Pyrrolo[1, 4]benzodiazepine Antibiotics. Biosynthetic Conversion of Tyrosine to the C2- and C3-Proline Moieties of Anthramycin, Tomaymycin, and Sibiromycin

This paper describes biosynthetic labeling experiments on the conversion of tyrosine to the C2- and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The biosynthetic fate of all of the aromatic and side-chain hydrogens has been determined in each antibiotic by using dual tagged (3H/4C) and 2H-labeled tyrosine molecules. In addition, experiments using [15N]tyrosine and the tritiated d and l isomers of tyrosine have shed some light on the biochemical reactions which take place at the a position of tyrosine. On the basis of results of all these experiments, a biosynthetic scheme has been proposed to rationalize the apparent inconsistencies which occur between the results for the three antibiotics. This scheme proposes that a common main pathway involving proximal extradiol cleavage of Dopa and condensation to form the pyrrolo ring leads ultimately to a C-7 branch point compound. Parallel pathways from this central branch point compound lead by well-known biochemical transformations to the C2- and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The reactions in these parallel pathways are suggested to be “cosmetic or after events”.