多环大环内酰胺（Polycyclic tetramate macrolactams，PTMs）类天然产物具有多样化的结构特征和丰富的药理活性。在PTMs骨架中，多元碳环是重要结构单元，其生物合成的成环机制尚不明确。本课题组在前期研究中发现，来源于具有自主知识产权的深海放线菌Streptomyces sp.SCSIO 02999菌株中PTM合成基因簇中的环化酶PacC，可以同时识别5/5环型和5/6环型PTM底物，分别催化形成内部六元环和五元环，生成5/5/6环型和5/6/5型两种代表性PTMs。本项目拟进行PacC的结构生物学研究，解析PacC晶体结构及其分别与两类底物（或产物）/辅酶复合的结构，结合PacC及其同源酶IkaC的定点突变和体外酶学测试，精确认识这类酶识别底物和选择催化路径的分子机制，有助于阐明PTMs内部环化机理，为定向合成丰富多样的PTMs及其新药开发提供理论支持。

Polycyclic tetramate macrolactams (PTMs) are a growing class of natural products with complex structures and diverse bioactivities. The carbocyclic ring systems play a great role in PTMs, while few is known for the cyclization mechanism.The alcohol dehydrogenase PacC was demonstrated as a bifunctional cyclase to mediate the formation of both six- and five-membered rings in PTMs. This project aims to unveil the substrate binding mode of PacC and the way to regulate enzymatic reaction routes, by crystal structures, site-directed mutation and in vitro biochemical assays, which will contribute to disclose the enzymatic machineries of PTMs polycycle formation.