Pyrrolo[1,4]benzodiazepine Antibiotics. Biosynthesis of the Antitumor Antibiotic 11-Demethyltomaymycin and Its Biologically Inactive Metabolite Oxotomaymycin by Streptomyces achromogenes

Laurence H. Hurley, Chandrachuranand Gairola, Nobel V. Das

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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 ÑIH 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 of the β hydrogens of this amino acid are retained in 11-demethyltomaymycin. It has been demonstrated in cultures and washed cell preparations that 11-demethyltomaymycin is enzyipatically 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 production phase, since trophophase cells and even cells from 11-demethyltomaymycin nbnproducing cultures of 5. achromogenes were equally active in converting 11-demethyltomaymycin to oxotomaymycin.

Original languageEnglish (US)
Pages (from-to)3760-3769
Number of pages10
Issue number17
StatePublished - Aug 1 1976
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry

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