Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743.
Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743.
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DOI：
10.1111/1462-2920.12908
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发表时间：
2015-10
影响因子：
5.1
通讯作者：
Sherman DH
中科院分区：
文献类型：
--
作者：
Schofield MM;Jain S;Porat D;Dick GJ;Sherman DH
海鞘素743（ET-743，Yondelis）是从加勒比海红树林被囊类海鞘中分离的临床批准的化学治疗天然产物。研究人员长期以来一直怀疑微生物可能是抗癌药物的真正生产者，但由于我们无法使用标准技术在实验室中培养细菌，因此其基因组仍然难以捉摸。在这里，我们直接从被囊动物中分离的宏基因组DNA中测序并组装了ET-743生产者Escheridatus Endoecteinascidia frumentensis的完整基因组。对~631 kb微生物基因组的分析揭示了内共生生活方式和极端基因组减少的有力证据。系统发育分析表明，这种抗癌药物的生产者在分类学上与其他测序的微生物不同，可能代表了一个新的γ-变形菌家族。完整的基因组也极大地扩展了我们对ET-743生产的理解，并揭示了分散在超过173 kb的小基因组中的新生物合成基因。基因簇的结构及其保存表明，药物可能是必不可少的微生物与其红树林被囊类宿主的相互作用。总之，这些研究阐明了一种独特的、具有重要药用价值的微生物的生活方式，并强调了能够生产有效天然产物的细菌的广泛多样性。
Ecteinascidin 743 (ET-743, Yondelis) is a clinically approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anti-cancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the laboratory using standard techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Analysis of the ~631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome reduction. Phylogenetic analysis suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 production and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster’s architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. Taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically-important microorganism and highlight the wide diversity of bacteria capable of making potent natural products.