Polyoxins, biosynthesis

The discovery of the polyoxin group (1) of antifungal nucleoside antibiotics (2) spurred the attention of synthetic chemists as well as biologists for a number of reasons. Their unusual structural features combined with unique biological activity fostered studies on many fronts (3). During their studies on the biosynthesis of the polyoxins, Isono, Crain and McCloskey (4) discovered three novel acidic nucleosides which they called octosyl acid A, B and C,... 

Fermentation procedures for preparing uridine 5 -(2-acetamido-2-deoxy-a-D-glucopyranosyl pyrophosphate) have also been reported. One of them255 involves the cultivation of Helminthosporium sativum in the presence of 2-amino-2-deoxy-D-glucose and the antibiotic polyoxin the latter is an inhibitor of chitin biosynthesis. The other256 utilized the incubation of yeast cells with uridine 5 -phosphate in the presence of an excess of 2-amino-2-deoxy-D-glucose and inorganic phosphate.257... 

Polyoxins are inhibitors of chitin biosynthesis. Chitin is a component of fungal cell walls except in Phycomycete fungi these contain cellulose as their major cell wall constituent, hence polyoxins are inactive against Plasmopara, Pythium and Phytophthora. 

Another group of fungicides interferes with cell wall formation. Two examples of this group include 1) the polyoxines, which prevent chitin formation by competitively inhibiting chitin-synthase, the final enzyme involved in chitin biosynthesis, and 2) melanine biosynthesis inhibitors, especially in Pyricularia oryzae. Examples of... 

The polyoxins (56) formed by S. cacaoi contain a 5-amino-5-deoxy-D-allofuranosyluronic acid residue. The biosynthesis of the polyoxins... 

Polyoxins polyoxin D (Chitin biosynthesis) 1 Reduced dipeptide pre-mease activity ... 

Polyoxins such as polyoxin A, B and D which block the biosynthesis of chitin are competitive inhibitors of uridine diphosphate-N-acetylglucosamine [65]. In resistant isolates of Altemaria kikuchiana, no uptake of dipeptides was observed suggesting that altered dipeptide permease may be responsible for polyoxin resistance [65]. 

A group of aminoacylamino- nucleoside antibiotics (more than 25 components) from cultures of Streptomyces tendae, see also polyoxins. The N. exhibit acar-icidal, insecticidal, and antifungal activities. The activity is based on an inhibition of chitin biosynthesis as a result of the structural analogy to UDP-Al-acetyl-... 

Polyoxins. Peptide nucleosides from cultures of Strep-tomyces species, including S. cacaoi. P. are soluble in water and, although of minor economic significance, are used as fungicides (against Pellicularia sasakii) in rice cultivation in Japan. They act as inhibitors of chitin biosynthesis in fungi. Examples are P. A... 

Biosynthesis of the nucleoside skeleton was initially considered to be originated by uridine (or UMP, uridine-5-monophosphate), first oxidized to the 5 -aldehyde, which undergoes aldol condensation with phosphoenolpyruvate to give the octofu-ranuloseuronic acid nucleoside. Subsequent elimination of two carbons (C-7 and C-8 ) followed by transamination would result in the formation of the nucleoside skeleton of the polyoxins. Such a pathway was supported by the isolation of octosyl acid (Figure 4.6) [26, 27]. 

In the polyoxin gene cluster, a series of proteins which very likely could catalyze the biosynthesis of the nucleoside skeleton were identified PoLB... 

PolA is responsible for the activation of UMP for accepting the PEP (phospho-enolpyruvic acid) moiety for the eventual formation of 3 -EUMP (3 -enolpyruvyl uridine-5-monophosphate). Dephosphorylation by PolJ (a putative tyrosine phosphatase) and cyclization of 3 -EUMPby PolH would immediately follow the reaction of PolA to generate an intermediate which is then converted to the aminohexuronic acid moiety with stepwise functions of PolK, PolD, and Poll, respectively. This latter proposal results in a slight modification of the previously proposed pathway for the biosynthesis of the polyoxin nucleoside skeleton, whose biosynthesis was proposed to be initiated by uridine and PEP as starting substrates [17]. 

The biosynthesis of the nucleoside skeleton of polyoxins has been studied using C- and C-labelled glucose, glycerate, and uridine substrates it was suggested that condensation of uridine as its 5 -aldehyde with phosphoenol pyruvate gives an octofuranuloseuronic acid nucleoside, which loses the two terminal carbon atoms by oxidative elimination followed by transamination to give the required uridyl-5-amino-5-deoxy-D-allofuranosyluronic acid structure. ... 

The biosynthesis of the uronic acid component of polyoxins has been studied by means of n.m.r using D-[l- C]glucose as precursor. ... 

Investigation of the biosynthesis of polyoxin antibiotics from labelled substrates by S. cacaoi has revealed that the 5-amino-5-deoxy-)3-D-allofuranosyl-uronic acid residue of these antibiotics is not derived via oxidation of either D-glucose or o-allose at C-6, but is formed from triose precursors. ... 

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