Translation in bacteria

Gualerzi, C. O., Brandi, L., Caserta, E., Garofalo, C., Lammi, M., La Teana, A., Petrelli, D., Spurio, R., Tomsic, J., and Pon, C. L. (2001). Initiation factors in the early events of mRNA translation in bacteria. Cold Spring Harh. Symp. Quant. Biol. 66, 363-376. 

Pharmacology Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 308 ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. 

FIGURE 27-28 Coupling of transcription and translation in bacteria. The mRNA is translated by ribosomes while it is still being transcribed from DNA by RNA polymerase. This is possible because the mRNA in bacteria does not have to be transported from a nucleus to the cytoplasm before encountering ribosomes. In this schematic diagram the ribosomes are depicted as smaller than the RNA polymerase. In reality the ribosomes (Mr 2.7 X 105) are an order of magnitude larger than the RNA polymerase (Mr 3.9 X 105). 

Regulation at the level of translation assumes a much more prominent role in eukaryotes than in bacteria and is observed in a range of cellular situations. In contrast to the tight coupling of transcription and translation in bacteria, the transcripts generated in a eukaryotic nucleus... 

Figure 4.1 Differences in transcription and translation in bacteria and eukaryotes (Watson, 1992).

Because of the large number of steps associated with the translation of mRNA into protein, there are numerous opportunities available for blocking it with inhibitors. The action of many antibiotics is based on blocking translation in bacteria. 

Chloramphenicol blocks translation in bacteria by inhibiting peptidyltransferase of the large ribosomal subunit. It does not interfere with peptidyltransferase in the large subunit of eukaryotic ribosomes. However, the mitochondrion of animal cells contains ribosomes that are similar to bacterial ribosomes, and chloramphenicol can block protein synthesis in this organelle. This could contribute to the side effects of this drug when used in the treatment of animals. 

The realization of functional human cytochrome P450 activity in bacteria requires delivering a supply of electrons via co-expression of the human NADPH cytochrome P450 reductase (CPR) with each cytochrome P450. In some cases modifications are required in either the coding sequence itself or in the codon usage to enhance translation in bacteria. Additionally, deletions and substitutions in the 5 -end of some of the genes have been made to allow more efficient expression in bacteria. Ultimately, the coupled enzymes must be capable of insertion into the membrane. 

The result is the immediate termination of translation and the release of a truncated protein. Two potent antibiotics that specifically inhibit bacterial translation, are tetracycline, which blocks the A site and prevents the entry of aminoacyl-tRNAs, and chloramphenicol, which inhibits the peptidyl transferase activity of the 23 S rRNA. The mechanisms of action of these antibiotics, including streptomycin, which alters the fidelity of translation in bacteria, are listed in Table 26.1. 

Knowled of individual enzymes and receptor-ligand interactions now provides the opportunity for a more directed approach to drug discovery and development. The rational mode of anti-microbial drug discovery has started to bear fhiit with the identification of small molecule inhibitors of the anthrax lethal factor, and the structure-guided discovery of a new inhibitor of RNA translation in bacteria. ... 

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