Ribosome-inactivating protein ricin

Delayed-action cytotoxin that inhibits protein synthesis (ribosomal inactivating protein) that is obtained from castor beans (Ricinus communis). Waste from production of castor oil contains about 5% ricin by weight. It is a white powder that is soluble in water and relatively heat stable. Aqueous solutions are resistant to chlorine at 10 ppm. It is persistent in the environment. 

Ricin is a lectin-type globular glycoprotein and consists of A and B chains (Doan, 2004 Li and Pestka, 2008). Ricin is considered a Type 2 ribosome-inactivating protein (RIP) (Millard and LeClaire, 2008). The ricin B chain attaches to the plasma membrane at the galactose receptors, pits are... 

Battelli, M.G., Citores, L., Buonamici, L., Ferreras, J.M., de Benito, F.M., Stirpe, F. and Girbes, T. (1997) Toxicity and cytotoxicity of nigrin b, a two-chain ribosome-inactivating protein from Sambucus nigra comparison with ricin. Arch Toxicol, 71, 360-364. 

Lubelli, C., Chatgilialoglu, A., Bolognesi, A., Strocchi, P., Colombatti, M. and Stirpe, F. (2006) Detection of ricin and other ribosome-inactivating proteins by an immuno-polymerase chain reaction assay. Anal Biochem, 355, 102-109. 

Like ricin, abrin is a type 2 ribosome inactivating protein with A and B chains linked by a disulphide bond. The abrin A chain comprises 251 amino acid residues compared to 267 in the ricin A chain, both having three folding structural domains and a molecular weight of approximately 30 kDa. The abrin B chain has a molecular weight of 35 kDa with 60% of its amino acid residues identical to those of ricin s B chain. Both B chains have two saccharide binding sites which are highly conserved between the two toxins. 

Various plant toxins, mostly ribosome-inactivating proteins (RIPs), have been identified that bind to any mammalian cell surface expressing galactose units and are subsequently internalized by RME (67). Toxins such as nigrin b (68), a-sarcin (69), ricin and saporin (70), viscumin (71), and modeccin (72) are highly toxic upon oral administration (i.e., are rapidly internalized). The possibility exists, therefore, that modified and, most important, less toxic subunits of these compound can be used to facilitate the uptake of macro-molecular compounds or microparticulates. 

Ricin toxin, found in the bean of the castor plant, Ricinis communis, is one of the most toxic and easily produced plant toxins. It is a lectin consisting of two polypeptide chains, the A-chain and the B-chain, linked by a disulfide bond. It is one of a group of dichain ribosome-inactivating proteins, which are specific for the depurination of a single adenosine in ribosomal ribonucleic acid (RNA).1 The active chain (ie, the A-chain) has the ability to modify catalytically the 28S subunit of... 

Mistletoe lectins have been extensively analyzed for their primary structure. Only the complete amino acid sequence of the A chain of mistletoe lectin 1 (VAA-1) has been determined thus far [25] but the data show a great homology with other ribosome inactivating proteins such as abrin a or ricin D with 111 and 103 amino acid residues conserved, respectively. 

The seeds of the ubiquitous castor bean plant (Ricinus communis) contain high concentrations of a highly toxic, relatively stable, heterodimeric, glycoprotein toxin called ricin, which is a type 2 ribosome-inactivating protein (RIP) (Burrows and Tyrl, 2001 Millard and LeClaire, 2008 Salem et al., 2008b). The inhibition of protein synthesis by ricin and related t5q>e 2 RIPs has been associated with endothelial toxicity and, depending on the route of exposure, severe gastrointestinal or respiratory... 

Due to the extraordinary toxicity of intact ribosome-inactivating toxins like ricin, abrin, and modeccin, purification and handling of these proteins must be done with extreme care. Even dust from crude seed powders or lyophilized proteins should be considered dangerous. During... 

Several other inhibitors of protein synthesis are notable because of their toxicity to humans and other mammals. Diphtheria toxin (Mr 58,330) catalyzes the ADP-ribosylation of a diphthamide (a modified histidine) residue of eukaryotic elongation factor eEF2, thereby inactivating it. Ricin (Afr 29,895), an extremely toxic protein of the castor bean, inactivates the 60S subunit of eukaryotic ribosomes by depurinating a specific adenosine in 23S rRNA. 

Shiga toxin produced by Shigella dysenteriae has similar structural features. The toxin binds to a glycolipid (Gb3), undergoes endocytosis, and the enzymatie Ai fragment, which is a specific N-glycosidase, removes adenine from one particular adenosine residue in the 28S RNA of the 60S ribosomal subunit. Removal of the adenine inactivates the 60S ribosome, blocking protein synthesis. Ricin, abrin, and a number of related plant proteins inhibit eukaryotic protein synthesis in a similar manner (Chapter 25). 

A group of plant lectins, such as abrin, ricin, and mod-eccin, are highly toxic to eukaryotic cells. Their mode of action consists of inhibition of protein synthesis by enzymatically inactivating the EF-2 binding region of the 60S ribosomal subunit, whereas the diphtheria toxin inactivates the EF-2 protein itself. Ricin is isolated from castor beans and has a molecular weight of 66,000. Like most plant and bacterial toxic proteins, ricin contains two... 

Likewise, the A chains of other plant [42-44] and bacterial [45-47] hetero-dimeric toxins are responsible for toxicity. These toxins contain a single A chain moiety which, in each case, has catalytic activity and efficiently inactivates its intracellular target [44]. The A chain is only toxic to intact cells when combined with B chain. The function of the B chain is to bind the toxin to cell-surface receptors, in the case of ricin to appropriate surface glycoproteins or glycolipids. This is the essential first step in the transfer of ricin A chain into the cytosol, where ribosome inactivation occurs [48]. Additionally, the B chain is believed to have a second function during the intoxication process in which it facilitates the transfer of the A chain across a membrane into the cytoplasm [49]. Separated A and B chains are essentially non-toxic, the toxic A chain lacking the ability to bind to and enter cells in the absence of the B chain. The toxicity of ricin therefore results from three sequential steps (1) binding of the whole molecule to the cell surface via the B chain (2) penetration of at least the A chain into the cytosol, and (3) inhibition of protein synthesis caused by the interaction of the A chain with the 60 S ribosomal subunit. 

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