protein and peptide biosynthesis

the biochemical synthesis of proteins. The synthesis of most peptides in living cells depends on the presence of ribosomes. This includes the small peptide hormones, such as oxytocin and vasopressin, which are synthesized as precursor proteins. Other peptides are not synthesized by means of ribosomes. Thus glutathione is synthesized by soluble enzymes in two steps. Many biologically active peptides, especially cyclic structures, are products of microorganisms. These include such antibiotic peptides as gramicidin S, the tyrocidines, and the polymyxins, which are synthesized by interacting multienzymes in which activated aminoacyl groups are transferred onto −SH groups to form intermediate thioesters. The multienzymes are unusual in size, ranging from 120 to 1700 kDa. They consist of repeating modules, each responsible for the incorporation of one amino-acid residue. The genes are arranged in clusters associated with genes encoding auxiliary proteins for the synthesis of precursors, modifying enzymes, exporting proteins, and regulatory systems. In addition to the amino acids and ATP, S-adenosylmethionine is required as methyl group donor if N-methylated bonds are involved. Due to their complexity (cyclosporin synthase for example, integrates 40 reactions on one polypeptide chain), the multienzyme systems have low turnover numbers. Cell-free systems for the production of various peptides and their analogues have been developed.

For synthesis involving ribosomes the first step is the activation of the amino acids to form amino-acid adenylates. The amino acids then become attached by an ester linkage to transfer RNA (tRNA). The template is messenger RNA (mRNA), which associates with the ribosomes themselves. The translation of the triplet codons in mRNA to provide a polypeptide involves three steps: chain initiation, chain elongation (see elongation factor), and chain termina-tion (see release factor). Chain initiation normally starts with the codon for methionine, AUG, and involves a unique initiator tRNA. Many protein factors play a part in the three processes and five molecules of ATP and GTP participate. The ribosomes participate in a cycle during which they subdivide into their two subunits only to reassemble. Hence the synthesis of a peptide bond is a surprisingly expensive process in terms of energy. The targeting of the newly synthesized proteins to their final destination is termed protein kinesis. The mechanism of ribosomal protein synthesis is very similar in all types of cell but there are subtle differences in the number and properties of the soluble factors, particularly concerning chain initiation: in prokaryotes this is by way of formylmethionine while in eukaryotes, apart from mitochondria, this involves methionine.

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