Biosynthesis of gramicidin

E Conti, T Stachelhaus, MA Marahiel, P Brick. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J 16 4174-4183, 1997. 

Elucidation of the biosynthesis of gramicidin S and of tyrocidin (Fig. 12), an additional component in Dubos tyrothricin, represents an important period in the development of our understanding of biochemistry. It took place at the time when the mechanism of protein-biosynthesis had just been recognized. In the 1950s, P. Zamecnik discovered that the synthesis of proteins in the cell occurs in organelles, later designated as ribosomes. Then M. Hoagland found a type of RNA, the transfer RNAs (t-RNAs) to which, in the presence of ATP, amino acids are attached in activated form. H.G. Zachau, G. Acs and F. Lipmann identified the mode of activation as esters of an adenosin residue in the t-RNA [30]. 

Esters of the substrate amino acids with alcohol residues of appreciable size are accepted by gramicidin S-synthetase and catalyze biosynthesis of gramicidin S (5). The activation mechanism for these compounds still needs to be elucidated. It is interesting that these findings are in contrast to the features observed for the ami noacyl adenylate activation of amino acids by tRNA synthetases in protein biosynthesis which are inhibited by substrate esters. From these results we infer that as in the tRNA synthetases the a-amino group of the substrate amino acids of gramicidin S synthetase is essential for their binding to the aminoacyl adenylate activation sites of the... 

The well-documented conclusions about the biosynthesis of gramicidin S seem-to apply also to the synthesis of a number of other peptide antibiotics. The length of peptides that can be synthesized by this mechanism is unknown. It is supposed that the size of the peptides is limited to about 30-35 amino acids (1). 

Gevers W, Kleinkauf H. Lipmann F. The activation of amino acids for biosynthesis of gramicidin S. Proc Natl Acad Sci USA 1968 60 269-276. 

Bhagavan etaLy I966) stated that the ribosomal pathway for biosynthesis of gramicidin S could no longer be detected. 

Eikhom, T. S., J. Jonsen, S. Laland, and T. Refsvik Studies on the biosynthesis of gramicidin S in whole cells of Bacillus hrevis. Biochim. et Biophys. Acta 80, 648 (1964). 

Okuda, K., G. C. Edwards, and T. Winnick Biosynthesis of gramicidin and tyrocidine in the Dubos strain of Bacillus hrevis. I. Experiments with growing cultures. J. BacterioL 85, 329 (1963). 

Uemura, I., K. Okuda, and T. Winnick Biosynthesis of gramicidins and tyrocidines in cell-free preparations from Bacillus brevis. Biochem. 2, 719 (1963). 

Winnick, R. E., H. Lis, and T. Winnick Biosynthesis of gramicidin S. I. General characteristics of the process in growing cultures of Bacillus brevis. Biochim. et Biophys. Acta 49, 451 (1961). 

Yukioka, M., Y. Tsukamoto, Y. Saito, T. Tsuji, S. Otani, and S. Otani Biosynthesis of gramicidin S by a cell-free system of Bacillus brevis. Biochem. Biophys. Research. Commun. 19, 204 (1965). 

Winnick and coworkers had described a system using cell-free extracts of Bacillus hrevis for the synthesis of gramicidin and tyrocidine. The s5mthesis appeared to be similar to that usually found for protein synthesis. It was inhibited by puromycin and chloramphenicol and was RNAase sensitive. As the galley proof for this review was being examined, a paper entitled The Biosynthesis of Gramicidin S. A Restudy was published by Winnick s laboratory (Bhagavan, Rao, Pollard, Rao, Winnick and Hall, 1966). It was reported that they were unable to repeat the previous experiments which had indicated that a ribosomal system was involved in peptide antibiotic synthesis and, consequently, a reassessment of the earlier reports was made. 

Hall The biosynthesis of gramicidin S. A restudy. Biochemistry 5, 3844 (1966). Birch, A. J. Remarks in discussion following A. W. Johnson s paper entitled Recent developments in actinomycin chemistry . In Ciba Foundation Symposium, Amino acids and peptides with antimetabolic activity (eds. G. E. W. Wol-STENHOLME and C. M. O Connor), p. 136. London Churchill 1958. 

Uemura, I., K. Okuda, and T. Winnick Biosynthesis of gramicidin and tyrocidines in cell-free preparations from Bacillus brevis. Biochemistry 2, 719 (1963). Warner, J., and A. Rich The number of soluble RNA molecules on reticulocyte ribosomes. Proc. Natl. Acad. Sci. U.S. 51, 1134 (1964). 

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