Synthesis, properties, and applications of oligonucleotides containing an RNA dinucleotide phosphorothiolate linkage.
Synthesis, properties, and applications of oligonucleotides containing an RNA dinucleotide phosphorothiolate linkage.
复制标题
含有RNA二核苷酸磷酸硫酸酯链接的寡核苷酸的合成，性质和应用。
DOI：
10.1021/ar200131t
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发表时间：
2011-12-20
影响因子：
18.3
通讯作者：
Piccirilli, Joseph A.
中科院分区：
文献类型：
--
作者：
Li, Nan-Sheng;Frederiksen, John K.;Piccirilli, Joseph A.
RNA代表了存在于所有生命系统中的一类重要的生物分子，在基因表达、调节和发育中起着许多重要作用。因此，许多生物过程取决于RNA的准确酶加工、修饰和切割。因此，了解这些酶的催化机制是在分子水平上定义生命系统的一个重要目标。在这种情况下，带有3′-或5′-S-硫代磷酸酯键的RNA分子可以说是现有的最敏锐的机制探针之一。他们在显示RNA剪接系统是金属酶和绘制RNA活性位点内的配体方面发挥了重要作用。这些模型反过来验证了晶体结构的功能相关性。在其他情况下，硫代磷酸酯为机械酶学家提供了一种实验策略，以规避动力学模糊的经典问题，并将催化基团作为一般酸或碱精确分配。这些对大分子功能的见解是通过合成带有硫代磷酸酯键的核酸及其赋予的独特化学性质实现的。本文综述了含硫代磷酸酯键的寡核苷酸和寡脱氧核苷酸的合成、性质和应用。硫代磷酸酯取代，其中硫取代磷酸二酯键内的一个或两个非桥接氧，现在广泛可用，并常规用于许多生物化学和医学应用。相比之下，硫代磷酸酯寡核苷酸，其中硫取代了特定的5′或3′桥氧，提出了更困难的合成挑战，需要对连接的糖部分进行化学改变。在这篇综述中，我们概述了用于访问这些RNA类似物的合成策略，并总结了它们对化学和酶促裂解剂的反应，以及它们的使用所产生的机械见解。
RNA represents a prominent class of biomolecules present in all living systems that plays many essential roles in gene expression, regulation, and development. Accordingly, many biological processes depend on the accurate enzymatic processing, modification, and cleavage of RNA. Understanding the catalytic mechanisms of these enzymes therefore represents an important goal in defining living systems at the molecular level. In this context, RNA molecules bearing 3′- or 5′-S-phosphorothiolate linkages comprise what are arguably among the most incisive mechanistic probes available. They have been instrumental in showing that RNA splicing systems are metalloenzymes and in mapping the ligands that reside within RNA active sites. These models have in turn verified the functional relevance of crystal structures. In other cases, phosphorothiolates have offered mechanistic enzymologists an experimental strategy to circumvent the classic problem of kinetic ambiguity and assign precise roles to catalytic groups as general acids or bases. These insights into macromolecular function are enabled by the synthesis of nucleic acids bearing phosphorothiolate linkages and the unique chemical properties they impart. Here, the synthesis, properties, and applications of oligonucleotides and oligodeoxynucleotides containing an RNA dinucleotide phosphorothiolate linkage are reviewed. Phosphorothioate substitutions, in which sulfur replaces one or both non-bridging oxygens within a phosphodiester linkage, are now widely available and are used routinely in numerous biochemical and medicinal applications. In contrast, phosphorothiolate oligonucleotides, in which sulfur replaces a specific 5′ or 3′ bridging oxygen, have presented a more difficult synthetic challenge, requiring chemical alterations to the attached sugar moiety. In this review, we outline the synthetic strategies used to access these RNA analogues and summarize their responses to chemical and enzymatic cleavage agents, as well as mechanistic insights their use has engendered.
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