Ricin

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Ricin
UniProt
P02879
Other data
EC number3.2.2.22
Chromosomewhole genome: 0 - 0.01 Mb
Search for
StructuresSwiss-model
DomainsInterPro
Ribosome-inactivating protein (Ricin A chain)
Identifiers
SymbolRIP
SCOP2
1paf / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Ricin-type beta-trefoil lectin domain (Ricin B chain)
Identifiers
SymbolN/A
SCOP2
1abr / SCOPe / SUPFAM
CAZyCBM13
CDDcd00161
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Ricin (

intraperitoneal injection. Oral exposure to ricin is far less toxic. An estimated lethal oral dose in humans is approximately one milligram per kilogram of body weight.[1]

Ricin is a toxalbumin and was first described by Peter Hermann Stillmark, the founder of lectinology. Ricin is chemically similar to robin.

Biochemistry

Ricin is classified as a type 2

disulfide bond to a B chain that is catalytically inactive, but serves to mediate transport of the A-B protein complex from the cell surface, via vesicle carriers, to the lumen of the endoplasmic reticulum (ER). Both type 1 and type 2 RIPs are functionally active against ribosomes in vitro; however, only type 2 RIPs display cytotoxicity due to the lectin-like properties of the B chain. To display its ribosome-inactivating function, the ricin disulfide bond must be reductively cleaved.[2]

Biosynthesis

Ricin is

disulfide bond formation between cysteines 294 and 318. The propolypeptide is further glycosylated within the Golgi apparatus and transported to protein storage bodies. The propolypeptide is cleaved within protein bodies by an endopeptidase to produce the mature ricin protein that is composed of a 267 residue A chain and a 262 residue B chain that are covalently linked by a single disulfide bond.[3]

Structure

In terms of structure, ricin closely resembles abrin-a, an isomer of abrin. The quaternary structure of ricin is a globular, glycosylated heterodimer of approximately 60–65 kDa.[5] Ricin toxin A chain and ricin toxin B chain are of similar molecular weights, approximately 32 kDa and 34 kDa, respectively.

A comparison of the similar structures of abrin-a (red) and ricin (blue)

While other plants contain the protein chains found in ricin, both protein chains must be present to produce toxic effects. For example, plants that contain only protein chain A, such as barley, are not toxic because without the link to protein chain B, protein chain A cannot enter the cell and do damage to ribosomes.[9]

Entry into the cytoplasm

Ricin B chain binds complex carbohydrates on the surface of

N-acetylgalactosamine or beta-1,4-linked galactose residues. In addition, the mannose-type glycans of ricin are able to bind to cells that express mannose receptors.[10] RTB has been shown to bind to the cell surface on the order of 106–108 ricin molecules per cell surface.[11]

The profuse binding of ricin to surface membranes allows internalization with all types of membrane

retrograde transport via early endosomes, the trans-Golgi network, and the Golgi to enter the lumen of the endoplasmic reticulum (ER).[15]

For ricin to function cytotoxically, RTA must be reductively cleaved from RTB to release a

Hsc70 and Hsp90 and their co-chaperones, as well as by one subunit (RPT5) of the proteasome itself, that results in its folding to a catalytic conformation,[19][24] which de-purinates ribosomes
, thus halting protein synthesis.

Ribosome inactivation

RTA has

ribosomes
per minute.

Depurination reaction

Within the active site of RTA, there exist several invariant amino acid residues involved in the

catalytic mechanism, and not substrate binding, with enzyme kinetic studies involving RTA mutants. The model proposed by Mozingo and Robertus,[7]
based on X-ray structures, is as follows:

  1. Sarcin-ricin loop substrate binds RTA active site with target adenine stacking against tyr80 and tyr123.
  2. Arg180 is positioned such that it can protonate N-3 of adenine and break the bond between N-9 of the adenine ring and C-1' of the ribose.
  3. Bond cleavage results in an oxycarbonium ion on the ribose, stabilized by Glu177.
  4. N-3 protonation of adenine by Arg180 allows deprotonation of a nearby water molecule.
  5. Resulting
    hydroxyl attacks ribose carbonium ion
    .
  6. Depurination of adenine results in a neutral ribose on an intact phosphodiester RNA backbone.

Toxicity

Castor beans
Castor oil seeds in the Royal Botanic Gardens, Kew Economic Botany Collection

Ricin is very toxic if inhaled, injected, or ingested. It can also be toxic if dust contacts the eyes or if it is absorbed through damaged skin. It acts as a toxin by inhibiting protein synthesis.[28][29] It prevents cells from assembling various amino acids into proteins according to the messages it receives from messenger RNA in a process conducted by the cell's ribosome (the protein-making machinery) – that is, the most basic level of cell metabolism, essential to all living cells and thus to life itself. Ricin is resistant, but not impervious, to digestion by peptidases. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract, where it may cause mucosal injuries. With appropriate treatment, most patients will make a good recovery.[30][31]

Symptoms

Because the symptoms are caused by failure to make protein, they may take anywhere from hours to days to appear, depending on the route of exposure and the dose. When ingested, gastrointestinal symptoms can manifest within six hours; these symptoms do not always become apparent. Within two to five days of exposure to ricin, its effects on the

adrenal glands, kidneys, and liver appear.[29]

Ingestion of ricin causes pain, inflammation, and hemorrhage in the mucosal membranes of the gastrointestinal system. Gastrointestinal symptoms quickly progress to severe nausea, vomiting, diarrhea, and difficulty swallowing (dysphagia). Haemorrhage causes bloody feces (melena) and vomiting blood (hematemesis). The low blood volume (hypovolemia) caused by gastrointestinal fluid loss can lead to organ failure in the pancreas, kidney, liver, and GI tract and progress to shock. Shock and organ failure are indicated by disorientation, stupor, weakness, drowsiness, excessive thirst (polydipsia), low urine production (oliguria), and bloody urine (hematuria).[29]

Symptoms of ricin inhalation are different from those caused by ingestion. Early symptoms include a cough and fever.[29]

When skin or inhalation exposure occur, ricin can cause an

wheezing; itchy, watery eyes; chest tightness; and skin irritation.[29]

Treatment

An antidote has been developed by the UK military, although as of 2006 it has not yet been tested on humans.[32][33] As of 2005 another antidote developed by the US military has been shown to be safe and effective in lab mice injected with antibody-rich blood mixed with ricin, and has had some human testing.[34] Monoclonal antibodies are under scientific investigation as a possible treatment for ricin poisoning.[35]

activated charcoal or by performing gastric lavage. Survivors often develop long-term organ damage. Ricin causes severe diarrhea and vomiting, and victims can die of circulatory shock or organ failure; inhaled ricin can cause fatal pulmonary edema or respiratory failure. Death typically occurs within 3–5 days of exposure.[29]

Prevention

Vaccination is possible by injecting an inactive form of protein chain A.[9] This vaccination is effective for several months due to the body's production of antibodies to the foreign protein. In 1978 Bulgarian defector Vladimir Kostov survived a ricin attack similar to the one on Georgi Markov, probably due to his body's production of antibodies. When a ricin-laced pellet was removed from the small of his back it was found that some of the original wax coating was still attached. For this reason only small amounts of ricin had leaked out of the pellet, producing some symptoms but allowing his body to develop immunity to further poisoning.[9]

Sources

The seeds of Ricinus communis are commonly crushed to extract

oil cake", and "press cake", can contain up to 5% ricin.[36] While the oil cake from coconut, peanuts, and sometimes cotton seeds can be used as cattle feed or fertilizer, the toxic nature of castor beans precludes their oil cake from being used as feed unless the ricin is first deactivated by autoclaving.[37] Accidental ingestion of Ricinus communis cake intended for fertilizer has been reported to be responsible for fatal ricin poisoning in animals.[28][38]

Deaths from ingesting castor plant seeds are rare, partly because of their indigestible seed coat, and because some of the ricin is deactivated in the stomach.[5] The pulp from eight beans is considered dangerous to an adult.[39] Rauber and Heard have written that close examination of early 20th century case reports indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management".[40]

Most acute poisoning episodes in humans are the result of oral ingestion of castor beans, 5–20 of which could prove fatal to an adult. Swallowing castor beans rarely proves to be fatal unless the bean is thoroughly chewed. The survival rate of castor bean ingestion is 98%.[9] In 2013 a 37-year-old woman in the United States survived after ingesting 30 beans.[41] Victims often manifest nausea, diarrhea, fast heart rate, low blood pressure, and seizures persisting for up to a week.[28] Blood, plasma, or urine ricin or ricinine concentrations may be measured to confirm diagnosis. The laboratory testing usually involves immunoassay or liquid chromatography-mass spectrometry.[42]

Therapeutic applications

Although no approved therapeutics are currently based on ricin, it does have the potential to be used in the

cancerous cells recognized by the antibody. The major problem with ricin is that its native internalization
sequences are distributed throughout the protein. If any of these native internalization sequences are present in a therapeutic agent, the drug will be internalized by, and kill, untargeted non-tumorous cells as well as targeted cancerous cells.

Modifying ricin may sufficiently lessen the likelihood that the ricin component of these

mucosal vaccines
.

Regulation

In the US, ricin appears on the

Department of Health and Human Services,[43] and scientists must register with HHS to use ricin in their research. However, investigators under the control of less than 1000 mg are exempt from regulation.[44]

Ricin is classified as an

extremely hazardous substance in the United States as defined in Section 302 of the US Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[45]

Chemical or biological warfare agent

History

A metal vial containing ricin from the 2003 ricin letters

The United States investigated ricin for its military potential during

Hague Convention of 1899 (adopted in U.S. law at 32 Stat. 1903), specifically Annex §2, Ch.1, Article 23, stating "... it is especially prohibited ... [t]o employ poison or poisoned arms".[47]

During

military symbol W or later WA.[citation needed] Interest in it continued for a short period after World War II, but soon subsided when the US Army Chemical Corps began a program to weaponize sarin.[49]

The

Soviet bloc, most famously in the Markov assassination.[50][51]

Control

In spite of ricin's extreme

castor bean plant from which ricin is derived is a common ornamental
and can be grown at home without any special care.

Under both the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, ricin is listed as a schedule 1 controlled substance. Despite this, more than 1 million metric tons (1,100,000 short tons) of castor beans are processed each year, and approximately 5% of the total is rendered into a waste containing negligible concentrations of undenatured ricin toxin.[52]

Ricin is several orders of magnitude less toxic than

Al Qaeda's experiments with ricin suggest their inability to produce botulinum or anthrax.[54]

Developments

A biopharmaceutical company called Soligenix, Inc. licensed an anti-ricin vaccine called RiVax from Vitetta et al. at UT Southwestern. The vaccine was found safe and immunogenic in mice, rabbits, and humans. Two successful clinical trials were completed.[55] Soligenix was issued a US patent for Rivax. The ricin vaccine candidate was granted orphan drug status in the US and the EEC and, as of 2019, was in clinical trials in the US. Grants from the National Institute of Allergy and Infectious Diseases and the US Food and Drug Administration supported development of the vaccine candidate.[56]

Synthesis

The first isolation of ricin is attributed to the Baltic-German microbiologist Peter Hermann Stillmark (1860–1923) in 1888.[57][58][59]

Terrorist use

Main article: List of incidents involving ricin

Ricin has been involved in a number of actual or planned attacks on individuals. In 1978, the Bulgarian dissident

communist regime. However, it was believed at the time that Bulgaria would not have been able to produce the pellet, and it was also believed that the KGB had supplied it. The KGB denied any involvement, although high-profile KGB defectors Oleg Kalugin and Oleg Gordievsky later confirmed the KGB's involvement. Soviet dissident Aleksandr Solzhenitsyn had (but survived) ricin-like symptoms after an encounter in 1971 with KGB agents.[61]

Ten days before the attack on Georgi Markov another Bulgarian defector, Vladimir Kostov, survived a similar attack. Kostov was standing on an escalator of the Paris metro when he felt a sting in his lower back above the belt of his trousers. He developed a fever, but recovered. After Markov's death the wound on Kostov's back was examined and a ricin-laced pellet identical to the one used against Markov was removed.[9]

Several terrorist individuals and groups have experimented with ricin or planned to use it.

James Mattis, and the other to Chief of Naval Operations, Admiral John Richardson.[66] A letter was received on 23 July 2019 at Pelican Bay State Prison in California which claimed to contain a suspicious substance. Authorities later confirmed it contained ricin; no detrimental exposures were identified.[67]

In 2020, some media in the Czech Republic reported, based on intelligence information, that a person carrying a Russian diplomatic passport and ricin had arrived in Prague with the intention of assassinating three politicians. Russian president

Marshal Konev; and Pavel Novotný, the mayor of Prague's southwestern Řeporyje district. They all received police protection.[68][69] Czech president Miloš Zeman later described the police protection of Zdeněk Hřib as an attempt by an insignificant politician to gain attention. Zeman also confused ricin with non-poisonous laxative castor oil.[70]

In 2018

FBI.[72]

In popular culture

Ricin has been used as a plot device, such as in the television series Breaking Bad.[73]

The popularity of Breaking Bad inspired several real-life criminal cases involving ricin or similar substances. Kuntal Patel from London attempted to poison her mother with

FBI agent. He was sentenced on 18 September 2015 to eight years imprisonment.[76]

In Agatha Christie's novel Partners in Crime, ricin was used as a plot device.

In the final season of Walker, Texas Ranger, ricin was used by Emil Lavocat to murder the titular Texas Ranger's best friend and former partner, C.D. Parker, out of revenge against them and all the Rangers in their company for busting up his organized crime ring and imprisoning his lieutenants. Though it was under the guise of a heart attack near the end of "The Avenging Angel", the truth about C.D.'s death comes out in the finale, "The Final Show/Down", when Walker and Trivette have his body exhumed and autopsied.

In the 2013 movie The Good Mother, a mother injects and feeds her daughters with ricin in a case of

Munchausen by proxy
; she is caught after a daughter dies.

In the 2014 movie

Kim Jong-un
via handshake.

See also

References

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