Thiostrepton biosynthesis

Smith TM. Genetic and biochemical studies of thiostrepton biosynthesis in Streptomyces km-lentii. Ph.D. dissertation, University of Washington. 1993. 

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Thiostrepton (C72H85N19O18S5, molecular mass of 1663) has an unusual type of biological activity, in that it binds to ribosomal RNA and to one of its associated proteins, thus disabling protein biosynthesis. It was the first macrocyclic antibiotic evaluated as selector for the synthesis of HPLC CSPs, together with vancomycin... 

C51H43N13O12S6, Mr 1222.38, yellow powder, mp. 310-312°C, a broad spectrum antibiotic produced by streptomycetes (e.g., Streptomyces actuosus), used as a fodder additive for livestock to promote growth. N. is related to thiostrepton. Like the latter, it inhibits protein biosynthesis through binding to the 23S ribosomal RNA and the protein L-11, in this way the GTP hydrolysis activity of the SOS subunit is inhibited. The producer protects itself by methylation of 23S rRNA (host site resistance). 

Thiostrepton (bryamycin, thiactin). C72H85N19O18S5, Mr 1664.91, mp. 246-255 C, [a]go -98.5 (CH3COOH), a bicyclic thiopeptide produced by Streptomyces aureus with activity against Gram-positive bacteria and used as a fodder additive in animal breeding. T. inhibits protein biosynthesis, the mechanism of action corresponds to that of the structurally related nosiheptide. The biosynthesis of T. is the subject of intense investigation, it is assumed that the core peptide chain is formed non-ribosomally via a multi-enzyme complex. 

Keller and coworkers succeeded in the preparation of several aromatic carboxylic acid-activating starter enzymes involved in the biosynthesis of actinomycin (4-methyl-3-hydroxyanthranilic acid) (105,113,114), triostin (qninoxaline-2-carboxylic acid) (105,115), and mikamycin (3-hydroxypicolinic acid) (105,116). More recently, related enzymes have been identified in the Actinomycetes that form the thiopeptides nosihep-tide and thiostreptone (117,118), and in the pristinamyctn biosynthetic system (de Crecy-Lagard V, personal communication). Whether direct acylation of the pantetheine-attached starter amino acid occurs, or an additional transferase frinction is required, has not been settled. 

A first question that needs to be resolved is whether thiostrepton, and by analogy nosi-heptide, is synthesized by a ribosomal or a nonribosomal process. Preliminary expert meats conducted to determine the mode of biosynthesis suggest that these compounds... 

Mocek U, Zeng Z, O Hagan D. Zhou P, Fan L-DG. Beale JM, Floss HG. Biosynthesis of the modified peptide antibiotic thiostrepton in Srreptoniyces atureiu and Strepiomyces laurentii. J Am ChemSoc 1993 115 7992-8001. 

Frenzet T, Zhou P, Floss HG. Formation of 2 meihyltryptophan in the biosynthesis of thiostrepton Isoiation of S-adenosylmethionine tryptophan Z-methyltransferase. Arch Biochem Biophys 1990 278 35-40. 

U., Zeng, Z., Yuen, L.-D., Frenzel, T., Unkefer, C.J., Beale, J.M., and Floss, H.G. (1989) Biosynthesis of the antibiotic thiostrepton. Methylation of tryptophan in the formation of the quinaldic acid moiety by transfer of the methionine methyl group with net retention of configuration. J. Am. Chem. Soc.,... 

P., and Floss, H.G. (1990) Formation of 2-methyltryptophan in the biosynthesis of thiostrepton isolation of S-adenosyl-methionine tryptophan 2-methyltransferase. Arch. Biochem. Biophys., 278, 35 40. 

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