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The Enterococcal Cytolysin Synthetase Coevolves with Substrate for Stereoselective Lanthionine Synthesis
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2016-07-11 00:00:00 , DOI: 10.1021/acschembio.6b00397 Weixin Tang 1 , Gabrielle N. Thibodeaux 1 , Wilfred A. van der Donk 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2016-07-11 00:00:00 , DOI: 10.1021/acschembio.6b00397 Weixin Tang 1 , Gabrielle N. Thibodeaux 1 , Wilfred A. van der Donk 1
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Stereochemical control is critical in natural product biosynthesis. For ribosomally synthesized and post-translationally modified peptides (RiPPs), the mechanism(s) by which stereoselectivity is achieved is still poorly understood. In this work, we focused on the stereoselective lanthionine synthesis in lanthipeptides, a major class of RiPPs formed by the addition of Cys residues to dehydroalanine (Dha) or dehydrobutyrine (Dhb). Nonenzymatic cyclization of the small subunit of a virulence lanthipeptide, the enterococcal cytolysin, resulted in the native modified peptide as the major product, suggesting that both regioselectivity and stereoselectivity are inherent to the dehydrated peptide sequence. These results support previous computational studies that a Dhx-Dhx-Xxx-Xxx-Cys motif (Dhx = Dha or Dhb; Xxx = any amino acid except Dha, Dhb, and Cys) preferentially cyclizes by attack on the Re face of Dha or Dhb. Characterization of the stereochemistry of the products formed enzymatically with substrate mutants revealed that the lanthionine synthetase actively reinforces Re face attack. These findings support the hypothesis of substrate-controlled selectivity in lanthionine synthesis but also reveal likely coevolution of substrates and lanthionine synthetases to ensure the stereoselective synthesis of lanthipeptides with defined biological activities.
中文翻译：
肠球菌溶血素合成酶与底物一起进化为立体选择性羊毛硫氨酸合成。
立体化学控制在天然产物生物合成中至关重要。对于核糖体合成的和翻译后修饰的肽（RiPP），实现立体选择性的机理仍然知之甚少。在这项工作中，我们集中于lanthipepteptides，这是一类主要的RiPPs，通过将Cys残基添加到dehydroalanine（Dha）或dehydrobutyrine（Dhb）中而形成的立体选择性羊毛硫氨酸。毒力肽肽的小亚基（肠球菌溶血素）的非酶环化作用导致天然修饰的肽成为主要产物，这表明脱水肽序列固有的区域选择性和立体选择性。这些结果支持了先前关于Dhx-Dhx-Xxx-Xxx-Cys基序的计算研究（Dhx = Dha或Dhb； Xxx =除Dha，Dhb，重新DHA或DHB的脸。用底物突变体酶促形成的产物的立体化学特征表明，羊毛硫氨酸合成酶可有效增强Re面部攻击。这些发现支持了在羊毛硫氨酸合成中受底物控制的选择性的假设，但也揭示了底物和羊毛硫氨酸合成的可能共同进化，以确保具有确定的生物学活性的长肽的立体选择性合成。
更新日期：2016-07-11
中文翻译：
肠球菌溶血素合成酶与底物一起进化为立体选择性羊毛硫氨酸合成。
立体化学控制在天然产物生物合成中至关重要。对于核糖体合成的和翻译后修饰的肽（RiPP），实现立体选择性的机理仍然知之甚少。在这项工作中，我们集中于lanthipepteptides，这是一类主要的RiPPs，通过将Cys残基添加到dehydroalanine（Dha）或dehydrobutyrine（Dhb）中而形成的立体选择性羊毛硫氨酸。毒力肽肽的小亚基（肠球菌溶血素）的非酶环化作用导致天然修饰的肽成为主要产物，这表明脱水肽序列固有的区域选择性和立体选择性。这些结果支持了先前关于Dhx-Dhx-Xxx-Xxx-Cys基序的计算研究（Dhx = Dha或Dhb； Xxx =除Dha，Dhb，重新DHA或DHB的脸。用底物突变体酶促形成的产物的立体化学特征表明，羊毛硫氨酸合成酶可有效增强Re面部攻击。这些发现支持了在羊毛硫氨酸合成中受底物控制的选择性的假设，但也揭示了底物和羊毛硫氨酸合成的可能共同进化，以确保具有确定的生物学活性的长肽的立体选择性合成。
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