Abstract
Biosynthetic studies on mithramycin (1, aureolic acid) using to a great extent modern genetic methods revealed several novel aspects of the biosynthesis of this class of antitumor agent. It could be proven that the aglycon moiety of the aureolic acids is constructed by a type II polyketide synthase via a single decaketide chain which undergoes a folding, as seen in the tetracyclines, followed by an initial 7,12-cyclization. Finally, after three more cyclizations, a linear tetracyclic intermediate (premithramycinone9) arises, which is a tetracycline-like molecule. Premithramycinone (9) is consecutively methylated and glycosylated (via premithramycins A111, A112, A213, and A314) to form premithramycin B (10), the ultimate tetracyclic intermediate, whose fourth ring finally gets oxidatively opened through a Baeyer-Villiger type oxidation to yield mithramycin1. Most of the gene cluster coding for the mithramycin biosynthesis has been identified and sequenced and several gene functions were identified through insertional inactivation of specific genes and structure elucidation of accumulated products.
Published Version
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