Biosynthesis of Peptide Antibiotics

Abstract

Elucidation of the biosynthetic mechanisms of gramicidin S (Kleinkauf and Gevers, 1969; Kleinkauf and Koischwitz, 1980; Kurahashi, 1974; Kurahashi et al., 1969; Laland and Zimmer, 1973; Lipmann, 1971; Lipmann et al., 1971; Saito et al., 1970) and tyrocidines (Froyshov et al., 1978; Kurahashi, 1974; Kurahashi et al., 1969; Lipmann, 1971; Lipmann et al., 1971) by cell-free enzyme systems revealed a novel feature of the synthesis of peptides of defined sequence, quite distinct from protein and glutathione synthesis. The former involves nucleic acids and ribosomes, and the latter is carried out by phosphoryl activation of glutamic acid and free γ-glutamylcysteine. In gramicidin S and tyrocidine synthesis, the constituent amino acids are first activated as aminoacyl adenylates by the respective subunit of the multienzyme synthetases followed by the transfer of the aminoacyl groups to thiols of the same subunit proteins to form thioesters. The subsequent peptide chain elongation is mediated by 4′-phosphopantetheine which is attached to a small subunit, a carrier protein, of the multienzyme. The specificity and sequence of the amino acids in the peptide antibiotics are determined by the substrate specificity and the spatial arrangement of the thiols on the subunits of the synthetases. Laland and Zimmer (1973) called such a mechanism of peptide biosynthesis the ‘protein thiotemplate mechanism’ and Lipmann et al. (1971) termed it the ‘protein template mechanism’. In a recent review Katz and Demain (1977) state that the biosynthesis of peptide antibiotics by the genus Bacillus is directed by multienzyme thiotemplates. The author considers that it describes best the novel type of peptide biosynthesis and proposes to term it the ‘multienzyme thiotemplate mechanism’.