Transcript amanitinx

Justin Hessinger
Tess Demeter
 A toxin is a poisonous substance that is
produced by one organism that has negative
effects on another organism
 They include small molecules, peptides, or
proteins
Cause
they’re
freakin’
cool!!!
 No, but really, we felt that
amatoxins (alpha-amitin) were
interesting because they are the
cause of over 100 human deaths
annually worldwide. The
organisms that are affected by
these seemingly harmless
shrooms suffer mild symptoms
hours after ingestion that
completely disappear only to kill
their unexpecting victims days
later.
 Class of toxins produced by certain types of
Amanita species of mushrooms
 Bicyclic octapeptide derivatives
zymogenic until they reach the host
 There are at least 10 known variants of
amanitin toxin
 Amatoxins account for 95% of fatal
mushroom poisoning
 Alpha-Amanitin is produced by some of the mushrooms
from the genus Amanita.
 The most common/deadly species:
Death cap mushroom
(Amanita phalloides)
Destroying
Angel
(Amanita virosa)
 There are around 600 known species,
some of which are actually edible
 They are distributed throughout the world
and found in regions such as;
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Mexico
Central Africa
Europe
Canada
South America
United States
 Alpha-amanitin causes inhibition of RNA
Polymerase II by:
 strong hydrogen bonding to the bridge helix on
RNA Polymerase referred to as pore 1.
 penetrates at pore1 and regulates
translocation and stops elongation at or before
translocation occurs.
 it does not affect NTP loading, rather it
prevents the bridge helix from flexing thus
preventing DNA translocation.
 Inhibition of RNA Polymerase II induces stress
activated kinases.
 Phosphorylation of p53 protein fraction on serine
residues
 This causes suppression of p53 degredation
 The accumulated p53 are translocated to
mitochondria and this increases permeability of
the outer membrane which causes the release of
cytochrome C to the cytosol.
 This causes programmed cell death.
 Amanitin toxicity is also associated with an
increase in the production of reactive oxygen
species through lipid peroxidation
 Increases hepatotoxicity
 Although many studies note this reaction
during amanitin toxicity, they are unclear in
stating how amanintin itself induces this
response
 These are all very similar in structure, often
only differing by 1 R-group.
• α-amanitin
• β-amanitin
• γ-amanitin
• ε-amanitin
• Amanullin
• Amanullinic Acid
• Amaninamide
• Amanin
•Proamanullin
 Toxicity depends on many factors:
 Amount of toxin ingested
 Age; multi-organ failure between 6-8 days
ranges
 10-20% adults
 22-50% children
 Immune Function
 Exposure Pathway; majority of exposure is
through oral administration, but there are
cases of intravenous injection.
 Although amatoxins are
extremely toxic to humans and
difficult to treat, there are
species that are immune to
these toxins. The mechanisms
of their immunity are highly
misunderstood
Caenorhabditis elegans
Drosophila melanogaster
 Structural mutations of RNAPII
 Alpha-amanitin is unable to bind in the proper
location
 Most plausible
 Metabolic degradation
 There are 3 possible modes of degredation
although the most plausible is by cytochrome
P450’s
 Behavioral Avoidance
 Why are the mushrooms that develop these
amatoxins not affected by them?
 Protein precursers are usually used when the protein
is potentially harmful to the host, but needs to be
available on short notice and in large quantities.
 The active form of the toxin is not present in the host
organisms.
 When entering a target species activation occurs by
cleavage of the 8 terminal amino acids present on the
toxin
 Enzymatic reaction catalyzed by prolyloligopeptidase
 The most common pathway is through oral
ingestion
 The toxin may be isolated and injected
peritoneally or intravenously, although this
method is really only reserved for lab research
and due to ethicalities, humans are not generally
the test subjects
 For humans:
 6-12 hours: incubation (no observable adverse
effects)
 Starts with gastrointestinal symptoms
 Vomiting, diarrhea, abdominal pain,
hypoglycemia, and dehydration
 48-72 hours: evident hepatocellular damage
 Coagulopathy and acute liver failure
 6-8 days: acute liver and kidney failure
 Haemorrhaging, encephalopathy, coma, and
death
 About 10% of individuals exposed to
amanitin in will die in the U.S.
 World wide, about 50% of those exposed to
aminitin toxin will die due to inadequate
and/or less accessible medical care
 Of those that survive, severe liver and kidney
damage is extremely common and some
patients may die due to complications
pertaining to organ failure
 Silybin
 Comes from the Milk Thistle (Silybum marianum)
 Competes with amanitin for transport systems in
the plasma membranes in cells
 Causes a decrease in penetration of amanitin into
hepatocytes
 Thioctic Acid
 Powerful antioxidant
 Inhibits free radical formation through lipid
peroxidation
 Prevents further oxidative tissue damage
 Benzylpenicillin
 Inhibits trasporting polypeptide 1B3 in the plasma
membrane which impedes amanitin penetration of
hepatocytes
 N-acetylcysteine
 Unclear mechanism
 May inhibit hepatic uptake of amanitin
 May act as strong antioxidant
 Cimetidine
 Listed as a treatment, but there was no known
mechanism found
 To date it seems that the most effective treatment
involves pumping the stomach right after eating the
toxin.
 Because this treatment is extremely time dependant
and symptoms may take hours to show up, it’s not
largely reliable.
 Although there are other proposed treatments, the
ones that we have included are the most common
across notable sources.
 The only treatment other than emptying the stomach
content, that has shown any potential benefits
through decrease in hepatic necrosis is Silybin.
 These results, as noted in various studies, can be
limited or nullified by the experimental conditions.
 There are other studies that have resulted positively
with different toxins, but themselves list a variety of
limitations and problems with their research
 Before eating a random mushroom, there are
a few things you can do:
 Meixner Test: tests for presence of amanitin
in the mushroom
 Limitations: cannot differentiate between toxic
and hallucinogenic species because psilocin
gives a false positive
 Mezler’s Reagent: tests for spores of amyloid,
non-amyloid, and dextranoid
 Used to identify different types of fungi
 There is potential for therapeutic use against
pancreatic carcinoma
 Through conjugation of Amanitin to Antiepithelial cell adhesion molecules (EpCAM),
antitumor properties have been shown
 EpCAM’s are over expressed in many
cancers.
 The conjugated molecules are able to bind
these markers and initiate apoptosis
 Although amatoxins are widely distributed
and extremely toxic, they are still very
misunderstood.
 The toxic effects suffered from exposure to
amatoxins are difficult to treat and the
mechanisms behind their action is still
unclear. Despite these difficulties, continued
research and understanding is very
important because they may be the key to
future treatments for other illnesses and
survivorship.
So remember kids,
be careful when
picking your
shrooms!!!
As we understand that peer-reviewing is a time-consuming
process and you may be tired, here is some legal fun you
can have with some awesome shrooms. ENJOY!!!
http://onlinesupermario.com/mario-world.php
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