Ricin ( RYE -sin ) is a highly toxic lectin that occurs natural (carbohydrate binding protein) produced in seeds from castor oil plant, Ricinus communis . One dose of purified rosin powder, the size of a few grains of table salt can kill an adult human. Median lethal dose (LD 50 ) of ricin is about 22 micrograms per kilogram of body weight if exposure from injection or inhalation (1.78 milligrams for the average adult). Oral exposure to risin is much less toxic because some toxins are inactive in the stomach. The estimated oral dose to humans is about 1 milligram per kilogram.
Video Ricin
Biochemistry
Ricin is classified as a type 2 ribosome-inactivating protein (RIP). While RIP type 1 consists of a single protein chain that has catalytic activity, type 2 RIP, also known as holotoxins, consists of two different protein chains that make up the heterodimeric complex. RIP type 2 consists of chain A functionally equivalent to RIP type 1, which is covalently linked by single disulfide bonds to chain B which is catalytically inactive but serves to mediate the transport of the AB protein complex from the cell surface, through the vesicle carrier, to lumen of the endoplasmic reticulum (ER). Both type 1 and type 2 RIP are functionally active against the ribosome in vitro ; However, only RIP type 2 exhibits cytotoxicity because of the lectin properties of the B chain. In order to show the ribosome-inactivating function, the ricin disulfide bond must be cut down reductively.
Biosynthesis
Ricin is synthesized in the endosperm of jatropha seeds. The precursor precursor of ricin is 576 long amino acid residues and contains signal peptides (residues 1-35), ricine chains A (36-302), linked peptides (303-314), and chain ricin B (315- 576). The N-terminal signal sequence provides the prepropolypeptide to the endoplasmic reticulum (ER) and then the split signal peptide. In the ER lumen propolipeptides are glycosylation and disulfide isomerase proteins catalyze the formation of disulfide bonds between cysteine ​​294 and 318. The propolipeptides further glycosylate in the Golgi apparatus and are transported to the protein storage body. Propolipeptides are cleaved in the body of proteins by endopeptidases to produce adult ricin proteins composed of 267 residue A chains and 262 chain B residues that are covalently linked by a single disulfide bond.
Structure
The quaternary structure of ricin is a globular glycosylated heterodimer of about 60-65 kDa. Ricin Poison The chain and chain of Rinin B toxins have the same molecular weight, each about 32 kDa and 34 kDa.
- Ricin toxic A chain (RTA) is an N-glycoside hydrolase composed of 267 amino acids. It has three structural domains with about 50% of polypeptides arranged into alpha-helices and beta-sheets. Three domains form a clear gap that is an active site of RTA.
- Ricin's toxic B chain (RTB) is a lectin consisting of 262 amino acids capable of binding to terminal galactose residues on the cell surface. RTBs form bilobal, structures such as barbells that lack alpha-helices or beta-sheets in which individual lobes contain three subdomains. At least one of the three subdomains in each homologous lobe has a sugar fastener bag that provides a functional character on the RTB.
While other plants contain the protein chains found in ricin, both protein chains must be present to produce toxic effects. For example, plants containing only the protein A chain, such as barley, are non-toxic because without link to the protein B chain, the protein A chain can not enter the cell and damage the ribosome.
Login to cytoplasm
The Ricin B chain binds complex carbohydrates to the surface of eukaryotic cells containing either galactose terminal residues of N-acetylgalactosamine or beta-1,4-linked. In addition, the mania-type glycans ricin is able to bind cells expressing mannose receptors. RTB has been shown to bind to the cell surface in the order of 10 6 -10 8 ricin molecules per cell surface.
The heavy binding of the ricin to the surface membrane allows internalization with all types of membrane invagination. Holotoxin can be taken by clathrin-coated pits, as well as with clathrin-independent pathways including caveolae and macropinocytosis. The intracellular vesicle carries the ricin to the endosome sent to the Golgi apparatus. Active intake of endosomes is thought to have little effect on the functional properties of the ricin. Because of the stable risin over a wide pH range, endosomal or lysosomal degradation offers little or no protection against ricin. Ricin molecules are thought to follow retrograde transport through the early endosomes, the Golgi-trans, and Golgi tissue to enter the lumen of the endoplasmic reticulum (ER).
In order for the risot to function cytotoxically, the RTA must be deductively reduced from the RTB to release the steric block from the RTA active site. This process is catalyzed by a PDI protein (protein disulphide isomerase) located in the ER lumen. Free RTA in the ER lumen is then partially revealed and partially buried into the ER membrane, where it is thought to mimic proteins associated with membranes that fail to fold. Roles for chaperone ER GRP94, EDEM and BiP have been proposed prior to the 'dislocation' of RTA from ER lumen to cytosol in a manner that utilizes endoplasmic reticulum-associated protein degradation (ERAD) pathway components. ERAD usually removes ER proteins that are misfolded to the cytosol for their destruction by the cytosolic proteasom. The RTA dislocation requires ER-integral-membrane E3 ubiquitin ligase complex, but RTA avoids ubiquitination which usually occurs with the ERAD substrate due to the low content of lysine residue, which is the usual attachment site for ubiquitin. Thus, RTA avoids the usual fate of detached proteins (destructions mediated by targeting ubiquitinylated proteins into cytosolic proteasom). In the mammalian cell cytosol, RTA subsequently undergoes triage by chewing the Hsc70 and Hsp90 cytosolic molecules and their co-chaperones, as well as by one subunit (RPT5) of the proteasome itself, resulting in a fold to the catalytic conformation, which breaks the ribosome, thus halting protein synthesis.
ribosomal inactivation
RTA has an N-glycosylase rRNA activity that is responsible for cleavage of glycosidic bonds in the large rRNA of the 60S subunit of eukaryotic ribosomes. RTA in particular and irreversibly hydrolyzes the N-glycosidic bond of the adenine residue at position 4324 (A4324) in the 28S rRNA, but leaves the phosphodiester backbone of the RNA intact. Ricin targets A4324 contained in a highly sustainable sequence of 12 nucleotides that are universally found in eukaryotic ribosomes. The sequence, 5'-AGUACGAGAGGA-3 ', is called the sarcin-ricin loop, important in binding the extension factor during protein synthesis. The incidence of rapid depuration and completely disabling the ribosome, resulting in toxicity from inhibited protein synthesis. A single RTA molecule in the cytosol is able to remove about 1500 ribosomes per minute.
Depreciation reaction
In the active sites of RTA, there are several invariant amino acid residues involved in the depurination of ribosomal RNA. Although the exact mechanism of the event is unknown, the identified principal amino acid residues include tyrosine at position 80 and 123, glutamic acid at position 177, and arginine at 180. In particular, Arg180 and Glu177 have been shown to be involved in the catalytic. mechanism, and does not bind to the substrate, with enzyme kinetic studies involving RTA mutants. The model proposed by Mozingo and Robertus, based on the X-ray structure, is as follows:
- Sarcin-ricin substrate loop binds to RTA active site with target adenine stacking against tyr80 and tyr123.
- Arg180 is positioned in such a way that it can symbolize N-3 adenine and break the bond between the N-9 of the adenine ring and C-1 'from the ribose.
- Result of bond cleavage in oxycarbonium ions on ribose, stabilized by Glu177.
- The N-3 protonation of adenine by Arg180 allows the deprotonation of nearby water molecules.
- Produces hydroxyls that attack the carbonium ribose ion.
- The depuration of adenine results in neutral ribose in the intact phosphodiester RNA spine.
Maps Ricin
Poisoning
Ricin is highly toxic by inhalation, injection, or digestion. It can also be toxic if dust is eye contact or if absorbed through the damaged skin. It acts as a toxin by inhibiting protein synthesis. It prevents cells from assembling various amino acids into proteins according to the message they receive from the messenger RNA in the process by the cell ribosome (protein-making machine) - that is, the most basic cell metabolic rate, essential for all living cells and thus life itself. Ricin is resistant, but not resistant, to digestion by peptidase. By swallowing, ricin pathology is largely confined to the gastrointestinal tract, where it can cause mucosal injury. With the right treatment, most patients will make a decent recovery.
Because the symptoms are caused by failure to make proteins, the symptoms can last from hours to days to appear, depending on the route of exposure and dose. When ingested, gastrointestinal symptoms can manifest in 6 hours; these symptoms are not always clear. Within 2 to 5 days of exposure to risin, the effects of ricin on the central nervous system, the adrenal glands, the kidneys, and the liver appear.
Ingestion of ricin causes pain, inflammation, and bleeding in the mucous membranes of the gastrointestinal system. Gastrointestinal symptoms rapidly develop into severe nausea, vomiting, diarrhea, and difficulty swallowing (dysphagia). Bleeding causes bloody stools (melena) and vomiting of blood (hematemesis). Low blood volume (hypovolemia) caused by loss of gastrointestinal fluid can cause organ failure in the pancreas, kidneys, liver, and digestive tract and develop into shock. Surprises and organ failure are characterized by disorientation, fainting, weakness, drowsiness, excessive thirst (polydipsia), low urine production (oliguria), and bloody urine (haematuria).
The inhalation symptoms of ricin differ from those caused by consumption. Early symptoms include cough and fever.
When skin or inhalation exposure occurs, ricin may cause allergies to develop. It is characterized by edema of the eyes and lips; asthma; bronchial irritation; dry, sore throat; congestion; skin redness (erythema); skin blister (vesikasi); wheezing; itchy and watery eyes; Asphyxiate; and skin irritation.
The toxic antidote has been developed by the British military, although it has not been tested in humans. Other antidotes developed by the US military have been shown to be safe and effective in laboratory mice injected with blood-rich antibodies mixed with risins, and have undergone several tests in humans.
Symptomatic and supportive care is available for ricin poisoning, but no common antidote is available for ricin. Existing treatments emphasize minimizing toxic effects. Possible treatments include intravenous fluids or electrolytes, airway management, aid ventilation, or medication to cure seizures and low blood pressure. If the ricin has been digested recently, the stomach can be flushed by swallowing the activated charcoal or by performing a gastric lavage. Survivors often develop long-term organ damage. Ricin causes severe diarrhea and vomiting, and the victim may die from circulatory shock or organ failure; Inhaled rhinin may cause fatal pulmonary edema or respiratory failure. Death usually occurs within 3-5 days after exposure.
Although no antidote is currently available for ricin poisoning, vaccination is possible by injecting inactive protein chains. Vaccination is effective for several months due to the production of antibodies to foreign proteins. In 1978, the Bulgarian defector, Vladimir Kostov, survived a ricin attack similar to that of Georgi Markov, possibly due to the production of his body's antibodies. When a coated pellet is removed from the bottom of his back, it is found that some of the original wax layers are still attached. For this reason only a few ricin are leaked out of the pellets, producing some symptoms but allowing his body to develop immunity against further poisoning.
The seeds of Ricinus communis are usually destroyed to extract castor oil. Because ricin is not soluble in oil, only a small amount is found in castor oil which is extracted. The extracted oil is also heated to over 80 ° C to denote any possible risin. The rest of the seeds are destroyed, so-called various "cakes", "oil cakes", and "cake press", can contain up to 5% risin. While oil cakes from coconut, peanuts, and sometimes cottonseed can be used as animal feed and/or fertilizer, the toxic nature of castor seeds blocks their oil cake from being used as feed unless the ricin is first deactivated by autoclaving. The consumption stings of Ricinus communis cake intended for fertilizer have been reported to be responsible for fatal ricin poisoning in animals.
Deaths due to eating sparse plant seeds are rare, in part because of an indigestible seed coat, and because the body can, though only with difficulty, digest the risin. Porridge from eight nuts is considered harmful to adults. Rauber and Hearing have written that a close examination of an early 20th century case report shows that public perceptions and ricin toxicity professionals "do not accurately reflect modern medical management capabilities".
Overdose
Most episodes of acute poisoning in humans are the result of consuming jatropha seed, 5-20 which can be fatal to adults. However, swallowing the sparse seeds proves to be fatal unless the nuts are chewed thoroughly. The survival rate of jatropha seed consumption is 98%. In 2013 a 37-year-old woman in the United States survived after swallowing 30 seeds. The victim often shows nausea, diarrhea, rapid heartbeat, low blood pressure, and seizures last up to a week. Blood, plasma, or rinin urine or ricinine concentrations can be measured to confirm the diagnosis. Laboratory testing usually involves immunoassay or liquid chromatography mass spectrometry.
Therapeutic app
Although no approved therapy is currently based on risin, it does have the potential to be used in the treatment of tumors, as a "magic bullet" to destroy targeted cells. Because ricin is a protein, it can be linked to monoclonal antibodies to target cancer cells identified by antibodies. The main problem with risin is that the internalization sequence is originally distributed throughout the protein. If one of these original internalization sequences is present in the therapeutic agent, the drug will be internalized by, and kill, non-targeted non-tumor cells as well as targeted cancer cells.
Modifying rosin may be enough to reduce the likelihood that the ricin component of these immunotoxins will cause the wrong cell to internalize it, while still maintaining cell carcass activity when it is internalized by the targeted cell. However, bacterial toxins, such as diphtheria toxin, used in denileukin diftitox, FDA-approved treatments for leukemia and lymphoma, have proven to be more practical. A promising approach to risin is to use a non-toxic B subunit (lectin) as a vehicle to deliver antigens into cells, greatly increasing their immunogenicity. The use of ricin as an adjuvant has potential implications for developing mucosal vaccine.
Rule
In the US, ricin appears on the list of selected agents of the Department of Health and Human Services, and scientists must register with HHS to use risin in their research. However, researchers who had less than 1000 mg were released from the regulation.
It is classified as a very dangerous substance in the United States as defined in Section 302 of the US Emergency Planner and Community Rights to Know Act (42 USC 11002), and is subject to strict reporting requirements by facilities that produce, store, or use in quantities which is significant.
Chemical or biological war agency
The United States investigated the risks to its military potential during World War I. At the time, it was being considered for use as a toxic dust or as a coating for bullets and shrapnel. The concept of dust clouds can not be adequately developed, and the concept of bullet/coated shrapnel would violate the Hague Convention of 1899 (adopted in U.S. law 32 Statutory 1903), especially Annex §§2, Ch.1, Article 23, which states "... it is strictly prohibited... [t] o using poison or poisonous weapons". World War I ended before ricin weapon United States.
During World War II, the United States and Canada conducted rape research in cluster bombs. Although there are plans for mass production and some field trials with different bomblet concepts, the final conclusion is that it is no more economical than using phosgene. This conclusion is based on the ratio of the last weapon, rather than the ricin toxicity (LCt 50 ~ 40Ã, mgÃ,  · min/m 3 ). Ricin is given a military symbol W or later WA . His interest continued for a short period after World War II, but soon subsided when the US Army Chemical Corps began a program to embroider sarin.
The Soviet Union also has weapons ricin. There is speculation that the KGB uses it outside the Soviet bloc; However, this has never been proven.
Given the extreme toxicity and utility as chemicals/biological warfare, it should be noted that the production of toxins is somewhat difficult to restrict. Peanut plant from which ricin originated is a common ornamental and can be planted at home without special care.
Based on the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, rosin is listed as controlled substance of schedule 1. Nevertheless, more than 1 million metric tons of jatropha seeds are processed annually, and about 5% of the total is given into waste containing the concentration of undenatured rinin toxin ignored.
Ricin is some order of magnitude less toxic than botulinum or tetanus toxin, but the latter is harder to come by. Compared with botulinum or anthrax as a biological weapon or chemical weapon, the amount of ricin required to achieve LD 50 over a large geographical area is significantly more than agents such as anthrax (tons of ricin vs. only kilograms of anthrax). Ricin is easy to produce, but is not practical or likely to cause many victims like other agents. Ricin is easily denatured by temperatures greater than 80 ° C (176 ° F) which means many methods of spreading the ricin will produce enough heat to change its properties. Once deployed, the area contaminated with ricin remains dangerous until the bond between chain A or B has been damaged, a process that takes two or three days. In contrast, anthrax spores can remain lethal for decades. Jan van Aken, a German biologist, explained in a report to The Sunshine Project that Al Qaeda's experiments with ricin showed their inability to produce botulinum or anthrax.
Developments
A biopharmaceutical company called Soligenix, Inc. has licensed an anti-ricin vaccine called RiVax (TM) from Vitetta et al. in UT Southwestern. The vaccine is safe and immunogenic in mice, rabbits, and humans. It has completed two successful clinical trials.
Incident
Ricin has been involved in a number of incidents. In 1978, Bulgarian dissident Georgi Markov was killed by a Bulgarian secret police who secretly shot him on the London road with a modified umbrella using compressed gas to fire a small pellet contaminated with risin to his feet. He died in the hospital a few days later and his body passed to a special poison branch of the British Ministry of Defense (MOD) who discovered pellets during the autopsy. The main suspects are Bulgarian secret police: Georgi Markov had defected from Bulgaria a few years earlier and then wrote the book and made a highly critical radio broadcast against the communist regime of Bulgaria. However, it is believed that at the time Bulgaria would not be able to produce pellets, and it is also believed that the KGB had supplied it. KGB rejects any involvement, although top-class KGB defectors Oleg Kalugin and Oleg Gordievsky have confirmed KGB engagement. Earlier, Soviet dissident Aleksandr Solzhenitsyn also suffered (but survived) ricin-like symptoms after a meeting in 1971 with a KGB agent.
Ten days before the attack on Georgi Markov, another Bulgarian defector, Vladimir Kostov, survived a similar attack. Kostov stood on the Paris metro escalator as he felt the sting on his lower back on his pants belt. He had a fever, but healed. After Markov's death, the wound on Kostov's back was examined and the pellets coated in ricin were identical to those used against Markov were removed.
Some terrorists and terrorist groups have experimented with risin and caused some poison incidents sent to US politicians. For example, on May 29, 2013 two cans sent to New York Mayor Michael Bloomberg contained traces. Others were sent to the Mayor's Office against Illegal Guns in Washington DC. A letter of risin is also alleged to have been sent to US President Barack Obama at the same time. An actress, Shannon Richardson, was later charged with committing the crime, and she pleaded guilty in December. On July 16, 2014, Richardson was sentenced to 18 years in prison plus a fine of $ 367,000 for restitution.
In popular culture
Ricin is often used as a plot device, as in the Breaking Bad television series (Season 2, Season 4 and Season 5).
The popularity of Breaking Bad inspired several criminal cases involving ricin or similar substance. Kuntal Patel from London attempted to poison his "controlling and selfish" mother with abrin after the latter disrupted his marriage plans. Daniel Milzman, a 19-year-old former Georgetown University student, is charged with risin in dorm rooms and the intent of "using ricin on other undergraduate students who have a relationship with him". Mohammed Ali from Liverpool, England was found guilty after trying to buy 500 mg of ricin via the dark web of an undercover FBI agent. He was sentenced, on September 18, 2015, to 8 years in prison.
See also
- Abrin (similar to risin but even more toxic)
- Incidents involving risin
- European mistletoe
References
External links
- Research shows a lack of jatropha oil toxicity from the US Public Health Service
- Jatropha seed information at Purdue University
- Toxic Plant for Livestock - Ricin Information at Cornell University
- Ririn cancer therapy is tested on the BBC
- Ricin - Emergency Preparation at CDC
- Emergency Response Card - Ricin on CDC
Source of the article : Wikipedia
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