Biosynthesis of polypeptide antibiotics

The intensive studies on the genetic code and on the proteins in recent years have led to a fairly good understanding of the mechanism of protein biosynthesis . The biosynthetic mechanism involved in the formation of peptides has not yet been studied in equal detail. Some physiologically active peptides like bradykinin and angiotensin are known to be derived from proteins by a specific enzymatic hydrolysis. Other peptides, like glutathione - , ophthalmic acid , the nucleotide-pentapeptide from Staph, aureus and y-polyglutamic acid have been shown to require for their synthesis only a soluble enzyme system. Their biosynthetic mechanism is therefore entirely different from that of the proteins. Such a different type of mechanism has also been demonstrated lately to be involved in the synthesis of peptide antibiotics. 

Reich and Tatum were able to demonstrate an inhibition of the biosynthesis of protein in cells of B. brevis by chloramphenicol and puromycin without affecting the synthesis of tyrocidine . Several analogues of amino acids were found, which inhibited the biosynthesis of tyrocidine without affecting that of protein and vice versa. In contrast to protein synthesis, the production of tyrocidine did not depend on the continuous synthesis of RNA. Furthermore, environmental factors were able to control the relative amounts of the different tyrocidines synthesized by genetically homogeneous cultures . Addition of phenylalanine to the culture medium resulted in the almost exclusive synthesis of tyrocidine A, whereas the unsupplemented culture produced tyrocidine A, B and C. In the presence of tryptophan, a new form of tyrocidine, called tyrocidine D, containing three tryptophan in place of three phenylalanine residues, was produced. This lack of absolute requirement for specific amino acids in the formation of a peptide bond is in contrast to the strict specificity of sequential incorporation of amino acids 

In contrast to these results, the process of tyrocidine and gramicidin biosynthesis has been compared to protein synthesis, but this evidence was obtained in cell-free systems of B. brevis . Yet a difference in the mechanism of protein and antibiotic synthesis has also been reported for gramicidin polymyxin and mycobacillin and seems now to be 

Bernlohr and Novelli reported that, although the mechanism of antibiotic synthesis differs from protein synthesis, there appears to be a competition between the two processes for the amino acids available in the cell. During active cellular growth with high protein synthesis, practically no bacitracin was produced. In contrast, bacitracin synthesis was high, when the requirements for protein synthesis were low, as at the end of the log phase or when protein synthesis was inhibited. The production of bacitracin, and some other antibiotics, seems to be related in some way to the sporeforming metabolism . In this phase a great part of the cell wall is dissolved, while protein production remains very low. 

The origin of the D-amino acids has been traced in a few cases and it has been found that D-amino acid residues are more efficiently labelled when the corresponding radioactive L-amino acids are added to the growing culture than when the radioactive D-isomers are used. D-Amino acids have been found to be competitive inhibitors of peptide synthesis. These experiments suggest that free D-amino acids are not obligatory intermediates in the formation of peptide antibiotics . The inversion of the configuration seems to occur at the peptide level . 

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