前期研究中，我们从一株番荔枝内生真菌Periconia sp. F-31中发现了一系列骨架新颖、结构多样的聚酮-氨基酸杂合物，包括9/6/5环系细胞松弛素Periconiasin A、6/6/5环系decalin化合物Peridecalin A以及6/6/5环系氧杂decalin化合物Pericoannosin A，推测它们来源于同一前体分子，经不同形式Diels-Alder反应形成。本研究拟在全基因组测序的基础上，建立遗传转化操作体系，通过基因敲除、突变株中间体分离及结构鉴定、蛋白外源表达及催化功能验证等技术手段，发现并确证这些化合物骨架构建酶，阐明其生物合成途径，解析同一基因簇控制同一前体化合物形成多样化骨架化合物、尤其是细胞松弛素大环形成的酶学机制。本研究立足于自主创新，将为利用生物合成方法实现该类新颖骨架活性化合物的高效制备及获取结构多样该类衍生物药物先导分子奠定基础。

Polyketide-amino acid (PK-AA) hybrid molecules with specific structure and significant bioactivity are an important source of innovative drugs. Their biosynthesis is performed by PKS-NRPS hybrids in vivo. In our previous investigation, a series of PK-AA hybrids with divergent skeleton were found in an Annona muricata endophytic fungus Periconia sp. F-31, including Periconiasin A (1, cytochalasin with 9/6/5 ring system), Peridecalin A (2, decalin with 6/6/5 ring system), and Pericoannosin A (3, oxadecalin with 6/6/5 ring system). We speculated that these compounds biosynthetically originated from one common precursor molecule and were formed by different types of Diels–Alder reaction, but the enzymatic mechanism of the biosynthesis is unclear. In this project, the genetic transformation system of Periconia sp. F-31 will be established on the basis of whole genome sequencing, and the biosynthetic gene cluster of target compounds 1–3 will be identified by gene knockout technique, isolation and structure identification of intermediates in the mutants, and heterologous expression and catalytic function validation of enzymes. Ultimately, the biosynthetic pathway of the target compounds will be elucidated, as well as the enzymatic mechanism of one gene cluster controlling one precursor to form structurally diverse compounds, especially the formation of cytochalasin macrocycles. This study, which is based on self-independent innovation, will lay the foundation for the efficient preparation of these bioactive compounds by biosynthetic methods, and for yielding more structurally diverse PK-AA hybrids for the discovery of drug lead compounds.