新型sactipeptide的发现及生物合成机制研究

Discovery of natural products with unique scaffolds and study of their bioynthetic pathways have now become an increasingly important part for microbial drug development and one of the most attractive field in mordern microbiology. This stduy focuses on sactipeptide natural products, a small but growing family of ribosomally synthesized and posttranslationally modified peptides. Sactipeptidesare sactionine-containing peptides, containing unusally thioether bonds that link a cysteine to the α-carbon of a second amino acid. Although sactipeptide family currently only consists of 6 members (5 members are antibotics), our previous analysis has shown that this family of natural product is widely distributed in nature and likely consists of more than 300 members from taxonomically different organisms including clostridia and bacteroidetes. Large scale of genome mining and detailed study of their biosynthetic mechansim will thus not only solve many mystery steps in the radical-mediated posttranlational modifications but also open a new filed of natural products in clostridia and bacteroidetes. Our study will also facilitate efforts in developing new antibacterial drugs.

发现具有独特化学结构和生物活性的天然产物及其生物合成机制阐明是当今微生物药物研发的重要环节，已成为现代微生物学最为关注的重要领域之一。本申请集中于一类特殊的核糖体天然产物sactipeptides，这类化合物含有特殊的sactionine结构，其中来源于半胱氨酸的硫原子与另一个氨基酸残基的α碳相连。虽然目前发现的这类化合物家族仅有6个成员，我们前期的工作表明这类化合物广泛的存在于自然界，具有巨大的研究潜力。本项目拟以将大规模的发现和阐明新型sactipeptide这一颇具药物发开潜力的天然产物，并对其生物合成中的酶学机制进行详细研究。我们的研究将不仅解决自由基介导的翻译后修饰中诸多基础的生物化学问题,　同时更将开启梭菌，拟杆菌甚至古细菌天然产物研究的大门，为新型抗生物药物的研发提供新的思路和基础。

Sactipeptide是一大类核糖体肽天然产物，在自然界广泛存在并具有丰富的结构及生物活性多样性。该类化合物起源于核糖体合成的前体肽，由一类独特的SAM自由基酶作用下，形成关键的还有Ca-硫醚键的sactionine 独特结构。我们发现诸如thuricin Z等多类新型的sactipeptide类化合物，并对其生物合成和作用机制进行了详细的研究。相关的研究成果在Nature Communications, Journal of the American Chemical Society, Angewandte Chemie International Edition 等国际主流期刊上发表文章二十余篇。相关工作被Chemistry & Engineering News, Faculty of 1000等媒体予以专文报道。相关的研究将促进人们对于核糖体肽类化合物的认识，并为更好地开发这类化合物在科研和临床上的应用提供了一些理论基础。