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

The biosynthesis of the thiopeptide antibiotic thiostrepton (1) has be en investigated by administration of isotopically labeled precursors t o cultures of Streptomyces azureus and Streptomyces laurentii. The ami no acid origin of all the components of the antibiotic was demonstrate d. Experiments with (S)-[1,2-C-13(2)]- and (S)-[2,3-C-13(2)]serine sho wed intact incorporation of serine into the thiazoline and thiazole ri ngs as well as the dehydroalanine, alanine, and tetrahydropyridine moi eties. (S)-[3-C-13,H-2(2)]Serine and (2S,3S)-[3-C-13,H-2(1)]serine wer e used to elucidate the stereochemistry of the various transformations of serine. The quinaldic acid moiety arises from (S)-tryptophan and t he methyl group of methionine; using methionine carrying a chiral meth yl group, it was shown that this methylation proceeds with retention o f 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 rea ction in which the bond between N1 and C2 of the indole ring is cleave d and a new bond is formed between this nitrogen and the side chain al pha carbon. This quinaldic acid moiety is elaborated separately and th en attached to the peptide backbone. Possible mechanisms of some of th e key reactions and the mode of assembly of the modified peptide struc ture are discussed.