Biosynthesis of Anthramycin. Determination of the Labeling Pattern by the Use of Radioactive and Stable Isotope Techniques

The building blocks for anthramycin, an antitumor antibiotic produced by a strain of Streptomyces refuineus, have been shown to be L-tryptophan, probably via 3-hydroxyanthranilic acid, L-tyrosine which loses two of its aromatic carbons, and L-methionine which contributes two methyl groups. While one of the two methyl groups is transferred intact, the other loses all of its hydrogens and becomes the carbonyl of an amide group. A mechanism involving extradiol cleavage of Dopa is proposed on the basis of double labeling and stable isotope experiments. A general scheme for the biosynthetic origin of the C₃-proline moieties of anthramycin, lincomycin A, and sibiromycin and the C₂-proline moieties of tomaymycin and lincomycin B is proposed.