微生物源脂肽的生物合成和分子调控

Biosynthesis and Molecular Regulation of Microbial Lipopeptides

微生物源脂肽具有抑制真菌和细菌的生长、抗病毒和抗肿瘤等多种生物活性,在农业生物防治、临床医疗、环境治理等多种领域具有巨大的应用潜力。然而,低产量一直是影响其推广应用的瓶颈。深入了解脂肽合成的关键因素和调控策略对于提高其产量和纯度至关重要。本文概括了3大家族脂肽surfactin、fengycin和iturin的结构、功能及应用前景,介绍了NRPS和NRPS-PKS两种合成系统的结构域和功能,阐释了脂肽生物合成过程中侧链脂肪酸的合成、脂肪酸的活化及与氨基酸的连接、肽链的延伸和环化三个阶段的模块组装和酶催化活动,以及三大家族脂肽合成操纵子开放阅读框的组成;总结了导入或缺失关键基因、定点突变、模块替换、强启动子替换、修饰前体路径等多种遗传操作对脂肽产量的影响,以及群体感应肽信息素、sigma因子等全局调控因子对脂肽合成基因表达的调节。指出利用多组学联用深入探讨脂肽合成的全局分子调控机制和加强结构域蛋白互作和分子动力学研究是提高脂肽产量和纯度以及创造新脂肽的理论基础,提出了利用基因组装和编辑等合成生物学方法及代谢工程技术提高脂肽产量和挖掘新型脂肽靶向性的可能途径,为推进脂肽的生产和应用进程提供科学参考。

Microbial lipopeptides have a variety of biological activities, such as inhibiting the growth of fungi and bacteria, antiviral and anti-tumor activities, and have great application potential in agricultural biological control, clinical medicine, environmental management and other fields. However, low yield has always been the bottleneck problem affecting its popularization and application. Deeper understanding the key factors and regulation strategies of lipopeptide synthesis is essential to improve its yield and purity. In this paper, the structures, functions and application prospects of three lipopeptide families containing surfactin, fengycin and iturin are sketched, and the domains and functions of NRPS and NRPS-PKS synthesis systems are introduced. Furthermore, the module assembly and enzyme catalysis activity in three stages of the process of lipopeptide biosynthesis including the synthesis of side-chain fatty acids, the activation of fatty acids and their connection to amino acids, the extension and cyclization of peptide chains, and the composition of open reading frames of biosynthesis operons of three major lipopeptide families are expounded;the effects of various genetic manipulations on the production of lipopeptide, such as transformation or deletion of key genes, site-directed mutation, module replacement, strong promoter replacement, and modification of precursor pathways, as well as the regulation of the expression of lipopeptide synthesis gene by global regulatory factors such as quorum sensing peptide pheromone and sigma factor, are summarized. Using conjoint analysis of multiomics to explore global molecular regulation mechanism of lipopeptide synthesis and strengthening the research on structure domain protein interactions and molecular dynamics are theoretical basis for enhancing lipopeptide yield and purity and creating novel lipopeptide. Strategies using gene assembly and editing methods of synthetic biology and metabolic engineering technology to improve the targeting of lipopeptide production and mining new lipopeptide are also summarized, which may provide scientific reference for accelerating the process of production and application of lipopeptide.