The glmS ribozyme: use of a small molecule coenzyme by a gene-regulatory RNA.
The glmS ribozyme: use of a small molecule coenzyme by a gene-regulatory RNA.
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DOI：
10.1017/s0033583510000144
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发表时间：
2010-11
影响因子：
6.1
通讯作者：
Ferre-D'Amare, Adrian R.
中科院分区：
文献类型：
--
作者：
Ferre-D'Amare, Adrian R.
glmS 核酶是第一个已知的天然核酶例子，它已经进化到需要结合外源小分子才能发挥活性。在革兰氏阳性细菌中，该 RNA 结构域是编码合成 6-磷酸葡萄糖胺 (GlcN6P) 必需酶的 mRNA 的一部分。当以生理浓度存在时，这种小分子与 glmS 核酶结合并揭示潜在的自裂解活性，最终导致 mRNA 降解。生化和结构研究表明，RNA 采用由三个假结稳定的刚性折叠以及针对核酶核心的外围结构域的包装。 GlcN6P 与这种预先组织好的 RNA 结合不会引起构象变化；相反，小分子充当辅酶，为活性位点提供催化必需的胺基。然而，核酶并不是一个被动的参与者。即使存在 GlcN6P，活性位点官能团对于活性也是必不可少的。除了作为一个出色的实验系统来分析 RNA 催化剂如何利用小分子辅酶来扩大其化学多功能性之外，glmS 核酶在许多病原菌中的存在使这种 RNA 成为开发新抗生素和抗菌策略的有吸引力的目标。
The glmS ribozyme is the first known example of a natural ribozyme that has evolved to require binding of an exogenous small molecule for activity. In Gram-positive bacteria, this RNA domain is part of the mRNA encoding the essential enzyme that synthesizes glucosamine-6-phosphate (GlcN6P). When present at physiologic concentration, this small molecule binds to the glmS ribozyme and uncovers a latent self-cleavage activity that ultimately leads to degradation of the mRNA. Biochemical and structural studies reveal that the RNA adopts a rigid fold stabilized by three pseudoknots and the packing of a peripheral domain against the ribozyme core. GlcN6P binding to this pre-organized RNA does not induce conformational changes; rather, the small molecule functions as a co-enzyme, providing a catalytically essential amine group to the active site. The ribozyme is not a passive player, however. Active site functional groups are essential for activity, even in the presence of GlcN6P. In addition to being a superb experimental system with which to analyze how RNA catalysts can exploit small molecule coenzymes to broaden their chemical versatility, the presence of the glmS ribozyme in numerous pathogenic bacteria make this RNA an attractive target for the development of new antibiotics and antibacterial strategies.