The antitumor compound psymberin as a model to develop heterologous expression systems for polyketides from uncultivated sponge symbionts

越来越多的证据表明，许多从海绵中分离出来的生物活性天然产物是由尚未培养的细菌共生体合成的。然而，到目前为止，这些微生物难以捉摸的生活方式阻碍了对其化学和药理潜力的系统探索。我们团队最近开发了一套元基因组技术，通过提供对生物合成基因的访问，首次证明了海绵衍生聚酮的细菌来源。拟议工作的目标是开发共生体基因的细菌表达系统，可用于产生稀有海洋天然产品的可持续生产来源。这些研究的模型化合物将是psymberin，一种从海绵Psammocinia aff中分离出来的有效的实体肿瘤抑制剂。球茎。利用各种预选的宿主菌株、基因转移系统和启动子，将在转录、翻译和代谢水平上评估表达，以产生psymberin中间体，并最终产生真正的天然产品。这项工作预计将为如何创建复杂代谢物的可再生来源提供基本见解，这些代谢物是由研究较少的不寻常生物的生物合成酶组装而成的。

There is increasing evidence that many bioactive natural products isolated from marine sponges are synthesized by as-yet unculturable bacterial symbionts. However, the elusive lifestyle of these microbes has so far precluded the systematic exploration of their chemical and pharmacological potential. Our group has recently developed a suite of metagenomic techniques that demonstrated for the first time a bacterial origin for sponge-derived polyketides by providing access to the biosynthetic genes. Goal of the proposed work is to develop bacterial expression systems for symbiont genes that can be used to generate sustainable production sources of rare marine natural products. The model compound for these studies will be psymberin, a potent inhibitor of solid tumors isolated from the sponge Psammocinia aff. bulbosa. Using various preselected host strains, gene transfer systems and promoters, expression will be assessed at the transcriptional, translational and metabolic level to produce psymberin intermediates and ultimately the authentic natural product. This work is expected to provide fundamental insights into how renewable sources for complex metabolites can be created that are assembled by poorly studied biosynthetic enzymes of unusual organisms.