Lecture 15: Fungal Toxins Flashcards Preview

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Flashcards in Lecture 15: Fungal Toxins Deck (13):
1

Ergotism

Ergot—from Claviceps purpurea—grows as sclerotia on individual rye kernels .

Symptoms: sometimes one or both
-gangrenous type—blood flow stops, mummified extremities and loss of limbs, painful.
-Convulsive type—neurological—numbness, blindness, convulsions, paralysis.

Active substances
ergotamine (LD50 10 ug/kg rodents):

LSD has ethyl groups on the R (lysergic acid).

2

Ergotamine/Dihydroergotamine

-a class of medications called ergot alkaloids
-used to treat migraine
-constrict intracranial blood vessels (vasoconstriction)
reduce neruogenic inflammation (a partial agonist )
5-HT1D receptor and alpha-adrenergic receptor

-also acts as a partial agonist for central 5HT1A receptors (nausea and dysphoria), dopamine D2 receptors (nausea and vomiting)

3

5-Hydroxytryptamine (Serotonin) Receptor

1. Affect various neurological processes: aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, thermoregulation.

2. Modulate the release of neurotransmitters and hormones: glutamate, GABA, acetylcholine, dopamine, norepinephrine/epinephrine, cortisol, substance P, oxytocin, vasopressin, etc.

3. Serotonin receptors are targets of pharmaceutical and illicit drugs: anti-depression, anti-migraine, anti-emetics, anti-psychotics, hallucinogens, entactogens (chemicals that induce the feelings of empathy). Nearly all known 5HT2A agonists produce hallucinogenic effects in humans.

4

5-HT1

Gi/Go; decrease intracellular cAMP

5

5-HT2

Gq/G11; increase intracellular IP3 and Diacylglycerol

6

Psilocybe cubensis

is a species of psychedelic mushroom whose principle active compounds are psilocybin and psilocin.
-Mode of Action: Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as an agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin (5-HT). About 1% of the weight of Psilocybe cubensis mushrooms is Psilocybin.

-Psilocybin binds to 5-HT2A with high affinity, and also 5-HT1A, 1D, 2C with lower affinity. It may also act through dopamine receptors.
-LD50 is 280 mg/kg BW, about 1.5 times that of caffeine.

7

Aflatoxin

Aflatoxin—from Aspergillus flavus—active ingredient is Aflatoxin B1.

Symptoms: hepatotoxin at high doses, carcinogenic at low doses (most potent liver carcinogen).

FDA allowable amount is 15 ppb in food products and 100 ppb in feed.
Mechanism of action—aflatoxin is a potent mutagen

8

Aflatoxin and Hepatitis

Aflatoxin is a mutagen that initiates cells and can lead to liver cancer.
Hepatitis B causes chronic liver inflammation which can promote cells through ROS and can also lead to liver cancer.

Aflatoxin (initiation) + hepatitis B (promotion) can lead to further liver cancers.

9

Death Cap Mushroom

Amanita phalloides—Death cap

Abdominal pains, diarrhea, vomiting (1-2 days)
Liver failure; can cause death
Treatment: liver transplant or plasmaphoresis
Toxic agents: amanitins—specific RNA polymerase II inhibitor—GI tract is where first symptoms occur, followed by liver destruction.

α-amanitin is a cyclic nonribosomal peptide of eight amino acids.

10

Mechanism of alpha-amanitin Action

The amanitin binding site is beneath a "bridge helix" extending across the cleft between the two largest pol II subunits, Rpb1 and Rpb2, in a
"funnel"-shaped cavity in the pol II structure.

From the crystal structure solved, α-amanitin interacts with the bridge helix in
the RNA polymerase II (pol II). This interaction interferes with the translocation
of RNA and DNA needed to empty the site for the next round of RNA synthesis.
The addition of α-amanitin can reduce the rate of pol II translocating on DNA
from several thousand to a few nucleotides per minute, but has little
effect on the affinity of pol II for nucleoside triphosphate, and a
phosphodiester bond can still be formed. Bridge helix is designed to be
flexibile for its movement is required for translocation. Binding of α-amanitin
puts a constraint on its mobility, hence slowing down the synthesis of RNA.

11

Mechanism of alpha-amanitin Action

There is a strong hydrogen bond between hydroxyproline 2 of alpha -amanitin and bridge
helix residue Glu-A822.

The derivative proamanullin, which lacks the hydroxyl group of hydroxyproline 2, involved in hydrogen bonding to bridge helix residue Glu-A822, is much less effective than alpha -amanitin

12

Phytoalexins

chemical produced in defense of attack from another plant or organism, or even physical stress or damage.

1. Potatoes—if potatoes are infected with a fungus, the fungus eventually stops growing.

-Active component is solanine (AChE inhibitor)
-Solanine has both fungicidal and pesticidal properties, and it is one of the plant's natural defenses.
-Solanine poisoning is primarily displayed by gastrointestinal and neurological disorders. Symptoms include nausea, diarrhea, vomiting, stomach cramps, burning of the throat, headaches and dizziness. Hallucinations, loss of sensation, and paralysis, fever, jaundice, dilated pupils and hypothermia have been reported in more severe cases.

13

Sweet potatoes—Ipomea batatas

—moldy sweet potato causes liver poisoning due to a toxic agent produced by sweet potato—dark ring inside sweet potato indicates there was fungal growth
Active component: ipomeamarone, ipomeanol