Biosynthetic studies on mithramycin (1, aureolic acid) using to a great extent modem 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 (premithramycinone 9) arises, which is a tetracycline-like molecule. Premithramycinone (9) is consecutively methylated and glycosylated (via premithramycins A1 11, A1 12, A2 13, and A3 14) to form premithramycin B (10), the ultimate tetracyclic intermediate, whose fourth ring finally gets oxidatively opened through a Baeyer-Villiger type oxidation to yield mithramycin 1. 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.
|Number of pages||14|
|State||Published - Feb 1999|
Bibliographical noteFunding Information:
The authors thank all their coworkers involved in the research on the aureolic acid group. Support came from grants of the Spanish Ministry of Education and Science to J.A.S. (BIO94-0037, BIO97-0771), the European Community to J.A.S. and J.R. (BIO4-CT96-0068), the Deutsche Forschungsgem-einschaft (SFB 416) and the Medical University of South Carolina to J.R.
ASJC Scopus subject areas
- Molecular Biology
- Drug Discovery
- Organic Chemistry