Flashcards in Plant and Animal Toxins Deck (33):
what are RIPs?
an important group of plant toxins
ribosomal inhibitory proteins
what are the 2 types of RIPs and give examples
type1- single polypeptide chain. e.g. dianthin- in leaves of carnation
type2- 2 polypeptide chains, A the enzymatically active chain and B. e.g. abrin and ricin
where is ricin found ?
found in the seeds of ricinus communis
- these seeds are crushed to get castor oil
what are the sizes of the chains in ricin ?
a - 30kDa enzymatically active
b- 30kDa binding toxin to target cells
why are type 1 RIPs less potent than type 2 ?
type 1 only have an a chain therefore they dont have a guidance system so they cannot penetrate cells as easily
what is the most toxin plant poison ?
what is the most toxic non-peptide ?
- organic compound that targets sodium/potassium ATPase
what are more poisonous natural toxins or synthetic poisons ?
what is the mechanism of action of ricin ?
1) BINDING TO SURFACE OF TARGET CELLS
- B chain binds to beta-1,4- galactose residues of glycoproteins/glycolipids - these are common parts of cell membranes so ricin can affect most cels
2) ENTERS BY ENDOCYTOSIS
- too large to cross by simple diffusion- it enters and is transferred to the early endosomes
3) TRANSPORT TO THE GOLGI COMPLEX
- on reaching early endosome most of the endocytosed toxin is either recycled back to cell membrane or goes via the late endosomes to the lysosome to be degraded. about 5% of endocytosed ricin is transported via vesicles to trans-golgi network
4) FROM GOLGI TO ER
- possible that ricin binds to a protein with a KDEL sequence and piggy backs its way to the ER- could be calreticulin
5) TRANSLOCATION FROM ER LUMEN TO CYTOSOL
- ricin undergoes reduction cleavage to release A chain. thought that A chain is treated as a mis folded protein and therefore is translocated out of the er using transport system for faulty proteins into cytosol for degradation
6) ACTION ON RIBOSOMES
- a chain released from ER acts on 60s ribosomal subunit to block protein synthesis - target is 28s rRNA- a chain splits the glycosidic bond between adenine and ribose at single but critical site - deadenylation may cause the loss of a binding site for the elongaion factors - preventing protein synthesis
what other function apart from prevent protein synthesis is ricin htought to cause ?
by DNA lyase - thought to chop DNA up within the cell
what are the 2 sugars present in the glycoproteins/lipids which ricin bind to ?
galactose and N-acetylglucosamine
how could ricin be used in cancer chemotherapy ?
target the toxin to specific cells to their target molecule
-produce an immunotoxin in which the B chain of ricin is replaced by antibody specific for either cell surface of tumour antigen or an antigen on the blood vessels of the tumour - this has worked in vitro and animal models
what is the worry about immunotoxins used in humans ?
drug may cause vascular leak syndrome characterised by widespread capillary leakage reducing cirulating volume of bloodm severe hypotension, hypoperfusion of organs and tissue oedema
why are the media and military interested in ricin ?
due to its potential as a chemical weapon
- likely it was used by bulgarain secret service to kill georgi markov in london 1978 - he was jabbed in the thigh by an agent carrying an umbrella and the tip had been modified to inject markovs skin with a small platinum capsule containing ricin- he died 2 days later
what are the 4 uses of ricin ?
cancer chemotherapy- immunotoxins, anti-viral agents, molecular neurosurgery= these have not been realised yet
what happens upon ingestion of ricin?
it targets epithelial cells as these are th first contacted cells
- causes severe diarrhoea, bleeding in the gut, haemorrhaging in the liver
inhalation causes haemorrhaging in the lungs and massive cell death
why have many animals evolved potent toxins?
for defence, hunting and digesting prey
e.g. snakes use them to catch prey and digest prey
what is a snake bite known as ?
how many people are killed worldwide by venomous snakes each year ?
what are the 4 families of poisonous snakes ?
ATRACTASPIDIDAE= venomous snakes found in africa and middle east- have side striking fangs and unique toxins = sarafotoxins
COLUBRIDAE= largest family, distrubuted globally, most a non venomous but those that are (boomslang) have fangs towards back of mouth
ELAPIDAE=widely distributed family, including sea snakes, most poisonous snakes in tropics and subtropics , responsible for most snake bite morbidity and mortality e.g cobras
VIPERIDAE= large diverse family in australia, 2 subfamilies- viperinae = old world vipers such as black adder and crotalidae= vipers with heat sensitive pit used for tracking prey by body heat- rattlesnakes
what is another name for sea snakes?
what are present in snake venoms?
they are a cocktail of proteins- many different proteins with different roles
- enzymes like collagenase, hyaluronidase, phospholipases and metalloproteinases
many of the proteins are neurotoxic
other than neurotoxic proteins in snake venom what other effects can they have ?
myo- and cardiotoxic- sarafotoxins=damage heart muscle
haemolysins- some interfere with blood clotting
toxins that disrupt coagulation of blood
how have snakes neurotoxic toxins evolved?
the beta neurotoxins are able to block neuromuscular transmission at presynaptic
the alpha neurotoxins are able to block neuromuscular transmission post synaptically
what proteins do the beta toxins contain?
- exhibit phospholipase A2 activity -this activity is independent of their ability to block neuromuscular transmission and hydrolyse membrane phospholipids
- block potassium channels
- inhibit the release of acetylcholine from nerve terminal
what snakes contain an AChE inhibitor and what is it called ?
venom of a black mamba contains it
called fasiculins - groups of peptides that can block AChE activity
what family of snakes are the only ones to have alpha neurotoxins?
what do alpha neurotoxins do ?
bind with very high affinity to the nAChR on surface of skeletal muscles - blocking binding of ach and therefore inhibit opening of ion channels
what do some crotalid venoms contain ?
acetylcholinesterase in addition to beta neurotoxins
what do sarafotoxins do ?
mimic action of endothelin and inducec profound vasoconstriction - especially coronary arteries
many snake venoms contain enzymes, what are they and what do they do ?
collagenase, hyaluronidase and metalloproteinases
- breakdown the connective tissue matrix at the site of envenomation - this promotes the absorption of toxins into the body
some venoms contain toxins that cause haemolysis of erythrocytes
why can a mongoose survive a snake bite?
the mongoose can survive snakes bites because the amino acid sequence for nAChR is very different to humans- it has a much lower affinity for the alpha toxins which normally block the receptor