67-99-2 Usage
Description
Gliotoxin is an immunosuppressive mycotoxin produced by pathogenic strains of Aspergillus and other fungi with diverse biological activities. It is a sulfur-containing mycotoxin that exhibits inhibitory activities against histone H3K9 methyltransferase, a key enzyme in the regulation of transcriptional activity by writing epigenetic marks. Gliotoxin also exhibits immunosuppressive properties by causing apoptosis of cells of the immune system. It is a potent epithiodioxopiperazine mycotoxin that inhibits a broad range of unrelated mechanisms at the cellular level, including inhibition of chymotrypsin-like activity of the 20S proteasome and Ca2+ release from mitochondria, activation of transcription factor NF-κB in response to a variety of stimuli in T and B cells, anti-inflammatory activity, and inhibition of farnesyltransferase and geranylgeranyltransferase. The mode of action appears to be via covalent interaction with proteins through mixed disulphide formation. Gliotoxin inhibits a number of thiol-requiring enzymes and also displays antioxidant and immunomodulatory activity. It is a pyrazinoindole with a disulfide bridge spanning a dioxo-substituted pyrazine ring and is presented as a white powder.
Uses
1. Used in Pharmaceutical Applications:
GLIOTOXIN is used as an immunosuppressive agent for its ability to inhibit the immune system by causing apoptosis of immune cells and reducing phagocytosis by neutrophils.
2. Used in Antiviral Applications:
GLIOTOXIN is used as an antiviral agent for its ability to suppress viral infection by Nipah and Hendra virus in HEK293T cells.
3. Used in Anti-inflammatory Applications:
GLIOTOXIN is used as an anti-inflammatory agent for its ability to inhibit leukotriene A4 hydrolase (LTA4H) epoxide hydrolase activity, leukotriene B4 (LTB4) synthesis in neutrophils and monocytes, and reduce LTB4 plasma levels.
4. Used in Enzyme Inhibition:
GLIOTOXIN is used as an enzyme inhibitor for its ability to inhibit a number of thiol-requiring enzymes, such as 20S proteasomal chymotrypsin activity, farnesyltransferase, and geranylgeranyltransferase.
5. Used in Antifungal and Antibiotic Applications:
GLIOTOXIN is used as a potential antifungal and antibiotic agent due to its diverse biological activities and inhibitory effects on various cellular mechanisms.
6. Used in Research and Development:
GLIOTOXIN is used as a research tool for studying its diverse biological activities, mode of action, and potential applications in various fields, including pharmaceuticals, anti-inflammatory, and antiviral treatments.
Biological Activity
Immunosuppressive agent; blocks phagocytosis, cytokine production and proliferation of T and B cells. Non-competitively inhibits chymotrypsin-like activity of 20S proteasome; prevents degradation of I κ B α , an endogenous blocker of NF- κ B. Also inhibits farnesyltransferase and geranylgeranyltransferase I (IC 50 values are 80 and 17 μ M respectively) and displays antitumor activity against breast cancer in vivo .
Safety Profile
Poison by intraperitoneal andintravenous routes. When heated to decomposition itemits very toxic fumes such as SOx and NOx.
Purification Methods
Purify gliotoxin by recrystallisation from MeOH. Its solubility in CHCl3 is 1%. The dibenzoyl derivative has m 202o (from CHCl3/MeOH). [Glister & Williams Nature 153 651 1944, Elvidge & Spring J Chem Soc Suppl 135 1949, Johnson et al. J Am Chem Soc 65 2005 1943, Bracken & Raistrick Biochem J 41 569 1947.]
References
Waring & Beaver (1996), Gliotoxin and related epipolythiodioxopiperazines; Gen. Pharmacol., 27 1311
Kroll et al. (1999), The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome; Chem. Biol., 6 689
Fitzpatrick et al. (2000), In vitro and in vivo effects of gliotoxin, a fungal metabolite: efficacy against dextran sodium sulfate-induced colitis in rats; Dig. Dis. Sci., 45 2327
Konig et al. (2019), Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase ; Cell Chem. Biol., 26 524
Hubmann et al. (2020), Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL; Cells, 9 1484
Check Digit Verification of cas no
The CAS Registry Mumber 67-99-2 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 7 respectively; the second part has 2 digits, 9 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 67-99:
(4*6)+(3*7)+(2*9)+(1*9)=72
72 % 10 = 2
So 67-99-2 is a valid CAS Registry Number.
InChI:InChI=1/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
67-99-2Relevant articles and documents
Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus
Scharf, Daniel H.,Remme, Nicole,Heinekamp, Thorsten,Hortschansky, Peter,Brakhage, Axel A.,Hertweck, Christian
, p. 10136 - 10141 (2010)
Gliotoxin (1), the infamous representative of the group of epipolythiodioxopiperazines (ETPs), is a virulence factor of the human pathogenic fungus Aspergillus fumigatus. The unique redox-sensitive transannular disulfide bridge is critical for deleterious effects caused by redox cycling and protein conjugation in the host. Through a combination of genetic, biochemical, and chemical analyses, we found that 1 results from GliT-mediated oxidation of the corresponding dithiol. In vitro studies using purified GliT demonstrate that the FAD-dependent, homodimeric enzyme utilizes molecular oxygen as terminal electron acceptor with concomitant formation of H2O 2. In analogy to the thiol-disulfide oxidoreductase superfamily, a model for dithiol-disulfide exchange involving the conserved CxxC motif is proposed. Notably, while all studied disulfide oxidases invariably form intra-or interchenar disulfide bonds in peptides, GliT is the first studied enzyme producing an epidithio bond. Furthermore, through sensitivity assays using wild type, ΔgliT mutant, and complemented strain, we found that GliT confers resistance to the producing organism. A phylogenetic study revealed that GliT falls into a clade of yet fully uncharacterized fungal gene products deduced from putative ETP biosynthesis gene loci. GliT thus not only represents the prototype of ETP-forming enzymes in eukaryotes but also delineates a novel mechanism for self-resistance.
New insights into the disulfide bond formation enzymes in epidithiodiketopiperazine alkaloids
Liu, Huan,Fan, Jie,Zhang, Peng,Hu, Youcai,Liu, Xingzhong,Li, Shu-Ming,Yin, Wen-Bing
, p. 4132 - 4138 (2021)
Epidithiodiketopiperazines (ETPs) are a group of bioactive fungal natural products and structurally feature unique transannular disulfide bridges between α, α or α, β carbons. However, no enzyme has yet been demonstrated to catalyse α, β-disulfide bond formation in these molecules. Through genome mining and gene deletion approaches inTrichoderma hypoxylon, we identified a putative biosynthetic gene cluster of pretrichodermamide A (1), which requires a FAD-dependent oxidoreductase, TdaR, for the irregular α, β-disulfide formation in1biosynthesis.In vitroassays of TdaR, together with AclT involved in aspirochlorine and GliT involved in gliotoxin biosynthesis, proved that all three enzymes catalyse not only the conversion of red-pretrichodermamide A (4) to α, β-disulfide-containing1but also that of red-gliotoxin (5) to α, α-disulfide-containing gliotoxin (6). These results provide new insights into the thiol-disulfide oxidases responsible for the disulfide bond formation in natural products with significant substrate and catalytic promiscuities.
TOTAL SYNTHESIS OF GLIOTOXIN, DEHYDROGLIOTOXIN AND HYALODENDRIN
Fukuyama, Tohru,Nakatsuka, Shin-Ichi,Kishi, Yoshito
, p. 2045 - 2078 (2007/10/02)
Two general methods, Method A and Method B in Scheme 19, to synthesize epidithiapiperazinediones, are described.A total synthesis of racemic and optically active gliotoxin (1) and of racemic dehydrogliotoxin (53) was achieved by using Method A, whereas a total synthesis of racemic hyalodendrin (52) was completed by using Method B.
