土曲霉中一类新型azaphilones化合物的生物合成机制研究

Azaphilones类化合物因其结构类型的复杂性、生物活性的多样性一直以来都是寻找药物先导化合物重要的化合物库。申请人近期研究工作中发现了一株土曲霉CIAT02能够产生结构新颖的、具有抗肿瘤活性的azaphilones类化合物azasperpyranones，初步研究表明该类化合物存在由三个PKS和一个NRPS-like基因分属两个基因簇组成的特殊生物合成途径和独特的调控机制。因此，在此基础上拟采用体内基因敲除、体外酶活测试、转录组分析等研究方法阐明它们在土曲霉中的合成机制。本研究对于提高土曲霉中azasperpyranones的产量，丰富该类化合物的结构多样性，发现催化特殊反应机制的酶，挖掘具有重要生物活性的新型azaphilones类化合物等都具有重要的意义。

Azaphilones have complicated structures and diversified biological activities, and are important libraries for searching lead compounds in drug discovery. In our recent work, we found Aspergillus terreus CIAT02 can produce azaphilones compounds named azasperpyranones with novel structures and antitumor activities. Preliminary results indicate that these compounds have a special biosynthetic pathway and unique regulation mechanism composed of three PKS genes and one NRPS-like gene belonging to two clusters. Therefore, we will use the methods including in vivo gene knockout, in vitro enzyme activities and transcriptional analysis to elucidate the synthetic mechanism of azasperpyranones in A. terreus. The research here will have a vital significance for improving the yields of azasperpyranones, enriching the diversity of those compounds, finding enzymes that catalyze special reactions and mining new azaphilones with important biological activities in A. terreus.