Inhibitors of protein synthesis

Methylmercury and trimethyltin also produce neuronopathies. Methylmercury inhibits protein synthesis, but experimental evidence suggests that additional or alternative mechanisms must exist to account for the neuronal degeneration. The mechanism of action of trimethyltin is unknown. 

Neurofilaments. Neurofilaments are presumed to be the target site for several neurotoxicants of environmental significance. Exposure to certain toxicants induces focal accumulations of neurofilaments within neurons and their processes. Accumulation may be within the cell body, or in proximal, middle, or distal regions of the axon. Within myelinated axons, these accumulations of neurofilaments generally occur at multiple, paranodal sites and produce axonal swellings. This common feature of multifocal accumulations of neurofilaments suggests that these toxicants share a common mechanism of action. 

This hypothesis is best supported in the case of the hexacarbons. Hexacarbons can react both in vitro and in vivo with lysine e-amino moieties of proteins to yield pyrrole adducts, which permit secondary auto-oxidative crosslinking. It has been postulated that pyrrole derivitization and secondary crosslinking of neurofilaments are the initiating events in hexacarbon neuropathy. Although this mechanism has been challenged, many studies support this mechanism for the hexacarbons. However, this hypothesis offers no explanation for the early effects on retrograde transport reported in hexacarbon neuropathy. 

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Ricin (toxin from Castor bean Ricinus communis) [A chain 96638-28-7 B chain 96638-29-8] Mr -60,000, amorphous. Crude ricin, obtained by aqueous extraction and (NH4)2S04 pptn, was chromatographed on a galactosyl-Sepharose column with sequential elution of pure ricin. The second peak was due to ricin agglutinin. [Simmons and Russell Anal Biochem 146 206 1985.) Inhibitor of protein synthesis. EXTREMELY DANGEROUS, USE EXTREME CARE [instructions accompany product]. 

Group 2 includes some 80 sesquiterpene trichothecenes, which are particularly associated with fungi belonging to the group Fusarium. Fusarium species are widely known both as plant pathogens and contaminants of stored foods snch as maize. Trichothecenes are strong inhibitors of protein synthesis in mammalian cells. There have been many incidents of poisoning of farm animals cansed by contamination of their food by these componnds. 

Aove Advanced Example Lactone (25) was needed in the synthesis of pcderamldc, an inhibitor of protein synthesis found in a beetle. Disconnection of the lactone reveals two stereochemical problems a c-ir, double bond is required and two adjacent chiral centres ( in 26) must be set up correctly. 

Inhibitors of protein synthesis 4 The problem of antibiotic resistance... 

Urease assay. When Proteus mirabilis grows in a urea-containing medium it hydrolyses the urea to ammonia and consequently raises the pH of the medium. This production of urease is inhibited by aminoglycoside antibiotics (inhibitors of protein synthesis Chapter 8). In practice, it is difficult to obtain reliable results by this method. 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

Siracusa, G., Whittingham, D. G., Molinaro, M., and Vivarelli, E. (1978). Parthenoge-netic activation of mouse oocytes induced by inhibitors of protein synthesis. J. Embryol. Exp. Morphol. 43 157-166. 

Novae, O., Guenier, A. S., and Pelletier, J. (2004). Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen. Nucleic Acids Res. 32, 902-915. 

Pestka, S. (1977). Inhibitors of Protein Synthesis. Academic Press, New York, NY. 

The second step of carotenogenesis, the period of protein synthesis, has clearly been separated from the sensory transduction by means of the inhibitors of protein synthesis cycloheximide12 78 142) and chloramphenical12 146 147). Regardless of their presence, light-induction was feasible, but carotenogenesis took place only after their removal. 

Stirpe, F., Olsnes, S., and Pihl, A. (1980) Gelonin, a new inhibitor of protein synthesis, nontoxic to intact cells. Isolation, characterization, and preparation of cytotoxic complexes with concanavahin A./. Biol. Chem. 255, 6947-6953. 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

Nucleocidin (LXXX) [353], an adenine nucleoside antibiotic whose structure has recently been elucidated, is also a potent inhibitor of protein synthesis. Studies with this compouna have led to the conclusion that nucleocidin forms a complex with ribosomes which is inactive in peptide bond formation. Binding... 

Jim6nez, A., Santos, A., Alonso, G. and Vazquez, D. 1976. Inhibitors of protein synthesis in eukaryotic cells. Comparative effects of some Amaryllidaceae alkaloids. Biochimica et Biophysica Acta, 425 342-348. 

Many of the inhibitors of protein synthesis are selective for prokaryotic ribosomes, which reduces potential for toxicity to humans. 

The drugs described in this chapter are bactericidal inhibitors of protein synthesis that interfere with ribosomal function. These agents are useful mainly against aerobic gram-negative microorganisms. 

The induction of the CYPs has been demonstrated in many different species including humans, and in various different tissues as well as the liver. Induction usually results from repeated or chronic exposure, although the extent of exposure is variable. The result of induction is an increase in the amount of an enzyme induction requires de novo protein synthesis, and therefore an increase in the apparent metabolic activity of a tissue in vitro or animal in vivo. Consequently, inhibitors of protein synthesis, such as cycloheximide, inhibit induction. It is a reversible cellular response to exposure to a substance. Thus, it can be shown in isolated cells, such as hamster fetal cells in culture, that exposure to benzo[a]anthracene induces aryl hydrocarbon hydroxylase (AHH) activity (CYP1A1). 

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. 

Many experimental results have confirmed the chemical basis of memory. For example, learning is facilitated by administration to animals of small doses of strychnine.1015 Puromycin and other inhibitors of protein synthesis disrupt the transfer of information into long-term memory. They are especially effective during the first hour after the initial learning event.1016 Increased synthesis both of mRNA and of proteins within the cell bodies of neurons is observed. 

Short-term memory is not affected by inhibitors of protein synthesis, but alteration of synaptic proteins and membranes may be induced by covalent modification of existing macromolecules.1016 One way in which this happens has been described for Aplysia. As the snail learns a simple gill-withdrawal reflex, the duration of the action potentials in sensory neurons is increased, and there is a greater release of transmitters. This change comes about because stimulation of the sensory neuron causes simultaneous activation of... 

Inhibitors of protein synthesis have been shown to block both the rapid and slow auxin-mediated growth responses. How do you explain these observations ... 

The structures of some antibiotic inhibitors of protein synthesis. All of the inhibitors shown function by binding to specific sites on the ribosome. 

Emetine and cephaeline are both potent inhibitors of protein synthesis, inhibiting at the translocation stage. They display antitumour and antiviral as well as antiamoebic activity, but are too toxic for therapeutic use. In recent studies, O-methylpsychotrine has displayed fairly low effects on protein synthesis, but a quite potent ability to curb viral replication through inhibition of HIV-reverse transcriptase. This may give it potential in the treatment of AIDS. 

Mechanism and Genetics of Induction in Mammals. Many different mechanisms may be involved in CYP induction. These include increased transcription of DNA, increased mRNA translation to protein, mRNA stabilization, and protein stabilization. Induction can only occur in intact cells and cannot be achieved by the addition of inducers directly to cell fractions such as microsomes. It has been known for some time that in most cases of increase in monooxygenase activity there is a true induction involving synthesis of new enzyme, and not the activation of enzyme already synthesized, since induction is generally prevented by inhibitors of protein synthesis. For example, the protein synthesis inhibitors such as puromycin, ethionine, and cyclo-heximide inhibit aryl hydrocarbon hydroxylase activity. A simplified scheme for gene expression and protein synthesis is shown in Figure 9.7. 

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