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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic
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Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic

机译：两组分羊毛硫抗生素haloduracin的发现和体外生物合成

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摘要

Lantibiotics are ribosomally synthesized peptides that undergo posttranslational modifications to their mature, antimicrobial form. They are characterized by the unique amino acids lanthionine and methyllanthionine, introduced by means of dehydration of Ser/Thr residues followed by reaction of the resulting dehydro amino acids with cysteines to form thioether linkages. Two-component lantibiotics use two pepticles that are each posttranslationally modified to yield two functionally distinct products that act in synergy to provide bactericidal activity. By Using genetic data instead of isolation, a two-component lantibiotic, haloduracin, was identified in the genome of the Gram-positive alkaliphilic bacterium Bacillus halodurans C-125. We show that heterologously expressed and purified precursor peptides HalA1 and HalA2 are processed by the purified modification enzymes HalM1 and HalM2 in an in vitro reconstitution of the biosynthesis of a two-component lantibiotic. The activity of each HalM enzyme is substratespecific, and the assay products exhibit antimicrobial activity after removal of their leader sequences at an engineered Factor Xa cleavage site, indicating that correct thioether formation has occurred. Haloduracin's biological activity depends on the presence of both modified pepticles. The structures of the two mature haloduracin pepticles Hal alpha and Hal beta were investigated, indicating that they have similarities as well as some distinct differences compared with other two-component lantibiotics.
机译：羊毛硫抗生素是核糖体合成的肽，它们经过翻译后修饰后变成其成熟的抗菌形式。它们的特征在于独特的氨基酸羊毛硫氨酸和甲基羊毛硫氨酸，其通过使Ser / Thr残基脱水然后使所得的脱氢氨基酸与半胱氨酸反应形成硫醚键而引入。两组分羊毛硫抗生素使用两个消化物，每个消化物均经过翻译后修饰，以产生两个功能不同的产物，这些产物协同作用以提供杀菌活性。通过使用遗传数据而不是分离，在革兰氏阳性嗜碱细菌嗜碱性芽孢杆菌C-125的基因组中鉴定出了两种成分的羊毛硫抗生素，卤杜拉星。我们显示异源表达和纯化的前体多肽HalA1和HalA2是由纯化的修饰酶HalM1和HalM2在体外重组两组分羊毛硫抗生素的生物合成中加工的。每种HalM酶的活性都是底物特异性的，测定产物在工程化的Xa因子切割位点除去其前导序列后表现出抗菌活性，表明已发生正确的硫醚形成。 Haloduracin的生物活性取决于两种修饰的消化物的存在。研究了两种成熟的氟杜拉霉素消化物Hal alpha和Hal beta的结构，表明它们与其他两组分羊毛硫抗生素相比具有相似性和一些不同之处。

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