ACHIEVING MULTIFUNCTIONAL CATALYSIS WITH METALLONUCLEASE

利用金属核酸酶实现多功能催化

• 批准号: 2190552
• 负责人: Eric V. Anslyn
• 金额: $ 8.65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2190552
• 关键词: antisense nucleic acid; catalyst; chelating agents; chemical cleavage; chemical synthesis; guanidines; hydrolysis; nuclease; nucleic acids; phosphoric ester; receptor binding; zinc

To achieve the catalytic hydrolysis of phosphodiesters, nature often capitalizes upon a multifunctional approach that involves cooperativity between three catalytic groups: metals, guanidiniums, and general bases. Despite the abundant natural examples, human kind has not yet mastered the design principles for constructing artificial enzymes that display such functional group cooperativity. The immediate goal of the proposed research is to delineate these design principles in the construction of a metallonuclease. The three catalytic groups common to nucleases will be systematically combined in artificial enzymes, and the energetics of catalysis will be studied. By examining the energetics of functional group cooperativity, we seek information that will be essential to the design of efficient artificial metallonucleases. Three Programs involving incremental increases in complexity are proposed: Bi, Tri, and Tetrafunctional Catalysis. As the mechanisms of catalysis in each Program are deciphered, the complexity will increase via the addition of more functional group. Deciphering each mechanism will consist of thermodynamic and kinetic studies of several structurally related synthetic receptors. For example, in each Program the angles and distances between the functional groups will be varied as a means of probing their preorganization and complementarity for phosphorane-like transition states. In addition, each Program will also involve an energetic analysis derived from Transition State Theory (TST). The TST analysis allows for the separation of electrostatics and shape changes in the stabilization of phosphorane-like transition states. The focus of all three studies will be upon delineating those factors that allow confident construction of multifunctional metallonucleases. Understanding the physical organic chemistry of catalysis will lead to both a better understanding of enzymology, and the production of small molecules with catalytic activity for applications as pharmaceuticals. Both of these aspirations can only be achieved after many generations of synthetic catalysts have been produced, and the rules for combining functional groups have been deciphered. Achieving these rules, and thereby the ability to rationally produce catalysts for biomedical applications, is the long term goal of the proposed research.

为了实现磷酸化剂的催化水解，自然常常 利用涉及合作的多功能方法 在三个催化基团之间：金属，鸟嘌呤和一般碱。 尽管有很多自然的例子，但人类尚未掌握 构建显示的人工酶的设计原理 这样的功能群体合作。拟议的直接目标 研究是为了构建这些设计原则 金属核酸酶。核酸酶共有的三个催化基将 系统地组合在人造酶中，以及 将研究催化。通过检查功能的能量学 小组合作，我们寻求的信息对 有效的人工金属核酸的设计。 复杂性增加的三个涉及增量增加的程序是 提议：BI，TRI和四功能催化。 作为机制 每个程序中的催化都被解密，复杂性会增加 通过添加更多功能组。破译每个机制 将由几个结构上的热力学和动力学研究组成 相关的合成受体。 例如，在每个程序中，角度和 官能团之间的距离将被变化 探测它们的预组织和类似磷酸盐的互补性 过渡状态。此外，每个程序还将涉及 源自过渡状态理论（TST）的能量分析。 TST 分析允许分离静电和形状变化 在磷酸盐样过渡状态的稳定中。重点 这三项研究将涉及描述那些允许的因素 自信地构造了多功能金属核酸酶。 了解催化的物理有机化学将导致 对酶学的更好理解和小型的产生 具有催化活性作为药物的分子。 这两个愿望只能在经过数代之后才能实现 已经生产了合成催化剂，并结合了 功能组已被解密。实现这些规则，并 从而能够合理生产生物医学催化剂 应用是拟议研究的长期目标。