Bipolaris sp. TJ403-B1中蛇孢菌素来源的二倍半萜新骨架衍生物的生物合成研究

Bipolarolides A-G是一类从真菌Bipolaris sp. TJ403-B1中分离出的，具有复杂环系的二倍半萜化合物。它们来源于蛇孢菌素（ophiobolins）生物合成基因簇，经过不同的环化机理，形成了三种新的骨架类型。生物活性上，bipolarolide A具有HMG-CoA还原酶抑制活性，另一种骨架的bipolarolide E、F具有显著的抗耐药细菌及抗真菌活性。针对这种“一个基因簇，多种骨架化合物”现象，本项目拟研究三种新骨架的生物合成，包括分子中四氢呋喃环及其他复杂多环体系的形成机理，以期发现新颖的微生物代谢反应。同时，鉴于bipolarolides具有真菌细胞毒性，我们推测该基因簇具有调控自身表达和自我保护机制。本项目拟解析簇中可能具有转录调控或解毒功能的基因元件，包括广泛存在于真菌基因组的功能未知结构域DUF3425，从而发现新颖的二级代谢产物调控机制。

Bipolarolides A-G are a series of sesterterpenoid compounds with complex ring systems isolated from fungus Bipolaris sp. TJ403-B1. They are derived from the ophiobolin biosynthetic gene cluster, and have been modified and cyclized by different mechanisms to form three new kinds of skeletons. In terms of biological activity, bipolarolide A showed HMG-CoA reductase inhibitory activity, while bipolarolide E and F, both belonging to another skeleton, exhibited antimicrobial activity against drug-resistant bacteria and the fungus Candida albicans. Intrigued by this "one gene cluster, multiple skeleton compounds" case, this project intends to study the biosynthesis of three new skeletons, including the formation mechanism of tetrahydrofuran ring and other complex multi-ring systems in the molecules, in order to discover novel microbial metabolic reactions. At the same time, considering bipolarolides' fungal cytotoxicity, we speculate that this gene cluster has managed to regulate its own expression and self-protection. Accordingly, this project will analyze the genetic elements in the cluster that may have transcriptional regulation or detoxification functions, including DUF3425, a function-unknown-domain widely present in the fungal genomes, so as to discover novel regulation mechanisms of secondary metabolism.