The Biosynthetic gene cluster for the antitumor rebeccamycin: Characterization and generation of indolocarbazole derivatives

César Sánchez; Igor A. Butovich; Alfredo F. Braña; Jürgen Rohr; Carmen Méndez; José A. Salas

doi:10.1016/S1074-5521(02)00126-6

The Biosynthetic gene cluster for the antitumor rebeccamycin: Characterization and generation of indolocarbazole derivatives

César Sánchez, Igor A. Butovich, Alfredo F. Braña, Jürgen Rohr, Carmen Méndez, José A. Salas

Research output: Contribution to journal › Article › peer-review

186 Scopus citations

Abstract

Rebeccamycin, a halogenated natural product of the indolocarbazole family, is produced by Saccharothrix aerocolonigenes ATCC39243. Several rebeccamycin analogues, which target DNA topoisomerase I or II, have already entered clinical trials as anticancer drugs. Using as a probe an internal fragment of ngt, a Saccharothrix aerocolonigenes gene encoding an indolocarbazole N-glycosyltransferase, we isolated a DNA region that directed the biosynthesis of rebeccamycin when introduced into Streptomyces albus. Sequence analysis of 25.6 kb revealed genes for indolocarbazole core formation, halogenation, glycosylation, and sugar methylation, as well as a regulatory gene and two resistance/secretion genes. Heterologous expression of subsets of these genes resulted in production of deschloro-rebeccamycin, 4′-demethyldeschloro-rebeccamycin, and deschloro-rebeccamycin aglycone. The cloned genes should help to elucidate the molecular basis for indolocarbazole biosynthesis and set the stage for the generation of novel indolocarbazole analogues by genetic engineering.

Original language	English
Pages (from-to)	519-531
Number of pages	13
Journal	Chemistry and Biology
Volume	9
Issue number	4
DOIs	https://doi.org/10.1016/S1074-5521(02)00126-6
State	Published - 2002

Bibliographical note

Funding Information:
The authors wish to thank K.H. van Pée, S. Zehner, and C. Schmid for providing us primers for halogenase genes and for facilitating information prior to publication. We thank the U.S. Department of Defense for support of J.R. et al. and Obra Social Cajastur for financial support to C.S. We acknowledge Drs. W. Cotham and M. Walla (University of South Carolina) for providing the high-resolution MS spectra.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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title = "The Biosynthetic gene cluster for the antitumor rebeccamycin: Characterization and generation of indolocarbazole derivatives",

abstract = "Rebeccamycin, a halogenated natural product of the indolocarbazole family, is produced by Saccharothrix aerocolonigenes ATCC39243. Several rebeccamycin analogues, which target DNA topoisomerase I or II, have already entered clinical trials as anticancer drugs. Using as a probe an internal fragment of ngt, a Saccharothrix aerocolonigenes gene encoding an indolocarbazole N-glycosyltransferase, we isolated a DNA region that directed the biosynthesis of rebeccamycin when introduced into Streptomyces albus. Sequence analysis of 25.6 kb revealed genes for indolocarbazole core formation, halogenation, glycosylation, and sugar methylation, as well as a regulatory gene and two resistance/secretion genes. Heterologous expression of subsets of these genes resulted in production of deschloro-rebeccamycin, 4′-demethyldeschloro-rebeccamycin, and deschloro-rebeccamycin aglycone. The cloned genes should help to elucidate the molecular basis for indolocarbazole biosynthesis and set the stage for the generation of novel indolocarbazole analogues by genetic engineering.",

author = "C{\'e}sar S{\'a}nchez and Butovich, {Igor A.} and Bra{\~n}a, {Alfredo F.} and J{\"u}rgen Rohr and Carmen M{\'e}ndez and Salas, {Jos{\'e} A.}",

note = "Funding Information: The authors wish to thank K.H. van P{\'e}e, S. Zehner, and C. Schmid for providing us primers for halogenase genes and for facilitating information prior to publication. We thank the U.S. Department of Defense for support of J.R. et al. and Obra Social Cajastur for financial support to C.S. We acknowledge Drs. W. Cotham and M. Walla (University of South Carolina) for providing the high-resolution MS spectra. ",

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AU - Butovich, Igor A.

AU - Braña, Alfredo F.

AU - Rohr, Jürgen

AU - Méndez, Carmen

AU - Salas, José A.

N1 - Funding Information: The authors wish to thank K.H. van Pée, S. Zehner, and C. Schmid for providing us primers for halogenase genes and for facilitating information prior to publication. We thank the U.S. Department of Defense for support of J.R. et al. and Obra Social Cajastur for financial support to C.S. We acknowledge Drs. W. Cotham and M. Walla (University of South Carolina) for providing the high-resolution MS spectra.

PY - 2002

Y1 - 2002

N2 - Rebeccamycin, a halogenated natural product of the indolocarbazole family, is produced by Saccharothrix aerocolonigenes ATCC39243. Several rebeccamycin analogues, which target DNA topoisomerase I or II, have already entered clinical trials as anticancer drugs. Using as a probe an internal fragment of ngt, a Saccharothrix aerocolonigenes gene encoding an indolocarbazole N-glycosyltransferase, we isolated a DNA region that directed the biosynthesis of rebeccamycin when introduced into Streptomyces albus. Sequence analysis of 25.6 kb revealed genes for indolocarbazole core formation, halogenation, glycosylation, and sugar methylation, as well as a regulatory gene and two resistance/secretion genes. Heterologous expression of subsets of these genes resulted in production of deschloro-rebeccamycin, 4′-demethyldeschloro-rebeccamycin, and deschloro-rebeccamycin aglycone. The cloned genes should help to elucidate the molecular basis for indolocarbazole biosynthesis and set the stage for the generation of novel indolocarbazole analogues by genetic engineering.

AB - Rebeccamycin, a halogenated natural product of the indolocarbazole family, is produced by Saccharothrix aerocolonigenes ATCC39243. Several rebeccamycin analogues, which target DNA topoisomerase I or II, have already entered clinical trials as anticancer drugs. Using as a probe an internal fragment of ngt, a Saccharothrix aerocolonigenes gene encoding an indolocarbazole N-glycosyltransferase, we isolated a DNA region that directed the biosynthesis of rebeccamycin when introduced into Streptomyces albus. Sequence analysis of 25.6 kb revealed genes for indolocarbazole core formation, halogenation, glycosylation, and sugar methylation, as well as a regulatory gene and two resistance/secretion genes. Heterologous expression of subsets of these genes resulted in production of deschloro-rebeccamycin, 4′-demethyldeschloro-rebeccamycin, and deschloro-rebeccamycin aglycone. The cloned genes should help to elucidate the molecular basis for indolocarbazole biosynthesis and set the stage for the generation of novel indolocarbazole analogues by genetic engineering.

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The Biosynthetic gene cluster for the antitumor rebeccamycin: Characterization and generation of indolocarbazole derivatives

Abstract

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ASJC Scopus subject areas

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