Ricin diphtheria toxin

The primary clinical targets of immunotoxins are tumors, based on the principle that the MAb will target the toxin to the tumor cells and the highly toxic moiety will then kill the cancer cells. Examples of toxins are ricin, diphtheria toxin and abrin, which are all glycoproteins. Their toxicity is based on their ability to block protein synthesis at the ribosomal protein assembly site. They are normally extremely toxic and not suitable for therapeutic purposes because they induce liver and vascular toxicity, even at low dose levels. 

K Sandvig, S Olsnes. (1982). Entry of toxic proteins abrin, modeccin, ricin, and diphtheria toxin into cells. I. Requirement for Ca2+. J Biol Chem 257 7495-7503. 

Oeltmann, T.N., and Forbes, J.T. (1981) Inhibition of mouse spleen cell function by diphtheria toxin fragment A coupled to anti-mouse Thy-1.2 and by ricin A chain coupled to anti-mouse IgM. Arch. Biochem. Biophys. 209, 362. 

C. botulinum toxins belong to the AB group of toxins, which also includes diphtheria toxin, pseudomonas exotoxin A, anthrax toxin, Shiga(like) toxin, cholera toxin, pertussis toxin, and plant toxins, e.g., ricin. Moiety A has an enzymatic activity and usually modified cellular-target entering cytosol. Moiety B consists of one or more components and binds the toxin to surface receptors, and is responsible for translocation of the A component into cells. AB toxins are produced in a non-active form and are activated by a split between two cysteine residues within a region (Falnes and Sandvig, 2000). 

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. 

Some bacterial toxins are used experimentally, such as tetanus and diphtheria toxins. Diphtheria toxin kills cells by interfering with the s5mthesis of proteins in a similar way to ricin. 

Fig. 3.3 shows the principle behind the design of immunotoxins. A number of protein toxins of bacterial and plant origin are useful for the production of immunotoxins. These include the diphtheria toxin and pseudomonas exotoxin from bacteria, and ricin, arbin, pokeweed antiviral proteins, saporin, and gelonin from plants (Pastan et al, 1986 Pastan and FitzGerald, 1991). All of these toxins kill cells by entering the cells, and enzymatically inactivating the translational machinery of the cells. Some, such as diphtheria toxin, arbin, and ricin, are composed of two protein chains, A and B. The B chains bind to the cell-surface... 

There is now a substantial literature on the synthesis and testing of chimeric molecules. These substances are each composed of at least two functional domains, such as a tissue-targeting domain and a pharmacologically active domain. One common strategy in constructing chimeric toxins is to isolate the binding domain of one toxin (e.g., diphtheria toxin) and attach this to the poisoning domain of another (e.g., ricin). This chimeric molecule attaches only to cells that have the diphtheria toxin receptor, and it expresses only the intracellular effects of ricin. 

Diphtheria toxin is produced as a single polypeptide chain (Fig. la) yyhich is easily cleaved ("nicked") by trypsin and trypsin-like proteases into two disulfide-linked fragments, A and B (Pappenheimer, 1977). The structure of the nicked toxin resembles that of the plant toxins ricin, abrin, modeccin, viscumin and others (Olsnes and Sandvig, 1985). 

Sundan A, Olsnes S, Sandvig K, Pihl A (1982) Preparation and properties of chi-maeric toxins prepared from the constituent polypeptides of diphtheria taxin and ricin. Evidence for the entry of ricin A-chain via the diphtheria toxin pathway. J Biol Cbem 257 9733-9739. 

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... 

Many clinically important antibiotics function by inhibiting protein synthesis. All steps of protein synthesis are susceptible to inhibition by one antibiotic or another. Diphtheria toxin inhibits protein synthesis by covalently modifying an elongation factor, thereby preventing elongation. Ricin, a toxin from castor beans, inhibits elongation by removing a crucial adenine from rRNA. 

Ricin, modeccin, diphtheria toxin, or Pseudomonas toxin induces apoptosis in human lymphoma U937 cells through an increase in caspase-3 and caspase-6 activities, but not caspase-1 activity... 

Komatsu, N., Oda, T. and Muramatsu, T. (1998) Involvement of both caspase-like proteases and serine proteases in apoptotic cell death induced by ricin, modeccin, diphtheria toxin, and pseudomonas toxin. J Biochem (Tokyo), 124, 1038-1044. 

MoyaM, Dautry-Varsat A, GoudB etal. (1985). Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not that of ricin toxin. J Cell Biol, 101, 548-559. 

Simpson JC, Smith DC, Roberts LM et al. (1998). Expression of mutant dynamin protects cells against diphtheria toxin but not against ricin. Exp Cell Res, 239, 293-300. 

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