The biosynthesis of aureolic acid group antibiotics

Biosynthetic studies on mithramycin (1, aureolic acid) using to a great ext ent modern genetic methods revealed several novel aspects of the biosynthes is of this class of antitumor agent. It could be proven that the aglycon mo iety 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 tet racyclines, followed by an initial 7,12-cyclization. Finally, after three m ore cyclizations, a linear tetracyclic intermediate (premithramycinone 9) a rises, which is a tetracycline-like molecule. Premithramycinone (9) is cons ecutively methylated and glycosylated (via premithramycins A(1) 11, A(1) 12 , A(2) 13, and A(3) 14) to form premithramycin B (10), the ultimate tetracy clic intermediate, whose fourth ring finally gets oxidatively opened throug h a Baeyer-Villiger type oxidation to yield mithramycin 1. Most of the gene cluster coding for the mithramycin biosynthesis has been identified and se quenced and several gene functions were identified through insertional inac tivation of specific genes and structure elucidation of accumulated product s. (C) 1999 Academic Press.