Biosynthesis of polypeptide antibiotics.

Peptide antibiotics possess a variety of chemical structures, e.g. cyclic diand oligopeptides. depsipeptides, linear peptides with repeating sequences of Land D-amino acids, substituted peptides containing non-peptide components. These antibiotics frequently contain amino acids which are not constituents of proteins. In general, biosynthesis of peptide antibiotics follows active growth and macromolecular synthesis by microorganisms. Studies to date indicate that the mechanism of formation of peptide antibiotics differs markedly from that of protein synthesis. In vivo experiments reveal that antibiotic synthesis is insensitive to inhibitors of protein and nucleic acid synthesis. Certain amino acid analogues can block either antibiotic or protein synthesis with minimal inhibition of the other process. Protein and peptide antibiotic synthesis probably compete for the intramolecular amino acid pool; when one process is inhibited there may be marked stimulation of the alternate system. In vitro experiments reveal that antibiotic synthesis is RNAse insensitive and there is no requirement for ribosomes, tRNA, or mRNA. Enzymatic synthesis generally requires ATP, Mg2 , a reducing agent, and the requisite amino acids. The process (gramicidin 5, tyrocidine) is catalysed by multi-enzyme complexes. The activation of amino acids is mediated by aminoacyl synthetases (in the protein complex) distinct from the aminoacyl-tRNA synthetases that activate amino acids for protein synthesis. The activated amino acids are transferred to thiol groups in the complex, and peptide synthesis occurs subsequently. The sequence of amino acids in the antibiotic is determined by the unique arrangement of specific enzymes in the multi-enzyme complex. Studies with cell-free systems as well as with intact organisms have revealed that chemically-related amino acids may substitute for normal constituents in antibiotic peptides. These data support the view that antibiotic peptide synthesis is catalysed by enzymes with relatively broad or low specificities. D-Amino acid biogenesis appears to involve an ATP-dependent racemization catalysed by a component of the multi-enzyme complex. Since the discovery of penicillin a large number of peptide antibiotics have been isolated and described in the literature16. These compounds, elaborated by a variety of microorganisms, contain one or more amino acids or moieties derived from amino acids. Studies have been carried out on the chemistry, biological activity, mode of action, and biosynthesis of these compounds. The evidence to date concerning the mechanism of formation of