title: Pyrrolo[1,4]benzodiazepine antibiotics. Biosynthesis of the antitumor antibiotic 11-demethyltomaymycin and its biologically inactive metabolite oxotomaymycin by Streptomyces achromogenes.
abstract: 11-Demethyltomaymycin, an antitumor antibiotic produced by Streptomyces achromogenes, and its biologically inactive metabolite oxotomaymycin are biosynthesized from L-tyrosine, DL-tryptophan, and L-methionine. The anthranilate part of 11-demethyltomaymycin is derived from tryptophan probably via the kynurenine pathway. The predominant loss of tritium from DL-[5-3H]tryptophan, during its conversion to 11-demethyltomaymycin and oxotomaymycin is interpreted to mean by NIH shift rules, that the main pathway to the 5-methoxy-4-hydroxy anthranilate moiety is through hydroxylation at C-8 prior to hydroxylation at C-7. The methoxy carbon is derived from the S-methyl group of methionine by transfer of an intact methyl group. The ethylideneproline moiety of 11-demethyltomaymycin is biosynthesized from tyrosine, without a 1-carbon unit from methionine. The results of biosynthetic feeding experiments with L-[1-14C, 3- or 5-3H]tyrosine are consistent with a "meta" or extradiol cleavage of 6,7-dihydroxycyclodopa as has also been demonstrated previously for anthramycin and lincomycin A. An experiment in which L-[1-14C, Ala-2,3-3H]tyrosine was fed showed that both the beta hydrogens of this amino acids are retained in 11-demethyltomaymycin. It has been demonstrated in cultures and washed cell preparations that 11-demethyltomaymycin is enzymatically converted to oxotomaymycin by an intracellular constitutive enzyme. Conversion of oxotomaymycin to 11-demethyltomaymycin by these same preparations could not be demonstrated. The enzymatic activity associated with the conversion of 11-demethyltomaymycin to oxotomaymycin is not limited to the 11-demethyltomaymycin to oxotomaymycin is not limited to the 11-demethyltomaymycin production phase, since trophophase cells and even cells from 11-demethyltomaymycin nonproducing cultures of S. achromogenes were equally active in converting 11-demethyltomaymycin to oxotomaymycin.
mesh_terms: D006916:5-Hydroxytryptophan / Q000378:metabolism; D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones / Q000096:biosynthesis*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006358:Hot Temperature; D008715:Methionine / Q000378:metabolism; D011758:Pyrroles / Q000096:biosynthesis; D013302:Streptomyces / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000096:biosynthesis
chemical_list: D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; D011758:Pyrroles; D062367:ortho-Aminobenzoates; C013184:oxotomaymycin; D014443:Tyrosine; C012872:11-demethyltomaymycin; D004295:Dihydroxyphenylalanine; D014364:Tryptophan; D008715:Methionine; D006916:5-Hydroxytryptophan