Cyanobacterial ent-Sterol-Like Natural Products from a Deviated Ubiquinone Pathway
Cyanobacterial ent-Sterol-Like Natural Products from a Deviated Ubiquinone Pathway
复制标题
DOI：
10.1002/anie.201611617
复制
发表时间：
2017-04-24
影响因子：
16.6
通讯作者：
Piel, Jorn
中科院分区：
文献类型：
--
作者：
Moosmann, Philipp;Ueoka, Reiko;Piel, Jorn
来自海洋动物的天然产物显示出开发新药的巨大潜力，但基于这些化合物的药物开发通常因其天然丰度低而受到阻碍。由于许多这些代谢物被怀疑或已知是由未培养的细菌共生体产生的，因此原核生物基因组测序的快速增长的多样性为通过计算确定天然产物的替代可培养来源提供了机会。在这项工作中，我们研究了利用该测序资源促进与海洋来源相关的类甲萜类化合物生产的潜力。这种基因组挖掘策略揭示了一个生物合成基因簇，该基因簇与从海绵中分离的与pelorol和其他化合物相关的高度修饰的细胞毒性美罗萜类化合物有关。萜烯环化酶MstE的功能表征表明，它可以从开链前体中产生与芳基片段融合的正甾醇样骨架，因此是化学酶制备合成挑战性化学支架的有前途的工具。
Natural products from marine animals show high potential for the development of new medicines, but drug development based on these compounds is commonly hampered by their low natural abundance. Since many of these metabolites are suspected or known to be produced by uncultivated bacterial symbionts, the rapidly growing diversity of sequenced prokaryotic genomes offers the opportunity to identify alternative, culturable sources of natural products computationally. In this work, we investigated the potential of using this sequenced resource to facilitate the production of meroterpenoid-like compounds related to those from marine sources. This genome-mining strategy revealed a biosynthetic gene cluster for highly modified cytotoxic meroterpenoids related to pelorol and other compounds isolated from sponges. Functional characterization of the terpene cyclase MstE showed that it generates an ent-sterol-like skeleton fused to an aryl moiety from an open-chain precursor and is therefore a promising tool for the chemoenzymatic preparation of synthetically challenging chemical scaffolds.