Protein synthesis inhibitors elongation

Components of the archaeal translation apparatus, however, display an intra-domain diversity, not encountered within the other two domains. This situation is exemplified by (i) the lack of a uniform compatibility between ribosomes and elongation factors from different archaeal lineages (see section 5.2) (ii) the impressive diversity of archaeal ribosomes and factors in their response to a host of protein synthesis inhibitors (see section 4) (iii) the heterogeneity in shape, mass and composition of archaeal ribosomal subunits (see sections 2.6.2, 2.6.3). Importantly, within-domain diversity is also exemplified by the different complexities of the RNA polymerase subunit patterns from the sulfur-dependent and the methanogenic-halophilic archaea (see Zillig et ah. Chapter 12 of this volume). 

MECHANISM OE ACTION Quinupiistin and dalfopristin are protein synthesis inhibitors that bind to the SOS libosomal subunit. Quinupiistin binds at the same site as macrolides and also inhibits polypeptide elongation. Dalfopristin binds at an adjacent site, changing the conformation of the SOS ribosome this synergistically enhances the binding of quinupiistin at its target site and also directly interferes with polypeptide-chain formation. The synergistic binding to the ribosome often results in bactericidal activity. 

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. 

Certain inhibitors - kirromycin, pulvomycin, fusidic acid and diphtheria toxin - which block protein synthesis by interacting with either elongation factor constitute potent probes to reveal eucaryal and/or bacterial traits on archaeal factors. 

Vectorial translation [31,32]. Polypeptides are made on membrane-bound polysomes. Many of these proteins are synthesized with a 16-30 amino acid extension at the NH2-terminus. This signal sequence is hydrophobic in nature. Protein synthesis and translocation, into or across the membrane, are obligatorily linked. Therefore, the transmembrane movement is co-translational and it is coupled to the elongation of the polypeptide chain. Consequently, the completed polypeptide chain is never present in the compartment where it is synthesized. The polypeptides that do not yet cross the membrane are shorter than the mature protein. Addition of inhibitors of protein synthesis immediately arrest movement of the polypeptide across the membrane. 

It is known that protein synthesis is necessary for BR-induced effects in root tissue (25), and BR-treatment increases nucleic acid and protein synthesis in bean stem (26). In the pea stem segment, kinetic studies with selected protein and nucleic acid synthesis inhibitors showed no evidence for competitive inhibition in polypeptide chain elongation, post-transcriptional polyA addition to heterogeneous RNA, DNA-dependent RNA synthesis, or of the DNA-dependent RNA polymerase... 

Diphtheria toxin is one of the most potent toxins known a single molecule of diphtheria toxin is sufficient to inactivate enough eukaryotic elongation factor eEF-2 in a cell to cause death. Ricin is derived from castor beans and its mode of action is to inactivate eukaryotic 28S rRNA molecules by removing a single adenine residue by N-glycolytic cleavage. The other inhibitor of eukaryotic protein synthesis shown in Table 26.1 is cycloheximide, which inhibits peptidyl transferase activity of the 60S ribosome subunit. 

Many of the differences between translation in prokaryotes and eukaryotes can be seen in the response to inhibitors of protein synthesis and to toxins. The antibiotic chloramphenicol (a trade name is Ghloromycetin) binds to the A site and inhibits peptidyl transferase activity in prokaryotes, but not in eukaryotes. This property has made chloramphenicol useful in treating bacterial infections. In eukaryotes, diphtheria toxin is a protein that interferes with protein synthesis by decreasing the activity of the eukaryotic elongation factor eEF2. 

Capreomycin is a mixture of four cyclic polypeptides, of which capreomycin la (R = OH) and lb (R = H) make up 90% of the mixture. Capreomycin is produced by Streptomyces capreolus and is quite similar to the antibiotic viomycin. Little, if anything, is known about its mechanism of action, but if the chemical and pharmacological similarity to viomycin carries over to the mechanism of action, then one might expect something similar. Viomycin is a potent inhibitor of protein synthesis, particularly that which depends on mRNA at the 70S ribosome (53). Viomycin blocks chain elongation by binding to either or both the 50S or 30S ribosomal subunits. A... 

Metabolic disruptions may result in inhibition of cell enlargement. Key (9) found that actinomycin D, an inhibitor of DNA directed RNA synthesis (10), and puromycin, an inhibitor of protein synthesis, will prevent cell enlargement in soybean Glycine max L. Merr.) hypocotyls. Key concluded RNA and protein synthesis are essential for the process of cell elongation to proceed at a normal rate. The following year, Cleland reported the inhibition of cell enlargement caused by actinomycin D was not caused by an inhibition of auxin-induced cell wall loosening... 

---