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http://purl.uniprot.org/citations/9889148http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/9889148http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/9889148http://www.w3.org/2000/01/rdf-schema#comment"

Background

Mithramycin is a member of the clinically important aureolic acid group of antitumor drugs that interact with GC-rich regions of DNA nonintercalatively. These drugs contain a chromophore aglycon that is derived from condensation of ten acetate units (catalyzed by a type II polyketide synthase). The aglycones are glycosylated at two positions with different chain length deoxyoligosaccharides, which are essential for the antitumor activity. During the early stages of mithramycin biosynthesis, tetracyclic intermediates of the tetracycline-type occur, which must be converted at later stages into the tricyclic glycosylated molecule, presumably through oxidative breakage of the fourth ring.

Results

Two intermediates in the mithramycin biosynthetic pathway, 4-demethyl-premithramycinone and premithramycin B, were identified in a mutant lacking the mithramycin glycosyltransferase and methyltransferase genes and in the same mutant complemented with the deleted genes, respectively. Premithramycin B contains five deoxysugars moieties (like mithramycin), but contains a tetracyclic aglycon moiety instead of a tricyclic aglycon. We hypothesized that transcription of mtmOIV (encoding an oxygenase) was impaired in this strain, preventing oxidative breakage of the fourth ring of premithramycin B. Inactivating mtmOIV generated a mithramycin nonproducing mutant that accumulated premithramycin B instead of mithramycin. In vitro assays demonstrated that MtmOIV converted premithramycin B into a tricyclic compound.

Conclusions

In the late stages of mithramycin biosynthesis by Strepyomyces argillaceus, a fully glycosylated tetracyclic tetracycline-like intermediate (premithramycin B) is converted into a tricyclic compound by the oxygenase MtmOIV. This oxygenase inserts an oxygen (Baeyer-Villiger oxidation) and opens the resulting lactone. The following decarboxylation and ketoreduction steps lead to mithramycin. Opening of the fourth ring represents one of the last steps in mithramycin biosynthesis."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.org/dc/terms/identifier"doi:10.1016/S1074-5521(99)80017-9"xsd:string
http://purl.uniprot.org/citations/9889148http://purl.org/dc/terms/identifier"doi:10.1016/s1074-5521(99)80017-9"xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Fernandez E."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Fernandez E."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Blanco G."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Blanco G."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Mendez C."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Mendez C."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Salas J.A."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Salas J.A."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Quiros L.M."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Quiros L.M."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Brana A.F."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Brana A.F."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Rohr J."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Rohr J."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Prado L."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Prado L."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Weissbach U."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/author"Weissbach U."xsd:string
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/date"1999"xsd:gYear
http://purl.uniprot.org/citations/9889148http://purl.uniprot.org/core/date"1999"xsd:gYear
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