| Abstract
| - Aklanonic acid, an anthraquinone natural product, is a common advanced intermediate in thebiosynthesis of several antitumor polyketide antibiotics, including doxorubicin and aclacinomycin A. Intensivesemisynthetic and biosynthetic efforts have been directed toward developing improved analogues of theseclinically important compounds. The primer unit of such polyfunctional aromatic polyketides is an attractivesite for introducing novel chemical functionality, and attempts have been made to modify the primer unit byprecursor-directed biosynthesis or protein engineering of the polyketide synthase (PKS). We have previouslydemonstrated the feasibility of engineering bimodular aromatic PKSs capable of synthesizing unnaturalhexaketides and octaketides. In this report, we extend this ability by preparing analogues of aklanonicacid, a decaketide, and its methyl ester. For example, by recombining the R1128 initiation module with thedodecaketide-specific pradimicin PKS, the isobutyryl-primed analogue of aklanonic acid (YT296b, 10) andits methyl ester (YT299b, 12) were prepared. In contrast, elongation modules from dodecaketide-specificspore pigment PKSs were unable to interact with the R1128 initiation module. Thus, in addition to revealinga practical route to new anthracycline antibiotics, we also observed a fundamental incompatibility betweenantibiotic and spore pigment biosynthesis in the actinomycetes bacteria.
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