U. Mocek et al., BIOSYNTHESIS OF THE MODIFIED PEPTIDE ANTIBIOTIC THIOSTREPTON IN STREPTOMYCES-AZUREUS AND STREPTOMYCES-LAURENTII, Journal of the American Chemical Society, 115(18), 1993, pp. 7992-8001
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.