Deciphering indolocarbazole and enediyne aminodideoxypentose biosynthesis through comparative genomics: Insights from the AT2433 biosynthetic locus
Deciphering indolocarbazole and enediyne aminodideoxypentose biosynthesis through comparative genomics: Insights from the AT2433 biosynthetic locus
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DOI：
10.1016/j.chembiol.2006.05.009
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发表时间：
2006-07-01
影响因子：
--
通讯作者：
Thorson, Jon S.
中科院分区：
文献类型：
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作者：
Gao, Qunjie;Zhang, Changsheng;Thorson, Jon S.
AT2433是一种吲哚咔唑类抗肿瘤抗生素，其结构特点是含有氨基二脱氧葡萄糖双糖和不对称卤化n -甲基化糖醛基。AT2433基因簇的克隆和序列分析，以及与rebeccamycin编码基因簇和calicheamicin编码基因簇的比较，为利用比较基因组学研究氨基二脱氧戊糖生物合成提供了机会。该基因座通过两种甲基转移酶（AT2433和rebeccamycin共有的一种，AT2433特有的另一种）的体外生化表征以及AT2433 n -糖基转移酶的异源表达和体内生物转化实验得到证实。对这三种酶的底物耐受性的初步研究揭示了吲哚咔唑酶多样化的潜力。此外，这项工作为未来研究吲哚咔唑马来酰亚胺氮和吲哚咔唑不对称的起源奠定了基础。
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.