Translation

Following transcription is translation. Translation is the synthesis of the protein or peptide, the gene product. Translation occurs on the ribosomes; some ribosomes are located on the membrane of the endoplasmic reticulum and some are free in the cell matrix. Ribosomes consist of RNA and protein. Ribosomal RNA makes up a large fraction of total cellular RNA. Ribosomal RNA is synthesized via RNA polymerase I in the cell nucleus as a large molecule; there, this RNA molecule is split and leaves the nucleus as a large and a small subunit. The large ribosomal unit serves as the 'docking' point for the activated amino acids bound to the transfer RNA (tRNA). The mRNA is bound to the small ribosomal unit. The two ribosomal units reassociate in the cytosol for the translation step. tRNA is used to bring an amino acid to the large ribosome, the site of protein synthesis. Each amino acid has a specific tRNA. Each tRNA molecule is thought to have a cloverleaf arrangement of nucleo-tides. This arrangement allows the formation of the maximum number of hydrogen bonds between base pairs. Hydrogen bonding stabilizes the tRNA. tRNA also contains a triplet of bases that pair to a corresponding triplet found in the mRNA. This triplet is not identical to the mRNA triplet and is called the anticodon. The bases pair in a preordained manner: adenine to thymine, guanine to uracil, guanine to guanine, uracil to cytosine, inosine to adenine, and so forth. The amino acid carried by tRNA is identified by the codon of mRNA through its anticodon; the amino acid is not involved in this identification.

Translation takes place in four stages, as illustrated in Figure 3. Each stage requires specific cofactors and enzymes. The first stage involves the esterification of the amino acids to specific tRNAs. Each of these esterification reactions requires a molecule of ATP. Here again is an explanation of why the provision of energy is crucial to protein synthesis. If a protein contains several hundred

amino acids, this step in translation will require several hundred molecules of ATP. Energy-deficient diets result in a shortfall in ATP and so protein synthesis is compromised.

During the second stage of translation, polypep-tide chain synthesis begins. mRNA binds to the small ribosome and an initiation complex is formed. The complex consists of the mRNA cap and the first activated amino acid-tRNA. The ribo-some finds the correct reading frame on the mRNA by 'scanning' for an AUG codon. This is the so-called start codon. The large ribosomal unit then attaches and forms a functional ribosome. A number of specific protein initiation factors are involved in this step.

In the third stage of translation, the peptide chain is elongated by the sequential addition of amino acids from the amino acid-tRNA complexes. The amino acid is recognized by base pairing of the codon of mRNA to the bases found in the anticodon of tRNA, and a peptide bond is formed between the peptide chain and the newly arrived amino acid. The ribosome then moves along the mRNA; this brings the next codon into the proper position for attachment to the anticodon of the next activated amino acid-tRNA complex. The mRNA and nascent polypeptide appear to 'track' through a groove between the two ribosomal subunits. This protects the protein being synthesized from attack by enzymes in the surrounding environment.

The final stage of translation is the termination and release of the amino acid chain. The mRNA contains a stop codon that signals termination at the carboxy terminus. The carboxy-terminal amino acid, although attached to the peptide chain, is also esterified to its cognate tRNA-ribosome. A protein release factor promotes the hydrolysis of the ester link between the tRNA and the amino acid. Now the polypeptide is released from the ribosome and is free to assume its characteristic three-dimensional structure.

Translation is influenced by nutritional status as well as by specific nutrients. Protein synthesis is dependent on the simultaneous presence of all the amino acids necessary for the protein being synthesized and on the provision of energy. If there is an insufficient supply of either, protein biosynthesis will not proceed at its normal pace. This is an example of the consequences of malnutrition with respect to gene expression. Malnourished individuals will not be able to support the full range of de novo synthesis of body proteins because their diets are energy poor and/or contain proteins of poor quality. This condition is known as protein-energy malnutrition. It is commonly found in children but may also be observed in adults under severe food deprivation.

An example of an effect of a nutrient on translation of a specific mRNA is that of iron in the synthesis of ferritin. Iron storage in cells occurs through chelation to a protein called ferritin. Ferritin synthesis is highly regulated by iron intake. In iron deficiency, the mRNA start site for ferritin translation is obstructed by an iron regulatory protein. This protein binds to the 5' untranslated region and inhibits the movement of the 40s ribo-some from the cap to the translation start site. When the diet contains sufficient iron and iron status is improved, the iron regulatory protein dissociates from the ferritin mRNA and translation proceeds. When iron availability is limited, the same iron regulatory protein binds to ferritin mRNA (to inhibit its translation) and to the trans-ferrin receptor mRNA, as described previously (to prevent its degradation and ensure its translation). These exquisite mechanisms serve to maintain iron homeostasis.

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