Lee Shaun W, Mitchell Douglas A, Markley Andrew L, Hensler Mary E, Gonzalez David, Wohlrab Aaron, Dorrestein Pieter C, Nizet Victor, Dixon Jack E
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5879-84. doi: 10.1073/pnas.0801338105. Epub 2008 Mar 28.
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.
细菌素是一大类核糖体合成的肽抗生素。在此，我们描述了一个广泛保守的生物合成基因簇的发现，该基因簇用于在核糖体合成的肽上合成噻唑和恶唑杂环。这些基因簇编码一种毒素前体以及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的毒素前体肽和形成杂环的合成酶蛋白，我们证明了链球菌溶血素S活性的体外重建。我们提供的证据表明，如我们的生物信息学分析所预测的，合成酶将杂环引入前体肽，从而为链球菌溶血素S的化学结构提供了分子层面的见解。此外，我们的研究表明，合成酶表现出宽松的底物特异性，并能修饰来自相关和远缘物种的毒素前体。基于我们的发现，类似肽类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。
