Antibiotics macrolides, biosynthetic pathway

Secondary metabolites generated via the propionate route are quite unusual in nature. Relevant exceptions are some antibiotic macrolides from Streptomycetes [42], but wholly propionate-derived macrolides are rare. This biosynthetic pathway has been well proved for erythromycin (13), where the aglycone is produced by assembling seven propionate units [43, 44], and for a few related antibiotics [45]. However, very sophisticated biosynthetic experiments [46] have established that some apparent propionate units in other macrolides (e.g., aplasmomycin [46]) from Streptomycetes could be formed either by C-methylation through S-adenosylmethionine or from glycerol. 

Macrolide antibiotics are glycosides with a macrocyclic lactone aglycon, which is formed in the polyketide biosynthetic pathway [38,39]. The lactone ring is 12-, 14-, 16-, or 18-mem-bered. The polyoxo-macrolides such as the classical antibiotic erythromycin are produced by streptomyces microorganisms and form a clinically important group of polyketide antibiotics. Erythromycin (O Fig. 5) is the major component out of a mixture of macrolide antibiotics which is formed by Saccharopolyspora erythraea. It contains two deoxysugars attached to the aglycon, L-cladinose and D-desosamine. 

Tylosin [46-49] (Fig. 6), produced by Streptomyces fradiae, was one of the first antibiotics for which a comprehensive set of blocked mutants was isolated. They were used to help define the biosynthetic pathway. Whereas erythromycin is a 14-membered macrolide, tylosin has a 16-membered lactone structure. The gene for the final step of biosynthesis was cloned by reverse genetics from the protein sequence of the enzyme [46], and specific segments of surrounding DNA were found to complement other classes of blocked mutants. The formation of tylosin aglycon, protylonolide, is involved in five polyketide synthases. 

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. 

Of course, such a conclusion must not be generalized without care. For instance it has been proposed that the biosynthetic formation of the cyclopen-tanol ring of brefeldin A, a Cjj macrolide antibiotic, would be analogous to the prostaglandin biosynthesis, but such a free radical pathway has recently been ruled out Nevertheless, the experimental evidence is indirect, since this conclusion was arrived at using a biosynthetic path involving cyclization of an allyloxyl radical. Indeed, such a path appears to be a forbidden process (see Section VIII.2.A), and hence another pathway, ionic or radical, must be sought. 

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