BIOSYNTHESIS OF THE MODIFIED PEPTIDE ANTIBIOTIC THIOSTREPTON IN STREPTOMYCES-AZUREUS AND STREPTOMYCES-LAURENTII

The biosynthesis of the thiopeptide antibiotic thiostrepton (1) has been investigated by administration of isotopically labeled precursors to cultures of Streptomyces azureus and Streptomyces laurentii. The amino acid origin of all the components of the antibiotic was demonstrated. Experiments with (S)-[1,2-C-13(2)]- and (S)-[2,3-C-13(2)]serine showed intact incorporation of serine into the thiazoline and thiazole rings as well as the dehydroalanine, alanine, and tetrahydropyridine moieties. (S)-[3-C-13,H-2(2)]Serine and (2S,3S)-[3-C-13,H-2(1)]serine were used to elucidate the stereochemistry of the various transformations of serine. The quinaldic acid moiety arises from (S)-tryptophan and the methyl group of methionine; using methionine carrying a chiral methyl group, it was shown that this methylation proceeds with retention of configuration of the methyl group. Efficient incorporation of (R,S)-2-methyl-[3'-C-13]tryptophan proved that the methylation is the first step in the sequence, followed by an intramolecular ring expansion reaction in which the bond between N1 and C2 of the indole ring is cleaved and a new bond is formed between this nitrogen and the side chain alpha carbon. This quinaldic acid moiety is elaborated separately and then attached to the peptide backbone. Possible mechanisms of some of the key reactions and the mode of assembly of the modified peptide structure are discussed.