白色链霉菌DSM 41398中洋橄榄菌素和放线吡喃酮的发现及其生物合成途径分析

【目的】从菌株Streptomyces albus DSM 41398的发酵产物中发掘结构多样的由I型聚酮合酶催化形成的化合物,以期找到具有新颖结构或强生物活性的化合物。在结构鉴定的基础上,对其生物合成途径进行分析。【方法】利用HPLC分析方法,通过系统比较野生型菌株S.albus DSM 41398与I型聚酮合酶编码基因簇失活突变株的发酵产物差异,实现目标化合物的定向分离。然后,利用~1H-和~(13)C-NMR以及HR-ESI-MS进行化合物的结构鉴定。最后,利用生物信息学等方法对化合物的生物合成途径进行推测和分析。【结果】从5 L的S.albus DSM 41398发酵产物中,分离得到了2个具有抗肿瘤活性的聚酮类化合物放线吡喃酮和洋橄榄菌素,分别定位了它们的生物合成基因簇,并分别对其生物合成途径进行了推导。其中,放线吡喃酮的生物合成基因簇为首次报道。【结论】本研究一方面为基因组发掘S.albus DSM 41398中其他由I型聚酮合酶催化形成的化合物提供参考,另一方面也为相关化合物的结构修饰改造奠定了良好的基础。

Exploration and biosynthetic mechanism analysis of elaiophylin and actinopyranone from Streptomyces albus DSM 41398

[Objective] The targeted type I polyketide-derived compounds was explored to discover diverse compounds with good biological activity from Streptomyces albus DSM 41398. The biosynthetic pathways of the isolates were further elucidated based on the structure determination and bioinformatics analysis. [Methods] The target compounds were discovered based on comparative HPLC analysis of the fermented broths of wild type and type I PKS gene cluster inactivated mutants. Their chemical structures were elucidated based on ¹H-,¹³C-NMR and HR-ESI-MS. Additionally, their biosynthetic pathways were illuminated by bioinformatics analysis. [Results] Two type I polyketide-originated compounds with antitumor activity, elaiophilin and actinopyranone, were isolated from 5 L fermented broth of S. albus DSM 41398. Their gene clusters were located, and the biosynthetic pathways were proposed, respectively. Notably, the biosynthesis gene cluster of actinopyranone was reported for the first time in this study. [Conclusion] The investigation of elaiophilin and actinopyranone not only offered a strategy to discover type I polyketide compounds through genome mining, but also paved ways for further compound structural modifications.