变型链球菌UA159中Mutanobactins生物合成机制的研究

Mutanobactins（MUBs）是口腔微生物变型链球菌UA159产生的环状脂肽类化合物，也是目前唯一的一类从人体口腔微生物中分离到的PKS-NRPS类天然产物。MUBs具有抑制真菌和免疫调节等生物活性。在分子结构上，MUBs具有新颖的C-C键连接的大环结构和一个含硫和氮的七元杂环结构。新颖的结构蕴含着新颖的化学和酶学反应机制。本项目将利用分子遗传学、化学和生物化学的手段，解析MUBs的生物合成途径，特别是形成C-C键的大环成环过程和七元杂环合成过程，阐明这些特殊结构的生物合成机制。本项目是首次针对人体微生物中PKS-NRPS类次级代谢产物进行深入的生物合成研究，对人体微生物次级代谢的研究具有重要意义。同时，MUBs中特殊的C-C键连接大环结构的解析将为通过合成生物学得到新结构的大环化合物奠定基础，对新药研发具有重要意义。

Mutanobactins (MUBs), macrocyclic lipopeptides produced by the oral bacterium –Streptococcus mutans UA159, are the only PKS-NRPS type of secondary metabolites isolated from the human oral microbiome. MUBs exhibit two distinct biological activities: inhibition hyphal formation of fungi and immunomodulatory activity. The structure of MUB comprises an unprecedented C-C bond forming macrocyclic scaffold and a unique 7-membered heterocycle containing sulfur and nitrogen, which implies involvement of novel chemical mechanisms and enzymatic reactions in the biosynthesis of MUBs. The proposed research aims to elucidate the biosynthetic mechanism of MUBs, especially the mechanism of the novel C-C bond macrocyclization and the unique 7-membered heterocycle formation, through studies combining the genetic, chemical and biochemical methods. The proposed research is groundbreaking in the area of secondary metabolism of the human microbes, considering that no thorough biosynthesis study of PKS-NRPS type metabolites has ever been published in this area. Meanwhile, the achievements of the proposed research will lay a solid foundation for the production of novel C-C bond macrocyclic compounds by enzymatic synthesis or combinatorial biosynthesis, which are significant to the area of drug discovery.