隐性次级代谢产物生物合成基因簇的激活及天然产物定向发现

Activation of cryptic microbial biosynthetic gene clusters and structure-guided natural product discovery

摘要:

传统的"活性-化合物"天然药物发现方法导致大量已知化合物被重复分离，大大加剧了新药发现的难度。规模化基因组测序揭示了微生物基因组中存在大量的隐性（cryptic）次级代谢产物生物合成基因簇，如何激活这些隐性基因簇成为当今世界天然产物研究领域的难点与热点。本文从途径特异性和多效性两个角度综述了隐性生物合成基因簇激活策略；同时，对基因组信息指导下结构导向（structure-guided）的化合物定向分离技术进行了归纳。隐性基因簇的激活为定向发掘具有优良活性的新型天然产物提供了新的契机。

关键词:激活;隐性生物合成基因簇;天然产物;定向发现

Abstract:

Traditional bioassay-guided natural product discovery has led to re-isolation of a large quantity of known compounds, and thus dramatically stunted the process of drug development. Large-scale genome sequencing revealed the existence of numerous cryptic biosynthetic gene clusters in microbes, which have attracted increasing attention in the research field of natural product discovery. In this review, we summarized the strategies for activation of microbial cryptic gene clusters at pathway-specific and pleiotropic levels, and discussed trends in structural identification technologies used for genome-guided compound mining. Activation of cryptic gene clusters will open new era for effective discovery of novel bioactive natural products.

Key words:activation;cryptic biosynthetic gene cluster;natural products;structure-guided discovery