Peptidyl nucleosides

The seven pacidamycins (121—127), which are isolated from the culture filtrates of S. coerukoruhidus are stmcturaHy similar to the mureidomycins. These seven peptidyl nucleoside antibiotics differ in the terminal amino acid residues (238). The biosynthesis of these nucleoside antibiotics is markedly affected by the amino acids added to the culture medium (239). 

Aminohexose Nucleosides. The 4-aminohexose nucleosides (128—140) are Hsted in Table 7 (1—4,240—242). A biosynthetic relationship between the 4-aminohexose peptidyl nucleoside antibiotics and the pentopyranines has been proposed (1). The 4-aminohexose pyrimidine nucleoside antibiotics block peptidyl transferase activity and inhibit transfer of amino acids from aminoacyl-tRNA to polypeptides. Hikizimycin, gougerotin, amicetin, and blasticidin S bind to the peptidyl transferase center at overlapping sites (243). 

A model study for the direct synthesis of peptidyl nucleosides used the benzyl imine of the reagent and the requisite ketene in a [2 + 2] cycloaddition to prepare p-lactams, which were further elaborated through deprotection and oxidation. Again, the stereoselectivity of the [2 + 2] cyclization was very high (eq 15). ... 

Polyoxin D and nikkomycin Z are Streptomyces derived peptidyl nucleoside antibiotics that have been shown to be competitive inhibitors of chitin synthetase in both fungal and insect in vitro systems [39-44]. Both polyoxin D and nikkomycin Z have structural similarities to the substrate UDP-N-acetylglucosamine, which most likely accounts for the competitive nature of their ability to inhibit chitin... 

Fig. 26.1.2. Structure of peptidyl nucleoside antibiotic inhibitors of chitin synthesis.

The final stages in the biosynthesis of the peptidyl-nucleoside antifungal agent blasticidin S, produced by Streptomyces griseochromogenes, have been eluci-... 

Polyoxin and nikkomycin analogs Recent design and synthesis of novel peptidyl nucleosides 13HC375. 

Nikkomycins are a group of peptidyl nucleoside antibiotics produced by Streptomyces tendae Tii901 [318] and Streptomyces ansochromogenes 7100 [319]. Since their structure is similar to that of the chitin synthase substrate... 

Lauer B, Russwurm R, Bormann C (2000) Molecular characterization of two genes from Streptorny-ces tendae Tu901 required for the formation of the 4-formyl-4-imidazolin-2-one-containing nucleoside moiety of the peptidyl nucleoside antibiotic nikko-mycin. Eur J Biochem 267 1698-1706... 

Bruntner C, Lauer B, Schwarz W, Mohrle V, Bor-mann C (1999) Molecular characterization of cotranscribed genes from Streptomyces tendae Tu901 involved in the biosynthesis of the peptidyl moiety of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 262 102-114... 

Blasticidin 5 has been referred to variously as a peptidyl nucleoside, as an amino-acyl nucleoside, and as a 4 aminoacyl-4 deoxypyranosyIcytosine. In this chapter it will be referred to by the first of these. We will focus on the biosynthesis of blasticidin S and its cometabolites, the mechanism of action of blasticidin S, and resistance exhibited by microorganisms, plants, and animals. 

Table I Blasticidin S and Other Peptidyl Nucleoside Antibiotics with a A -3-Hexenuronic Acid Moiety...

Table 2 Gougcrocin 3nd Related Peptidyl Nucleoside Antibiotics vtth a 3 4 Dideoxy 4 AminO Pyranose Moiety...

Functionally, CGA synthase belongs to the family of UDP-glucuronosyltransferases (UDP-OTs). Though these are common in mammalian metabolism and at least two have been reponed from fungi (86,87), CGA synthase is the first such enzyme repotted from a prokaryote. The eukaryotic UDP-CTs are membrane associated in vivo (88) and require added phospholipid (e.g., phosphatidylcholine) when purified (89,90). They catalyze glu-curonidation of a wide variety of lipophilic endogenous metabolites and xenobiotics (89). CGA synthase may also be involved in the biosynthesis of other peptidyl nucleoside antibiotics (17-19,23,24,85,90,91). 

Blasticidin S and Related Peptidyl Nucleoside Antibiotics Steven J. Gould... 

Park and coworkers [35] reported the efficient synthesis of (+)-polyoxamic acid (23), a key amino acid moiety of a family of peptidyl nucleoside antibiotics (polyoxins). The key step in this procedure was a stereoselective conjugate addition of glycine Schiff base 14 to acceptor 24 catalyzed by the chiral PTC 25. This gave the key intermediate 26 in quantitative yield and with very high enantioselectivity. The intermediate 26 was then successfully transferred further to yield (+)-polyoxamic acid (23) in seven steps with a high overall yield of 46% (Scheme 3). 

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