Deciphering indolocarbazole and enediyne aminodideoxypentose biosynthesis through comparative genomics: Insights from the AT2433 biosynthetic locus

被引：57
作者：
Gao, Qunjie
Zhang, Changsheng
Blanchard, Sophie
Thorson, Jon S.
机构：
[1] Univ Wisconsin, Sch Pharm, Lab Biosynthet Chem, Pharmaceut Sci Div, Madison, WI 53705 USA
[2] Univ Wisconsin, Natl Coooperat Drug Discovery Grp Program, Madison, WI 53705 USA
来源：
CHEMISTRY & BIOLOGY | 2006年 / 13卷 / 07期
基金：
美国国家卫生研究院;
关键词：
D O I：
10.1016/j.chembiol.2006.05.009
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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-glycosyl-transferase. 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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页码：733 / 743
页数：11
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