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Alpha-amanitin

Identifiers

CAS number

PubChem
2100

Properties

Molecular formula
C39H54N10O14S

Molar mass
918.96966

Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox references

Alpha-amanitin or α-amanitin is a cyclic nonribosomal peptide of eight amino acids. It is possibly the most deadly of all the amatoxins, toxins found in several members of the Amanita genus of mushrooms, one being the Death cap (Amanita phalloides) as well as the Destroying angel, a complex of similar species, principally A. virosa and A. bisporiga. It is also found in the mushrooms Galerina marginata and Conocybe filaris. The oral LD50 of amanitin is approximately 0.1 mg/kg.

The structure of the polypeptide is atypical of most polypeptides, due to the branching of the amino acid chain. Two modified amino acids (dihydroxylated tryptophan and a sulfinated cysteine) allow the formation of a second “inner loop”, as seen in the diagram at right. The “outer loop” is formed by the normal peptide bond of the carboxyl terminus to the amino terminus of the peptide chain.

Contents

1 Scientific use
2 Symptoms of poisoning
3 Mode of inhibitory action
4 References
5 See also
6 External links

Scientific use

alpha-Amanitin is an inhibitor of RNA polymerase II. This mechanism makes it a deadly toxin.

alpha-Amanitin can also be used to determine which types of RNA polymerase are present. This is done by testing the sensitivity of the polymerase in the presence of alpha-amanitin. RNA polymerase I is insensitive, RNA pol II is highly sensitive, and RNA pol III is slightly sensitive.

Symptoms of poisoning

Alpha-amanitin has an unusually strong and specific attraction to the enzyme RNA polymerase II. Upon ingestion, it binds to the RNA polymerase II enzyme, effectively causing cytolysis of hepatocytes (liver cells).

Around 15% of those poisoned will die in around 10 days progressing through a comatose stage to renal failure, liver failure, hepatic coma, respiratory failure and death. Those who recover are at risk of permanent liver damage. Diagnosis is difficult, centered around the described clinical symptoms as well as alpha-amanitin content excreted in the urine. Urine screening is generally most useful within 48 hours of ingestion. Treatment is mainly supportive (gastric lavage, activated carbon, fluid resuscitation) but includes various drugs to counter the amatoxins, including intravenous penicillin and cephalosporin derivatives, and, in cases of greater ingestion, can extend to an orthotopic liver transplant. The most reliable method to treat amanitin poisoning is through having the stomach pumped immediately after ingestion; however, the onset of symptoms is generally too late for this to be an option.

Mode of inhibitory action

α-Amanitin (red) bound to RNA polymerase II from Saccharomyces cerevisiae (brewer’s yeast). From PDB 1K83.

From the crystal structure solved by Dr. Bushnell et al., The bridge helix has evolved to be flexible and its movement is required for translocation of the polymerase along the DNA backbone. Binding of α-amanitin puts a constraint on its mobility, hence slowing down the translocation of the polymerase and the rate of synthesis of the RNA molecule.

References

^ B. Meinecke and S. Meinecke-Tillmann (1993) Journal of Reproduction and Fertility 98:195-201
^ D. Michelot and R. Labia (1988) Drug Metabol Drug Interact 6:265-74.
^ A. Mas (2005) Mushrooms Journal of Hepatology 42:166-169
^ Benjamin DR. “Amatoxin syndrome”: 198–214. in: (1995) Mushrooms: poisons and panaceas — a handbook for naturalists, mycologists and physicians. New York: WH Freeman and Company.
^ a b Structural basis of transcription: alpha-amanitin-RNA polymerase II cocrystal at 2.8 A resolution. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1218-22.
^ Chafin, D. R. , Guo, H. & Price, D. H. (1995) J. Biol. Chem. 270, 19114-19119.
^ Rudd, M. D. & Luse, D. S. (1996) J. Biol. Chem. 271, 21549-21558.
^ Cochet-Meilhac, M. & Chambon, P. (1974) Biochim. Biophys. Acta 353, 160-184.
^ Vaisius, A. C. & Wieland, T. (1982) Biochemistry 21, 3097-3101.
^ Gu, W. , Powell, W. , Mote, J., Jr. & Reines, D. (1993) J. Biol. Chem. 268, 25604-25616.