Discovery of a widely distributed toxin biosynthetic gene cluster
Discovery of a widely distributed toxin biosynthetic gene cluster
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DOI：
10.1073/pnas.0801338105
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发表时间：
2008-04-15
影响因子：
11.1
通讯作者：
Dixon, Jack E.
中科院分区：
文献类型：
--
作者：
Lee, Shaun W.;Mitchell, Douglas A.;Dixon, Jack E.
细菌素是一大类核糖体产生的肽类抗生素。在这里，我们描述了一个广泛保守的生物合成基因簇的发现，用于在核糖体产生的肽上合成噻唑和恶唑杂环。这些簇编码毒素前体和毒素成熟和输出所需的所有蛋白质。利用人类病原体化脓性链球菌毒素前体肽和杂环形成合成酶蛋白，我们在体外重建了溶链素S的活性。我们提供的证据表明，正如我们的生物信息学分析所预测的那样，合成酶在前体肽上引入杂环，从而为链霉素s的化学结构提供了分子洞察力。此外，我们的研究表明，合成酶表现出放松的底物特异性，并修饰来自近缘物种和远缘物种的毒素前体。鉴于我们的发现，类似肽毒素的发现很可能会迅速扩展到现有和新出现的基因组中。
Bacteriocins represent a large family of ribosomally produced peptide antibiotics. Here we describe the discovery of a widely conserved biosynthetic gene cluster for the synthesis of thiazole and oxazole heterocycles on ribosomally produced peptides. These clusters encode a toxin precursor and all necessary proteins for toxin maturation and export. Using the toxin precursor peptide and heterocycle-forming synthetase proteins from the human pathogen Streptococcus pyogenes, we demonstrate the in vitro reconstitution of streptolysin S activity. We provide evidence that the synthetase enzymes, as predicted from our bioinformatics analysis, introduce heterocycles onto precursor peptides, thereby providing molecular insight into the chemical structure of streptolysin S. Furthermore, our studies reveal that the synthetase exhibits relaxed substrate specificity and modifies toxin precursors from both related and distant species. Given our findings, it is likely that the discovery of similar peptidic toxins will rapidly expand to existing and emerging genomes.