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Polyketide Antibiotic Biosynthesis: Assembly-Line Enzymology, Page 1 of 2
< Previous page Next page > /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap12-2.gifAbstract:
The chemistry practiced by polyketide synthases (PKSs) is closely parallel to that of fatty acid synthases (FASs), which have been extensively studied for decades to decipher mechanisms and organization and have provided precedents for understanding PKS logic. The four rings of the tetracycline family of antibiotics, such as oxytetracycline and chlortetracycline and also of tetracenomycin and the antitumor antibiotic doxorubicin are produced by type II polyketide synthases along with some partner aromatases and cyclases also expressed in the clusters. In biosynthesis of daunorubicin or doxorubicin, the starter unit is propionyl-CoA and all extender units are malonyl-CoA. In biosynthesis of daunorubicin or doxorubicin, the starter unit is propionyl-CoA and all extender units are malonyl-CoA. After nine condensation cycles a decaketidyl-S-ACP is built up, in which all 10 of the ketone groups are thought to persist without reductive modification in the acyl chain. The first cyclase, TcmN, closes three rings to make TcmF2, and TcmI closes the last ring to give the fused four-ring system analogous to the tetracycline skeleton. The macrolides of the erythromycin class contain 14-membered macrolactone rings while the tylosins have 16-membered rings. Many of the macrolide antibiotics are glycosylated, to provide hydrogen bond interactions with the ribosome 23S rRNA, highlighted by the contacts of the desosamine sugar of erythromycin to A2058. In turn, the genes that encode their biosynthesis are also found clustered with the rest of the antibiotic biosynthesis and resistance genes along with the specific glycosyltransferases.