Bioorganic Reactivity: Patterns, Principles and Applications

生物有机反应：模式、原理和应用

• 批准号: RGPIN-2020-04113
• 负责人: Kluger, Ronald
• 金额: $ 3.5万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716801
• 关键词: Bioorganic; Reactivity; Patterns; Principles; Applications

I propose that my students and I will do interesting and significant research that is at the intersection of chemistry and biology. We have three principal areas of interest. In one, we learn how biological systems are able to produce CO2 with compounds that are otherwise stable. We will study compounds with characteristics that relate to those in enzymes. This allows us to compare the rates and products. The parallels and differences reveal the critical parts of the enzyme. We focus on enzymes that form intermediates derived from combining the reacting compound with a derivative of vitamin B1. The enzymes change the reactivity of the compound that will lose CO2. We can follow the exact components without an enzyme that lead to a slower path and different products. This contrast allows us to focus on the detailed steps that account for the difference. We will examine the consequences of those differences. The first thing we will learn is how the enzyme, with the aid of a protein, speeds up the process. Then from that lesson, we will develop improved reactions that work without the protein. We want to find how CO2 is released very rapidly as a result of metabolism, a common occurrence in living systems, while the same compounds without an enzyme are persistent. We will test ideas by which we may achieve a similar outcome in a solution reaction as occurs on the enzyme. Through these efforts, the students will gain insights that would not have otherwise accessible. Our approach involves adding a trapping component (an auxiliary acid) to the nonenzymic reaction system that could block the return of CO2, as it would occur on the enzyme. This should enhance the rate of the overall process without the enzyme and therefore produce more rapid reactions without the enzyme. This gives students diverse knowledge, challenges that develop reasoning, and valuable technical skils. We also work in other areas where chemistry interacts biology. We are developing new chemical methods that will allow the addition of unnatural amino acids in place of amino acids in proteins. This will create proteins in ribosomes with unnatural amino acid components. This would make new proteins with useful properties and many applications. We will do this by developing new chemical reactions that add the unnatural amino acids onto transfer RNA, which carries them into the ribosome where then are added to form a protein. We also will use the same method to modify carbohydrates for use as materials that are altered at specific sites. Finally, we are developing ways to allow the natural oxygen carrier, hemoglobin, to survive outside red blood cells in solutions, as in circulation in place of red blood cells. Such a product would have many applications, from red cells replacements, to oxygen carriers for perfusion. Our approach takes hemoglobin from red cells that are not used for transfusions and convert them.

我建议我的学生和我将在化学和生物学的交叉点上做有趣而有意义的研究。我们有三个主要的兴趣领域。第一，我们了解了生物系统是如何产生二氧化碳的，这些二氧化碳是由其他稳定的化合物产生的。我们将研究具有与酶有关的特性的化合物。这使我们能够比较价格和产品。相似之处和不同之处揭示了酶的关键部分。我们关注的是通过将反应化合物与维生素B1衍生物结合而形成中间体的酶。酶会改变化合物的反应性，使其失去二氧化碳。我们可以在没有酶的情况下跟踪确切的成分，而酶会导致更慢的路径和不同的产物。这种对比使我们能够专注于解释差异的详细步骤。我们将研究这些差异的后果。我们要了解的第一件事是这种酶在蛋白质的帮助下是如何加速这一过程的。然后从这一课中，我们将开发出没有蛋白质的改进反应。我们想知道二氧化碳是如何在新陈代谢过程中迅速释放的，这是生命系统中常见的现象，而没有酶的相同化合物是如何持续存在的。我们将测试一些想法，通过这些想法，我们可以在溶液反应中获得与酶反应相似的结果。通过这些努力，学生们将获得其他方式无法获得的见解。我们的方法包括在非酶反应系统中添加一种捕获成分（一种辅助酸），可以阻止二氧化碳的返回，因为它会发生在酶上。这样可以在没有酶的情况下提高整个过程的速率，从而在没有酶的情况下产生更快的反应。这为学生提供了多样化的知识，培养推理能力和有价值的技术技能的挑战。