肉桂酰脂结构单元新颖生物合成分子机制及其组合生物合成

肉桂酰型非核糖体肽（CCNPs）因其新奇独特的结构、广泛而显著的活性而备受人们的关注。该类化合物N端稀有的邻位取代肉桂酸脂（CL）基团，对维持N端稳定性及调节化合物性质具有重要作用。CL结构单元的独特性暗示了其组装机制的新颖性。前期研究推测其是由一类非经典的多烯Type II 聚酮合酶（PKS）体系编码而成，然而各功能元件在CL结构单元组装过程中扮演的角色，特别是苯环形成的分子机制尚属空白。本项目拟采用体内遗传学和体外生化实验等手段阐明CL结构单元在微生物体内的生物合成过程，揭示各个元件在组装过程中的作用，挖掘其中新颖的酶催化机制，进一步构建CL结构单元组合生物合成体系。研究结果不仅将加深和拓宽我们对大自然中新颖的分子生物合成体系的认识，丰富活性天然产物生物合成功能元件库，并且将为利用合成生物学手段创制含有特定N端CL基团的活性CCNP类化合物提供可靠的理论指导。

Cinnamoyl-containing nonribosomal peptides (CCNPs) represent a very interesting class of natural products due to their unique structural architectures as well as their potent and diverse biological activities. Different from other nonribosomal peptides, CCNPs harbor a N-terminal cinnamoyl lipid (CL) moiety, which is important for protecting the N terminus from degradation or modulating specific properties. CL moieties harbor a rarely seen orth-substituted lipid chain, implying that they are assembled via novel biosynthetic machinery. It was proposed that a non-conventional type II polyketide synthase (PKS) is in charge of the CL biosynthesis, however, the role of individual functional part of the CL PKS system, especially the mechanism of the phenol ring formation are still unknown. In this project, we are going to decipher the biosynthetic machinery of the CL moiety catalyzed by the CL PKS system, and elucidate the role played by each member in the assembly line. The novel enzymatic mechanisms involved are going to be probed. In addition, the combinatorial biosynthesis of the CL moieties will be explored. Our results would on one hand broaden and deepen our understanding about the novel biosynthetic system in nature; on the other hand, will provide important functional parts as well as theoretical guidance for rationally making a particular CL-containing CCNP with attractive bioactivities.