Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways.
Structural determinants of macrocyclization in substrate-controlled lanthipeptide biosynthetic pathways.
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DOI：
10.1039/d0sc01651a
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发表时间：
2020-06-25
期刊：
影响因子：
8.4
通讯作者：
van der Donk WA
中科院分区：
文献类型：
--
作者：
Bobeica SC;Zhu L;Acedo JZ;Tang W;van der Donk WA
蓝硫肽的特点是由翻译后修饰形成的硫醚交联。相对于许多其他可能的环状结构，环状结构更倾向于单一环状结构的环化过程一直是许多推测的主题。最近的研究表明，对于某些体系，环化模式和立体化学不是由酶决定的，而是由前体肽的序列决定的。然而，控制环化过程结果的因素尚不清楚。本研究展示了通过核磁共振波谱测定的7种镧硫肽的三维结构，包括5种原氯苷和构成溶细胞素的两种肽，溶细胞素是粪肠球菌产生的一种毒力因子，与人类疾病直接相关。之所以选择这些多肽，是因为它们的底物序列决定了环型（原氯苷）或环化的立体化学（溶细胞素）。我们得到了prochlorosins 1.1, 2.1, 2.8, 2.10和2.11的结构，这是prochlorosins的第一个三维结构。我们的研究结果提供了对环化的分子决定因素的见解，以及为什么一些prochlorosins可能比其他的更好地作为文库生成的起点。肠球菌溶细胞素的大小亚基的结构表明，这些肽具有长螺旋拉伸，迄今为止表征的镧硫肽罕见的观察。这些螺旋可以解释它们的孔隙形成活性，并表明小亚基可能识别一个分子目标，然后招募大亚基跨越膜。为了了解影响硫硫肽天然产物硫醚环化的环型和立体化学的因素，我们利用核磁共振光谱测定了5种原氯苷（蓝色）和2种肠球菌溶细胞素（红色）的结构。
Lanthipeptides are characterized by thioether crosslinks formed by post-translational modifications. The cyclization process that favors a single ring pattern over many other possible ring patterns has been the topic of much speculation. Recent studies suggest that for some systems the cyclization pattern and stereochemistry is determined not by the enzyme, but by the sequence of the precursor peptide. However, the factors that govern the outcome of the cyclization process are not understood. This study presents the three-dimensional structures of seven lanthipeptides determined by nuclear magnetic resonance spectroscopy, including five prochlorosins and the two peptides that make up cytolysin, a virulence factor produced by Enterococcus faecalis that is directly linked to human disease. These peptides were chosen because their substrate sequence determines either the ring pattern (prochlorosins) or the stereochemistry of cyclization (cytolysins). We present the structures of prochlorosins 1.1, 2.1, 2.8, 2.10 and 2.11, the first three-dimensional structures of prochlorosins. Our findings provide insights into the molecular determinants of cyclization as well as why some prochlorosins may be better starting points for library generation than others. The structures of the large and small subunits of the enterococcal cytolysin show that these peptides have long helical stretches, a rare observation for lanthipeptides characterized to date. These helices may explain their pore forming activity and suggest that the small subunit may recognize a molecular target followed by recruitment of the large subunit to span the membrane. To understand factors that determine ring pattern and stereochemistry of thioether cyclization of lanthipeptide natural products, the structures of five prochlorosins (blue) and two enterococcal cytolysins (red) were determined by NMR spectroscopy.
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影响因子：
2.9
作者：
Acedo, Jeella Z.;van Belkum, Marco J.;Vederas, John C.
通讯作者：
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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S连锁糖肽Sublancin的NMR结构168。
影响因子：
4
作者：
De Gonzalo, Chantal V. Garcia;Zhu, Lingyang;Oman, Trent J.;van der Donk, Wilfred A.
通讯作者：
van der Donk, Wilfred A.