Deciphering Indolocarbazole and Enediyne Aminodideoxypentose Biosynthesis through Comparative Genomics: Insights from the AT2433 Biosynthetic Locus

Qunjie Gao; Changsheng Zhang; Sophie Blanchard; Jon S. Thorson

doi:10.1016/j.chembiol.2006.05.009

Deciphering Indolocarbazole and Enediyne Aminodideoxypentose Biosynthesis through Comparative Genomics: Insights from the AT2433 Biosynthetic Locus

Qunjie Gao, Changsheng Zhang, Sophie Blanchard, Jon S. Thorson

Producción científica: Article › revisión exhaustiva

62 Citas (Scopus)

Resumen

AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases-one common to AT2433 and rebeccamycin, the other unique to AT2433-as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.

Idioma original	English
Páginas (desde-hasta)	733-743
Número de páginas	11
Publicación	Chemistry and Biology
Volumen	13
N.º	7
DOI	https://doi.org/10.1016/j.chembiol.2006.05.009
Estado	Published - jul 2006

Nota bibliográfica

Funding Information:
This work was supported in part by National Institutes of Health grants CA84374, AI52218, and GM70637, and a National Cooperative Drug Discovery Group grant from the National Cancer Institute (U19 CA113297). J.S.T. is a Romnes fellow. The authors want to thank Professors Peng George Wang (The Ohio State University) and David L. Van Vranken (UC Irvine) for graciously providing materials and Drs. Byron R. Griffith and Aqeel Ahmed for technical assistance. The authors also wish to acknowledge the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for MS and NMR support.

Financiación

This work was supported in part by National Institutes of Health grants CA84374, AI52218, and GM70637, and a National Cooperative Drug Discovery Group grant from the National Cancer Institute (U19 CA113297). J.S.T. is a Romnes fellow. The authors want to thank Professors Peng George Wang (The Ohio State University) and David L. Van Vranken (UC Irvine) for graciously providing materials and Drs. Byron R. Griffith and Aqeel Ahmed for technical assistance. The authors also wish to acknowledge the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for MS and NMR support.

Financiadores	Número del financiador
National Cooperative Drug Discovery Group
National Institutes of Health (NIH)	GM70637, CA84374, AI52218
National Childhood Cancer Registry – National Cancer Institute	U19 CA113297

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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title = "Deciphering Indolocarbazole and Enediyne Aminodideoxypentose Biosynthesis through Comparative Genomics: Insights from the AT2433 Biosynthetic Locus",

abstract = "AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases-one common to AT2433 and rebeccamycin, the other unique to AT2433-as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.",

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note = "Funding Information: This work was supported in part by National Institutes of Health grants CA84374, AI52218, and GM70637, and a National Cooperative Drug Discovery Group grant from the National Cancer Institute (U19 CA113297). J.S.T. is a Romnes fellow. The authors want to thank Professors Peng George Wang (The Ohio State University) and David L. Van Vranken (UC Irvine) for graciously providing materials and Drs. Byron R. Griffith and Aqeel Ahmed for technical assistance. The authors also wish to acknowledge the Analytical Instrumentation Center of the School of Pharmacy, UW-Madison, for MS and NMR support. ",

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doi = "10.1016/j.chembiol.2006.05.009",

language = "English",

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AU - Thorson, Jon S.

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N2 - AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases-one common to AT2433 and rebeccamycin, the other unique to AT2433-as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.

AB - AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases-one common to AT2433 and rebeccamycin, the other unique to AT2433-as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.

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Deciphering Indolocarbazole and Enediyne Aminodideoxypentose Biosynthesis through Comparative Genomics: Insights from the AT2433 Biosynthetic Locus

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