多功能萜类P450酶组合生物合成策略定向挖掘新型抗肝纤维化杂二萜

肝纤维化进展最终导致肝硬化和肝癌，严重危害着人类的生命健康。然而，目前国际上并无治疗肝纤维化的特效药。我们预实验首次发现经过P450酶后修饰的真菌来源杂二萜可以显著抑制和逆转肝纤维化的进程。为此我们提出假说：真菌来源杂二萜或可在抗肝纤维化先导化合物发现方面提供一定借鉴。为了验证这一假说，我们将首次利用组合生物合成的策略，以前期基因组导向发现的两条真菌来源杂二萜生物合成基因簇为靶标，利用前期发现和候选的多功能P450氧化酶对这些基因簇进行体外异源重构，最后对所得到的新杂二萜进行抗肝纤维化体内外活性评价和机制探索，以期发现更多结构新颖和生物活性好的化合物。本研究将从多功能萜类P450酶与杂二萜组合生物合成发现全新抗肝纤维化天然产物这个新视点，为基因组导向挖掘抗肝纤维化天然产物提供一定的研究思路。

Progression of liver fibrosis eventually leads to cirrhosis and liver cancer, which seriously threat human life and health. The pre-experimental results showed that the fungal-derived meroditerpenoids modified by P450 enzyme can significantly inhibit and reverse the progression of liver fibrosis. Therefore, we hypothesized that the study of meroditerpenoid produced by fungal might provide some reference for the discovery of anti-hepatic fibrosis lead compounds. In order to verify this hypothesis, we firstly intend to use bioinformatics method to analyze the genome sequence from the NCBI database to find more homologues gene clusters target anti-hepatic fibrosis meroditerpenoids. Secondly, two candidate meroditerpenoid gene clusters and a series of multifunctional terpenoid P450 enzymes have been found. Thirdly, we will use combinatorial biosynthesis to heterologous expression of these multifunctional terpenoid P450 enzymes together with the two candidate meroditerpenoid gene clusters to find the novel natural products. Lastly, all of these new natural products will be evaluated for anti-hepatic fibrosis activity in vitro and in vivo. We expected to find some new structures and biological compounds. This project will firstly use a combinatorial biosynthesis to study multifunctional terpenoid P450 enzymes for discovery of new anti-hepatic fibrosis meroditerpenoids. In addition, we also hope that this project could provide new ideas for genome mining novel anti-hepatic fibrosis natural product from natural source.