Automated genome mining of ribosomal peptide natural products.

Automated genome mining of ribosomal peptide natural products.
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DOI:
10.1021/cb500199h
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发表时间:
2014-07-18
影响因子:
4
通讯作者:
Dorrestein, Pieter C.
Dorrestein, Pieter C.
中科院分区:
生物学2区
文献类型:
--
作者:
Mohimani, Hosein;Kersten, Roland D.;Liu, Wei-Ting;Wang, Mingxun;Purvine, Samuel O.;Wu, Si;Brewer, Heather M.;Pasa-Tolic, Ljiljana;Bandeira, Nuno;Moore, Bradley S.;Pevzner, Pavel A.;Dorrestein, Pieter C.

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核糖体合成和翻译后修饰肽(RiPPs)是一类具有生物活性的天然产物,是新型(生物)化学和生物活性的重要来源鉴于微生物基因组数据库呈指数级增长和基于质谱(MS)的代谢组学平台的改进,需要一种计算工具,将微生物基因组序列预测的天然产物基因型与代谢组学数据集中相应的化学型联系起来。本文介绍了一种用于微生物RiPPs鉴定的串联质谱数据库搜索工具RiPPquest,并将其应用于镧硫肽的发现。RiPPquest使用基因组学将搜索空间限制在RiPP生物合成基因附近,并使用蛋白质组学分析广泛的肽修饰并计算肽谱匹配(psm)的p值。我们通过将链霉菌提取物中的多个RiPPs与它们的基因簇连接起来,并通过从病毒色链霉菌(Streptomyces viridochromogenes) DSM 40736中发现新的III类肽,信息肽(informatipeptin)来强调RiPPquest,以反映它是一种天然产物,是通过使用算法工具基于质谱的基因组挖掘发现的,而不是手工检查质谱数据和遗传信息。所介绍的工具可在cyclo.ucsd.edu上获得。
Ribosomally synthesized and posttranslationally modified peptides (RiPPs), especially from microbial sources, are a large group of bioactive natural products that are a promising source of new (bio)chemistry and bioactivity.1 In light of exponentially increasing microbial genome databases and improved mass spectrometry (MS)-based metabolomic platforms, there is a need for computational tools that connect natural product genotypes predicted from microbial genome sequences with their corresponding chemotypes from metabolomic data sets. Here, we introduce RiPPquest, a tandem mass spectrometry database search tool for identification of microbial RiPPs, and apply it to lanthipeptide discovery. RiPPquest uses genomics to limit search space to the vicinity of RiPP biosynthetic genes and proteomics to analyze extensive peptide modifications and compute p-values of peptide-spectrum matches (PSMs). We highlight RiPPquest by connecting multiple RiPPs from extracts of Streptomyces to their gene clusters and by the discovery of a new class III lanthipeptide, informatipeptin, from Streptomyces viridochromogenes DSM 40736 to reflect that it is a natural product that was discovered by mass spectrometry based genome mining using algorithmic tools rather than manual inspection of mass spectrometry data and genetic information. The presented tool is available at cyclo.ucsd.edu.
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