Bacterial toxins, synthesis

Coronafacic acid, a bacterial toxin, was synthesized using a key step that involves three sequential pericyclic reactions. Identify them, and propose a mechanism for the overall transformation. How would you complete the synthesis ... 

A third type of bacterial toxin, diphtheria toxin, catalyzes the ADP-ribosylation of eukaryotic elongation factor (EFTU), a type of small G protein involved in protein synthesis (Table 19-2). The functional activity of the elongation factor is inhibitedby this reaction. Finally, a botulinum toxin ADP-ribosylates and disrupts the function of the small G protein Rho, which appears to be involved in assembly and rearrangement of the actin cytoskeleton (Table 19-2). These toxins maybe involved in neuropathy (see Ch. 36) and membrane trafficking (see Ch. 9). 

Highly potent bacterial toxins such as ricin and diphtheria can completely inhibit cellular protein synthesis at very low levels [26]. The bacterial toxin exerts cytotoxicity through enzymatic inactivation of factors essential for protein synthesis (e.g., riboso-mal RNA, elongation factor 2 or EF2). Inactivation of these proteins, which are... 

The major immunobiological effect of IL-10 is the regulation of the TH1/TH2 balance. TF cells are involved in cytotoxic T-cell responses whereas TH2 cells regulate B-cell activity and function. IL-10 is a promoter of TH2 response by inhibiting IFN-y production from THi cells. This effect is mediated via the suppression of IL-12 synthesis in accessory cells. IL-10 is involved in assisting against intestinal parasitic infection, local mucosal infection by costimulating the proliferation and differentiation of B cells. Its indirect effects also include the neutralization of bacterial toxins. 

Galanos, C., Luderitz, O., Kusumoto, S., and Shiba, T. (1983). The chemistry of bacterial lipopolysaccharides with emphasis on the structure and chemical synthesis of their lipid A component. In Handbook of Natural Toxins, Vol II, Bacterial Toxins (Tu, Habig and Hardegree, eds.) Marcel Dekker, Inc., New York. 

After infection and immune cell activation, endothelial cells are variously activated to bind peripheral blood leucocytes. Bacterial toxins such as lipopolysaccharide (LPS), inflammatory cytokines such as tumour necrosis factors a and (5 (TNFa and TNFP) and interleukin-1 (5 (IL-ip) increase the synthesis of cell surface E- and P-selectins in endothelial cells. Histamine and thrombin increase PM P-selectins in endothelial cells and platelets. L-selectins are constitutively expressed in monocytes and lymphocytes. The selectins are involved in the initial adhesion of leucocytes with endothelial cells via selectin-selectin receptor interactions, for example, monocyte L-selectin-endothelial L-selectin ligand binding and T-lymphocyte-endothelial selectin-integrin interactions. This initial phase of leucocyte-endothelial adhesion enables an early stage of leucocyte rolling through successive formation and breakage of adhesive interactions. 

The ribosomal elongation Factor 11 is the acceptor protein for the ADP-ribosyltransferase activity of diphtheria toxin and P. aeruginosa exotoxin A, as well as a mammalian cytosolic ADP-ribosyltransferase. ADP-ribosylation results in loss of activity. The uncontrolled action of the bacterial toxins causes the cessation ofprotein synthesis andhence cell death. The more regulated action of the endogenous ADP-ribosyltransferase is part of the normal regulation of protein synthesis. 

The protein synthesis inhibitors tetracycline, chloramphenicol, and streptomycin all block bacterial protein synthesis. Several eukaryotic translational inhibitors have also been found and they include diphtheria toxin, ricin, and cycloheximide. Puromycin causes premature chain termination in both prokaryotes and eukaryotes by functioning as an aminoacyl tRNA analog. 

From a biochemist s point of view, most metabolic diseases are caused by enzymes and other proteins that malfunction and the pharmacological drugs used to treat these diseases correct that malfunction. For example, individuals with atherosclerosis, who have elevated blood cholesterol levels, are treated with a drug that inhibits an enzyme in the pathway for cholesterol synthesis. Even a bacterial infection can be considered a disease of protein function, if one considers the bacterial toxins that are proteins, the enzymes in our cells affected by these toxins, and the proteins involved in the immune response when we try to destroy these bacteria. 

Shiga toxin, a bacterial toxin produced by Shigella dysenteriae belonging to the AB5 toxins family. It is structurally related to verotoxin and cholera toxin. Shiga toxin is composed of two subunits. The monomeric A-subunit has a N-glycosidase activity causing inhibition of protein synthesis and cell death. The B-subunit is a homopentamer which is responsible for receptor binding, internalization and intracellular transport of the holotoxin [E. A. Meritt, W. G. Hoi, Curr. Opin. Struct. Biol. 1995, 5, 165 D. G. Pina et al., Biochim. Biophys. Acta 2007, 1768, 628]. 

It has been known since long ago which virulent bacteria bring about infectious diseases, that are caused by the production of special substances (mainly proteins) of bacteria or toxins. A variety of studies have been conducted on their structures and effects to prevent or treat the infectious diseases [1]. Bacterial toxins include the types that affect nerves, destroy cells, and inhibit protein synthesis. These effects often lead to the appearance of peculiar clinical symptoms at local sites or in the whole body [ 1 ]. These terrifying toxins have the potential to become useful in the sector of metal materials which is different from biology. 

Protein synthesis is a central function in cellular physiology and is the primary target of many naturally occurring antibiotics and toxins. Except as noted, these antibiotics inhibit protein synthesis in bacteria. The differences between bacterial and eukaryotic protein synthesis, though in some cases subtle, are sufficient that most of the compounds discussed below are relatively harmless to eukaryotic cells. Natural selection has favored the evolution of compounds that exploit minor differences in order to affect bacterial systems selectively, such that these biochemical weapons are synthesized by some microorganisms and are extremely toxic to others. Because nearly every step in protein synthesis can be specifically inhibited by one antibiotic or another, antibiotics have become valuable tools in the study of protein biosynthesis. 

Many bacterial cells contain self-replicating, extrachromosomal DNA molecules called plasmids. This form of DNA is closed circular, double-stranded, and much smaller than chromosomal DNA its molecular weight ranges from 2 X 106 to 20 X 106, which corresponds to between 3000 and 30,000 base pairs. Bacterial plasmids normally contain genetic information for the translation of proteins that confer a specialized and sometimes protective characteristic (phenotype) on the organism. Examples of these characteristics are enzyme systems necessary for the production of antibiotics, enzymes that degrade antibiotics, and enzymes for the production of toxins. Plasmids are replicated in the cell by one of two possible modes. Stringent replicated plasmids are present in only a few copies and relaxed replicated plasmids are present in many copies, sometimes up to 200. In addition, some relaxed plasmids continue to be produced even after the antibiotic chloramphenicol is used to inhibit chromosomal DNA synthesis in the host cell. Under these conditions, many copies of the plasmid DNA may be produced (up to 2000 or 3000) and may accumulate to 30 to 40°/o of the total cellular DNA. 

The enzymatic specificity of diphtheria toxin deserves special comment. The toxin ADP-ribosylates EF-2 in all eukaryotic cells in vitro whether or not they are sensitive to the toxin in vivo, but it does not modify any other protein, including the bacterial counterpart of EF-2. This narrow enzymatic specificity has called attention to an unusual posttranslational derivative of histidine, diphthamide, that occurs in EF-2 at the site of ADP-ribosylation (see fig. 1). Although the unique occurrence of diphthamide in EF-2 explains the specificity of the toxin, it raises questions about the functional significance of this modification in translocation. Interestingly, some mutants of eukaryotic cells selected for toxin resistance lack one of several enzymes necessary for the posttranslational synthesis of diphthamide in EF-2 that is necessary for toxin recognition, but these cells seem perfectly competent in protein synthesis. Thus, the raison d etre of diphthamide, as well as the biological origin of the toxin that modifies it, remains a mystery. 

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