Polyene antibiotics biosynthesis

Early studies demonstrated that oils and fatty acids stimulated the production of the polyene macrolide antibiotics fungichromin and filipin, but not amphotericin B or candicidin (89). The stimulation polyene antibiotic biosynthesis by oils might be a simple precursor effect. Catabolism of fatty acids results in a increased pool of acetyh QiA. which is subsequently used for polyene biosynthesis. 

Zhang, J., Van Lanen, S.G., Ju, J. et al. (2008) A phosphopantetheinylatingpolyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 105, 1460. 

Regulation of secondary metabolites by glucose or ocher easily assimilated carbon sources (glucose repression) occurs in the biosynthesis of several antibiotics (penicillin, aciinomycin, streptomycin, siomycin, bacitracin, etc.) (fora review, see Refs. 89 and 90), but not in the biosynthesis of polyene antibiotics, because glucose is required for their biosynthesis. 

It is not clear at present why oils stimulate the biosynthesis of some polyene macnoiides (fungichromin and filipin) and have an inhibitoiy effect on the biosynthesis of others (89). When ethyl (Z) 16 phenyIhexadec 9-enoate, an anal(% of ethyl oleate, was added to cultures of the fungichromin producer Streptomycfs ceStdow ATCC 12625, the cultures showed a drastic reduction of fungichromin biosynthesis but produced four new polyene antibiotics (93). 

Gil JA, Liras P, Martin JE The polyenes Properties, biosynthesis and fermentation. Van-damme EJ, ed. Biotechnology of Industrial Antibiotics. New York Marcel Dekker, 1983 513-529. 

When nystatin was added to the growing mycelium in the intensive growing phase, the effect of the antibiotic on the lipid metabolism can better be seen. Sensitivity is followed by the relative decrease of linoleic and stearic acids and the relative increase of palmitic and linolenic acids. These changes and the Increased anrx)unt of the shorter fatty acids suggest that the Inhibition in the fatty acid biosynthesis is responsible for the sensitivity of the nrK)uids to saponin or polyene antibiotics. 

Martin JF (1984) Biosynthesis, regulation, and genetics of polyene macrolide antibiotics. In Omura S (ed) Macrolide antibiotics Chemistry Biology, and Practice Academic Press, Orlando, 405... 

The first polyether antibiotic to be isolated was nigericin 1 in 1951. By 1983, more than 70 terrestrial polyether antibiotics had been reported and Cane et al. (1) had proposed a unified stereochemical model to account for their biosynthesis, including the polyene-polyepoxide model of polyether formation. It took almost 20 years for the first polyether gene cluster to be reported (2). In contrast, the first marine polyethers were reported in 1981, and a model to explain the biosynthesis of marine polyether ladder compounds was proposed in 2006 (3) no genetic information is available currently for the marine polyethers. 

A different mechanism was adopted in the biosynthesis of cyclic polyethers such as monensin. These PK-derived polycycles are formed in a cascade fashion with other enzymatic transformations. For example, in the biosynthesis of monensin (Equation 8.2), the cascade polyether formation is triggered by epoxidation of a polyene template [40]. Similar mechanisms can probably be used to make other polyether antibiotics containing tetrahydrofurans and tetrahydropyrans [41]. 

B. (2000). Biosynthesis of the polyene antifungal antibiotic nystatin in Streptomyces noursei ATCC 11455 Analysis of the gene cluster and deduction of the biosynthetic pathway. Chem. Biol. 7, 395 03. 

No in vitro studies have been carried out specifically on the biosynthesis of the aminosugar moieties of polyene macrolide antibiotics however, the similarity with the biosynthesis of aminosugars of nonpolyene macrolides and bacterial lipopotysaccharides provides some data on the probable biosynthetic pathway. 

Figure R Proposed pathway of biosynthesis of the aminosugar moieties of polyene macrolide antibiotics.

There are several reports in the literature that suggest that antibiotic synthesis may be repressed by ammonia and other rapidly utilized nitrogen sources (96). However, there are no detailed studies on the possible nitrogen regulation of the biosynthesis of mycosamine or other aminosugars of polyenes. 

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