TY - JOUR
T1 - The Biosynthetic gene cluster for the antitumor rebeccamycin
T2 - Characterization and generation of indolocarbazole derivatives
AU - Sánchez, César
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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U2 - 10.1016/S1074-5521(02)00126-6
DO - 10.1016/S1074-5521(02)00126-6
M3 - Article
C2 - 11983340
AN - SCOPUS:0036235877
SN - 2451-9448
VL - 9
SP - 519
EP - 531
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 4
ER -