Collaborative Biosynthesis of a Class of Bioactive Azaphilones by Two Separate Gene Clusters Containing Four PKS/NRPSs with Transcriptional Crosstalk in Fungi
Collaborative Biosynthesis of a Class of Bioactive Azaphilones by Two Separate Gene Clusters Containing Four PKS/NRPSs with Transcriptional Crosstalk in Fungi
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DOI：
10.1002/anie.201915514
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发表时间：
2020-01-30
影响因子：
16.6
通讯作者：
Lu, Xuefeng
中科院分区：
文献类型：
--
作者：
Huang, Xuenian;Zhang, Wei;Lu, Xuefeng
氮杂霉酮是一类真菌多酮类代谢产物，具有多种化学结构和生物活性，核心为高氧吡喃醌双环。本文在土曲霉中鉴定出一类具有6/6/6/6 /6四环环体系的氮化霉酮，具有潜在的抗癌活性。基因缺失和生化研究表明，这些氮蚜酮是由两个独立的团簇协同合成的，其中包含四个核心酶，两个非还原性PKS，一个高度还原性PKS和一个类似nrps的PKS。更有趣的是，我们发现基于三种转录因子的两个基因簇之间的串扰机制协调调节生物合成。这是一种有意义的真菌次生代谢机制，它使真菌能够合成更复杂的化合物并获得新的生理功能。这些结果为真菌天然产物的生物合成提供了新的见解。
Azaphilones are a family of fungal polyketide metabolites with diverse chemical structures and biological activities with a highly oxygenated pyranoquinone bicyclic core. Here, a class of azaphilones possessing a 6/6/6/6 tetracyclic ring system was identified in Aspergillus terreus, and exhibited potential anticancer activities. The gene deletions and biochemical investigations demonstrated that these azaphilones were collaboratively synthesized by two separate clusters containing four core-enzymes, two nonreducing PKSs, one highly reducing PKS, and one NRPS-like. More interestingly, we found that the biosynthesis is coordinately regulated by a crosstalk mechanism between these two gene clusters based on three transcriptional factors. This is a meaningful mechanism of fungal secondary metabolism, which allows fungi to synthesize more complex compounds and gain new physiological functions. The results provide a new insight into fungal natural product biosynthesis.