically or as a

transcriptional activator GliZ, as deletion of the GliZ resulted in abrogated gliotoxin biosynthesis.[17] This leads to the possible targeting of GliZ itself rather than any gene-based methodology to prevent it from binding to the gli gene cluster and activate transcription of the genes required for gliotoxin biosynthesis.[18] One possible strategy for disrupting the regulation of gliotoxin transport is depleting the amount of GipA in the cell.[18] GipA is a transcriptional regulator for the expression of the GliA transporter protein, which is required for gliotoxin secretion.[18] These biosynthetic strategies for reducing the toxicity of pathogenic fungal strains that produce gliotoxin are still in their early stages of exploration but could provide novel methodologies for the adoption of therapeutic uses for gliotoxin.[18]

Possible uses

While gliotoxin exposure at high concentrations shows cytotoxic effects via a multitude of different pathways, low-dose gliotoxin has been shown to have beneficial biological functions.

CD8+ T-cells that are involved in the elimination of HIV-infected cells.[18] While research on this possible gliotoxin use is in early stages, this provides a possible future direction for HIV diagnosis and treatment.[18]

References

  1. PMID 22575049
    .
  2. PMID 22176580
    .
  3. PMID 15618207
    .
  4. S2CID 689907
    .
  5. S2CID 12919491
    .
  6. PMID 17537180
    .
  7. PMID 18508703
    .
  8. S2CID 211084907
    .
  9. S2CID 9504461
    .
  10. ISSN 0002-7863
    .
  11. ^
    PMID 22405895
    .
  12. ^
    S2CID 4133538
    .
  13. ^
    ISSN 0002-7863
    .
  14. ^
    S2CID 7184381
    .
  15. PMID 18608908
    .
  16. ^
    PMID 16893972
    .
  17. ^
    PMID 25766143
    .
  18. ^
    PMID 34948306
    .
  19. ^
    PMID 61223
    .
  20. ^ The Aspergillosis Website . (n.d.). Aspergillus & Aspergillosis Website. Retrieved May 08, 2017, from http://www.aspergillus.org.uk/content/aspergillosis-2
  21. PMID 19597008
    .
  22. ^ a b "Safety Data Sheet: Gliotoxin" (PDF).

Further reading

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