Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin
Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin
复制标题
DOI：
10.1016/j.chembiol.2008.07.020
复制
发表时间：
2008-10-20
影响因子：
--
通讯作者：
van der Donk, Wilfred A.
中科院分区：
文献类型：
--
作者：
Cooper, Lisa E.;McClerren, Amanda L.;van der Donk, Wilfred A.
lantibiotic haloduracin由两种后杀菌处理的肽Halm和Halo组成，它们协同作用以提供杀菌活性。使用体外卤度拉新生产系统来检查破坏每种肽中的单个硫醚环的生物学影响。令人惊讶的是，含有高度保守的CTLTXEC基序的Hal α B环是可消耗的。该基序已被提出与卤度拉星的预测靶点脂质II相互作用。交换谷氨酸残基在这个基序的丙氨酸或谷氨酰胺完全废除抗菌活性。这项研究还确定了Hal α-Ser 26和Hal β-Ser 22逃避脱水，需要修改以前提出的Halo结构。由生产菌株分泌的细胞外蛋白酶可以去除前导肽，并且被生物活性抑制的Hal α胱氨酸保护Hal α免于进一步的蛋白水解降解。
The lantibiotic haloduracin consists of two post-translationally processed peptides, Halm and Halo, which act in synergy to provide bactericidal activity. An in vitro haloduracin production system was used to examine the biological impact of disrupting individual thioether rings in each peptide. Surprisingly, the Hal alpha B ring, which contains a highly conserved CTLTXEC motif, was expendable. This motif has been proposed to interact with haloduracin's predicted target, lipid II. Exchange of the glutamate residue in this motif for alanine or glutamine completely abolished antibacterial activity. This study also established that Hal alpha-Ser26 and Hal beta-Ser22 escape dehydration, requiring revision of the Halo structure previously proposed. Extracellular proteases secreted by the producer strain can remove the leader peptide, and the Hal alpha cystine that is dispensable for bioactivity protects Hal alpha from further proteolytic degradation.