Du Yi-Ling, Ryan Katherine S
Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
ACS Synth Biol. 2015 Jun 19;4(6):682-8. doi: 10.1021/sb5003218. Epub 2015 Jan 2.
Cladoniamides are indolotryptoline natural products that derive from indolocarbazole precursors. Here, we present a microbial platform to artificially redirect the cladoniamide pathway to generate unnatural bisindoles for drug discovery. Specifically, we target glycosyltransferase, halogenase, and oxidoreductase genes from the phylogenetically related indolocarbazole rebeccamycin and staurosporine pathways. We generate a series of novel compounds, reveal details about the substrate specificities of a number of enzymes, and set the stage for future efforts to develop new catalysts and compounds by engineering of bisindole genes. The strategy for structural diversification we use here could furthermore be applied to other natural product families with known biosynthetic genes.
克拉多酰胺是源自吲哚咔唑前体的吲哚色胺天然产物。在此，我们展示了一个微生物平台，可人工重新引导克拉多酰胺途径以生成用于药物发现的非天然双吲哚。具体而言，我们靶向来自系统发育相关的吲哚咔唑瑞贝克霉素和星形孢菌素途径的糖基转移酶、卤化酶和氧化还原酶基因。我们生成了一系列新型化合物，揭示了多种酶的底物特异性细节，并为未来通过双吲哚基因工程开发新催化剂和化合物的努力奠定了基础。我们在此使用的结构多样化策略还可应用于其他具有已知生物合成基因的天然产物家族。
