In the castor bean plant there is a protein, ricin, which is one of the most potent natural toxins in existence, and can be considered a biological weapon. The main product of castor oil is oil, which generally has 90% of ricinoleic acid, which gives it some interesting properties such as high solubility in ethanol and high lubricity; which is an important source for biodiesel production and for the production of plastics, synthetic fibers, enamels, resins and lubricants. After extraction of the oil, ricin is concentrated in making it unfeasible for animal feed.
Ricin (rye-sin) is a chemical poison found in castor beans. Castor beans can be cultivated and processed all over the globe to produce castor oil; however, Ricin is the proportion of the got from the seeds after the oil has been extracted. The pulp that remains of the seed after pressing the Castor contains 5% of the weight of the ricin, and the description of the process to concentrate it is publicly known, since it can be found in the patent itself (Aggarwal, Aggarwal, & Chugh, 2017). Intentional exposure to ricin is relatively impossible in reality and it is never frequent, and thus it can only be deliberately induced as a poison. Individuals can get poisoned through breathing in ricin in either mist or powder form. Besides, individuals may also be poisoned when they swallow or eat ricin-contaminated food or water or any other object.
Moreover, Ricin can possibly penetrate the body via the skin pores when mixed with other specific chemicals or when the skin is destroyed since Pellets of ricin easily get dissolved in a fluid. Finally, it can also be injected into a person's body. It should be noted that the severity of the poison depends on the path of exposure, and the amount of ricin. Ricin is a lectin which is a carbohydrate-binding protein retrieved from the castor oil plant seeds, Ricinus communis is extremely potent toxin and can kill a human being; and the lethal dose (LD50) of ricin is around 22 micrograms per kilogram of body weight when exposed via injection or inhalation; however, Oral exposure is relatively less poisonous since some of the toxicity is being inactivated by some of the stomach chemicals.
However, Ricin has been discovered to poses some potential medical application and is essential in treating some killer diseases like cancer. But on the other hand, ricin has always been used as a bioweapon by terrorist and during wars due to its excessive poisonous chemical content and ease of dispersion to the people. And due to the fact that ricin as a substance is relatively stable and cannot readily break down in room temperature or the ever-changing outdoor temperatures; therefore, making it a significant target as a bioweapon.
Molecular mechanism and biosynthesis
Ricin is categorized as a RIP (type 2 ribosome-inactivating proteins) which constitutes two varied protein chains thus forming a heterodimer complex. The type II PIPs comprises of an A chain which is functionally the same as a type I RIP and linked by one disulfide bond to a B chain that tends to be inactive catalytically;however, it acts as means of transferring of the A-B protein complex from the surface of the cells to ER(lumen of the endoplasmic reticulum). Nonetheless, type 1 and 2 RIPs are functionally active against ribosomes in vitro; but, only type 2 RIPs shows cytotoxicity as a result of the lectin-like properties of the B chain; the ricin disulfide bond has been cleaved reductively. The ricin precursor protein is 576 amino acid residues in length and composes a signal peptide (residues 1-35), the ricin A chain (36-302), a linker peptide (303-314), and the ricin B chain (315-576). The propolypeptide is mainly 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.
As stated before, Ricin is a high toxicity glycoprotein consisting of two chains linked by a single disulfide bond. The A chain of ricin has about 32,000 daltons and the B chain, about 34,000 daltons, totaling, in the native protein, about 66KDa; Some authors refer to ricin also as two subunits, but both with 32 KDa (Pinkerton et al, 1999; JACKSON et al, 2006). The B chain is a lectin, which binds to carbohydrates from the membrane surface of the cell, triggering a process of endocytosis that culminates in the entry of the A chain into the cytosol (inside the cell).
Chemical structure of Ricin
Ricin is part of the group of ribosome-inactivating proteins (RIPs) of type 2, which are characterized by two polypeptide chains: one capable of inhibiting protein synthesis and another with lectin properties, that is, capable of binding to carbohydrates. Ricin is the main representative of type 2 RIPs [18,19] and is constituted by an A chain (RTA), of 267 amino acids and 30-32 kDa, linked by a disulfide bridge to a B chain (RTB), of 262 amino acids and 32-34 kDa. The disulfide bridge between both chains is established by the cysteine residues at position 259 of the RTA and 4 of the RTB. RTA can inhibit protein synthesis by having N-glycosidase enzymatic activity (N-glycosylase rRNA, N-glycosidase rRNA, EC 22.214.171.124), hydrolyzing the N-glycosidic bond between an adenine (A4324 in rat liver) and a ribose of ribosomal ribonucleic acid (rRNA) from eukaryotic cells (Al-Agamy, 2011). RTB is a lectin that presents a preference for galactose binding. In its structure there are four disulfide bridges and two domains, each with four subdomains (l, a, v and gh). Subdomains 1a and 2gh are those that have the capacity to bind to galactose, although the possible existence of a third point of union in the subdomain 1v has been suggested. Ricin is a glycoprotein, with two glycosylation zones in the PBR (Asn95 and Asn135) and one or two in the RTA (Asn10 and, in some cases, Asn236).
Entry of the Ricin into the cytoplasm
Ricin B chain combines complex carbohydrates on the eukaryotic cells' surfaces constituting either N-acetylgalactosamine or beta-1, 4-linked galactose residues. Besides, the mannose-type glycan's of ricin have the ability to bind to cells which indicate mannose receptors. For instance, RTB can bind to the surfaces of the cell on the order of 106-108 ricin molecules per cell surface. The binding of ricin to surface membranes enables the internalization with all types of membrane segment. The holotoxin can be engulfed by clathrin-coated pits and clathrin-independent routes such as caveolae and macropinocytosis. Intracellular vesicles transport ricin to endosomes which are then is given to the Golgi apparatus. It is, however, presumed that the active acidification of endosomes is having a relative impact on the functional properties of ricin.
The degradation of in endosomes or lysosomes provides lesser protection against ricin since ricin is relatively active over a wide pH scope. For ricin to operate cytotoxically RTA has to be reductively cleaved from RTB to relieve a steric block of the functional site of RTA; the procedure is actively facilitated by PDI (protein disulfide isomerase) which is found within the lumen of the ER. However, during the process, the Free RTA within the ER lumen gradually unfolds and engulfs into the ER membrane, and seems to mimic a misfolded membrane-associated protein (Bozza, Tolleson, Henderson, Griffey, & Cheng, 2010). The responsibilities for the ER chaperones GRP94 and BiP is the programmed before the display of RTA from the ER lumen to the cytosol in a way that makes use of the components of the endoplasmic reticulum-associated protein degradation (ERAD) route. ERAD regularly get rid of misfolded ER proteins to the cytosol for their depletion by cytosolic proteasomes. However, the displacement of RTA needs ER membrane-integral E3 ubiquitin ligase complexes, but RTA prevents the ubiquitination which usually happens with ERAD substrates due to its minimum composition of lysine residues that act as the attachment sites for ubiquitin. Therefore, RTA prevents the regular fate of dislocated proteins.
Ricin acts by blocking protein synthesis, resulting in cell death, which leads to multiorgan failure and, finally, death between 36-72 hours after exposure, depending on the route of exposure, which can be ingestion, inhalation and injection1. In the seed, ricin is associated with a lectin, Ricinus communis agglutinin (RCA-I or RCA120), which has haemagglutinating activity with a much lower toxicity than ricin (He, McMahon, Henderson, Griffey, & Cheng, 2010). The similarity between the polypeptide chains of both toxins is 84-93%. This causes that, in many diagnostic techniques, especially immunological, there is a cross reaction between both toxins, obtaining false positives with agglutinin.
Ricin uses a very effective strategy to kill, similar to that of other bacterial and plant toxins such as cholera toxin, (mdm 9-2005). Ricin is composed of two protein chains, as shown in the figure on the right (PDB file 2aai). Chain A (red) is cytotoxic, chain B (blue) helps the toxin enter the target cell. When a person is poisoned, millions of ricin molecules bind to carbohydrates on the surface of the cells and try to get the toxic portion in. Most toxins fail to reach the cytoplasm, but only one is needed to kill the cell. A disulfide bridge (shown in yellow) is broken between the two chains and chain A enters the cytoplasm where it deactivates 1500 ribosomes per minute and thus kills the cell (Kanchan, Atreya, & Shekhawat, 2016). Ricin attacks the Achilles heel of ribosomes, a trait called sarcin / ricin segment which is essential for the interaction of ribosomes with elongation factors (mdm 09-2006). Ricin eliminates a single adenine base at the end of the segment, and this is sufficient to deactivate the ribosome forever. This is why ricin is so incredibly toxic: it can jump from one ribosome to another, destroying them all one at a time until the protein synthesis (which is promoted by ribosomes) is completely blocked in the cell. On the side, the major subunit of the yeast ribosome (PDB file 3u5d and 3u5e) is shown, with the sarcine / ricin segment highlighted in yellow and the adenine target in red.
One of the problems associated with castor bean cultivation is the presence of toxic proteins found in the endosperm of its seeds, the main one being ricin. Ricin is poisonous to humans, animals and insects; was named by Stillmark in 1888 when he tested the castor bean extract on red blood cells and noted that they clumped. Nowadays, agglutination is known to be due to another toxin present in the castor bean endosperm, agglutinin, also called RCA (Ricinus communis agglutinin), or RCA 120, as a reference to its molecular mass. This protein is a potent lectin (proteins with sugar binding sites) and, according to Jackson et al. (2006), although distinct from ricin - because it does not have direct cytotoxic activity - it has red blood cell affinity, causing agglutination and hemolysis (Maman & Yehezkelli, 2009). Although ricin (also known as RCA 60, because it has 60 kDa) is a potent cytotoxin is a weak hemagglutinin, contrasting with RCA which is a weak cytotoxin and a powerful hemagglutinin. It is also called Ricinus communis agglutinin II and could be used as a bioterrorism weapon of great lethal power. The ricin molecule consists of two subunits: The A chain, cytotoxic and the B chain, receptor-binding (lectin), joined by a single covalent disulfide bond (-SS-). The toxic effect is due to the ability to inactivate the specific eukaryotic ribosomes and irreversibly, promoting the death of cells by the inhibition of protein synthesis. The two chains together constitute one of the most potent cytotoxins in nature, considering that no toxic effects are known for the isolated chains.
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