Chemistry and Biology：华人科学家用基因组学方法破译生物合成

生物谷

        在7月的Chemistry  and  Biology杂志上，来自威斯康星州大学的华人学者高群杰、张常胜等人公布了有关通过比较基因组学方法来破译吲哚咔唑(indolocarbazole)和Enediyne  Aminodideoxypentose生物合成的文章。

        AT2433是一种吲哚咔唑抗肿瘤药物，其结构的独特性在于它的具有含aminodideoxypentose的二糖（disaccharide）和不对称的卤化N-methylated  aglycon。利用比较基因组学方法，对AT2433基因束的克隆和测序分析并对这种基因座与编码rebeccamycin和calicheamicin进行比较能够研究aminodideoxypentose的生物合成。

        这种基因座两种甲基转移酶的离体生化特征以及利用AT2433  N-glycosyltransferase进行杂交表达和活体生物转化实验所确证。其中一种甲基化酶能修饰AT2433和蝴蝶霉素(Rebeccamycin)；另外一种酶则对AT2433具有特异性。

        对底物对这三种酶的耐受性分析的初步结果表明有可能扩展indolacarbazoles的酶多样性。而且，这项研究也为进一步研究indolocarbazole  maleimide  nitrogen和indolocarbazole的不对称性奠定了基础。

部分英文原文：

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

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.