Ribosome-inactivation protein toxins

Kodama, T., Doukas, A.G. and Hamblin, M.R., Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves. Cancer Lett., 189, 69-75 (2003). 

BOX 29-A THE DIPHTHERIA TOXIN AND OTHER RIBOSOME-INACTIVATING PROTEINS... 

Examination of genotoxicity of pharmaceuticals is required to assess the interaction of the drug with DNA. These studies are generally not applicable to immunotoxins. Unlike chemotherapeutics that cause cell death through DNA interaction, immunotoxins mediate cell death by preventing protein synthesis. However, immunotoxins use a linker to connect the toxin to the antibody that may need to be examined if it is an organic linker and has the ability to bind DNA (per ICH S6). The majority of immunotoxins use either a nonreducible thioether linker for intact toxins or a disulfide bond for A chains and ribosome-inactivating proteins and do not interact with DNA. 

Toxin entry retrograde transport through the secretory pathway (Lord and Roberts, 1998) Ribosome-inactivating proteins a plant perspective (Nielsen and Boston, 2001)... 

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. 

Stripe, F. Ribosome-Inactivating Proteins. Protein Toxins and Their Use in Cell Biology. Rappuoli, R. Montecucco, C. Edsl997. Oxfod University Press, Oxford, U.K. p 57-58. 

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... 

Many molds and plants produce toxins, which are protective reagents, termed ribosome-inactivating proteins (RIPs), directed at particular cells and their ribosomes. These toxins are classified as either type I or type II RIPs according to the number of polypeptide chains. 

Ribosome-inactivating proteins (RIPs) are toxins that act intracellularly. They consist of two different subunits a subxmit A that is responsible for the enzymatic activity of the toxin and a subunit B that binds to a specific receptor on the host cell membrane, thus allowing the A subxmit. 

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... 

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). 

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